Notes 195-241

195. Saquinavir is an HIV protease inhibitor. Viral protease cleavage of a polyprotein is necessary for production of the viral coat protein.
The HIV protease inhibitors include ritonavir, indinavir, nelfinavir, and amprenavir in addition to saquinavir. Currently available HIV protease inhibitors are not sufficient for monotherapy because of the rapid emergence of resistance due to mutations in the viral protease. Combination therapy using saquinavir with two reverse transcriptase inhibitors such as zidovudine, lamivudine, abacavir, or didanosine is currently effective in reducing viral load.
Incorporation into RNA is part of the mechanism of action for the antitumor agent 5-fluorouracil (5-FU). Inhibition of thymidylate synthase is another part of the mechanism of action for the antitumor agent 5-FU. 5-FU is converted to 5-FdUMP, a potent inhibitor of thymidylate synthase.
Inhibition of viral DNA polymerase is a mechanism of action for the anti-herpesvirus nucleosides acyclovir, valacyclovir, famciclovir, and ganciclovir. These agents are metabolized to their nucleotide triphosphate forms, which competitively inhibit the herpesvirus polymerase. Acyclovir and valacyclovir also cause DNA chain termination.
Inhibition of viral reverse transcriptase is a property of the nucleosides zidovudine (AZT), didanosine (ddI), lamivudine (3TC), stavudine (d4T), and zalcitabine (ddC). These nucleosides are metabolized to the triphosphate forms that competitively inhibit reverse transcriptase.
Nonnucleoside reverse transcriptase inhibitors include nevirapine, delavirdine, and efavirenz. Combinations of agents are used because resistance, through mutations in the reverse transcriptase sequence, frequently arises during monotherapy.




196. In severely affected males with fragile X syndrome, amplifications are so great that restriction enzymes bracketing the triplet repeat region yield 500–2000 bp fragments that are easily dis- tinguished from normal sizes of 15–60 bp.
Analogous blotting techniques were named as puns on the name of Southern, including “Northern” blotting to detect RNA molecules and “Western” blotting to detect proteins. Immunoblotting is one version of the “Western” blot technique where proteins are separated by electrophoresis and transferred to a membrane for probing with antibody to the proteins of interest. Reverse transcription of RNA into single, then double-stranded DNA, followed by polymerase chain reaction amplification (RT-PCR), is a more sensitive method for RNA measurement. RT-PCR could demonstrate altered levels of fragile X mRNA but would not measure triplet repeats because these are outside of the fragile X coding region.



197. Patients may develop fever as a result of infectious or noninfectious diseases. The term fever of unknown origin (FUO) is applied when significant fever persists without a known cause after an adequate evaluation. Several studies have found the leading causes of FUO to include infections, malignancies, collagen vascular diseases, and granulomatous diseases. As the ability to more rapidly diagnose some of these diseases increases, their likelihood of causing undiagnosed persistent fever lessens. Infections such as intraabdominal abscesses, tuberculosis, hepatobiliary disease, endocarditis (especially if the patient had previously taken antibiotics), and osteomyelitis may cause FUO. In immunocompromised patients, such as those infected with HIV, a number of opportunistic infections or lymphomas may cause fever and escape early diagnosis. Self-limited infections such as influenza should not cause fever that persists for many weeks. Neoplastic diseases such as lymphomas and some solid tumors (e.g., hypernephroma and primary or metastatic disease of the liver) are associated with FUO. A number of collagen vascular diseases may cause FUO. Since conditions such as systemic lupus erythematosus are more easily diagnosed today, they are less frequent causes of this syndrome. Adult Still’s disease, however, is often difficult to diagnose. Other causes of FUO include granulomatous diseases (i.e., giant cell arteritis, regional enteritis, sarcoidosis, and granulomatous hepatitis), drug fever, and peripheral pulmonary emboli. Factitious fever is most common among young adults employed in health-related positions. A prior psychiatric history or multiple hospitalizations at other institutions may be clues to this condition. Such patients may induce infections by selfinjection of nonsterile material, with resultant multiple abscesses or polymicrobial infections. Alternatively, some patients may manipulate their thermometers. In these cases, a discrepancy between temperature and pulse or between oral temperature and witnessed rectal temperature will be observed.



198. The acute monoarticular arthritis in association with linear calcification of the cartilage of the knee suggests the diagnosis of pseudogout, also called calcium pyrophosphate dihydrate deposition disease. The disease resembles gout. Positive birefringent crystals (looking blue when parallel to the axis of the red compensator on a polarizing microscope) can be demonstrated in joint fluid. Serum uric acid and calcium levels are normal, as is the rheumatoid factor. Pseudogout is about half as common as gout but becomes more common after age 65. Calcium pyrophosphate dihydrate deposition disease is diagnosed in symptomatic patients by characteristic x-ray findings or crystals in synovial fluid. The disease is treated with NSAIDs or colchicine. Linear calcifications or chondrocalcinosis are often found in the joints of elderly patients who do not have symptomatic joint problems; such patients do not require treatment.


199. Behçet syndrome is a multisystem disorder that usually presents with recurrent oral and genital ulcers. Onefourth of patients develop superficial or deep vein thrombophlebitis. Iritis, uveitis, and nondeforming arthritis may also occur.



200. The 19-year-old with low back pain, morning stiffness, and eye pain has complaints that suggest ankylosing spondylitis. This is an inflammatory disorder that affects the axial skeleton. It is an autoimmune disorder that has a close association with HLA-B27 histocompatibility antigen. Anterior uveitis is the most common extraarticular complaint. Aortic regurgitation occurs in a few percent of patients.



201. Giant cell arteritis, also referred to as temporal arteritis or cranial arteritis, is a disease of elderly patients that classically affects the temporal arteries. Giant cell arteritis, named for the presence of giant cells and granulomata that disrupt the internal elastica of the vessel, may present with headache, anemia, a high ESR (although a normal ESR does not rule out the diagnosis), and occasionally a syndrome known as polymyalgia rheumatica. This includes stiffness, aching, and tenderness of the proximal muscles. These patients describe weakness of the hip and shoulder girdles, but there is no objective weakness of the muscles, and the muscle enzymes are normal. Giant cell arteritis usually responds to steroid therapy with 40 to 60 mg/d of prednisone; polymyalgia rheumatica typically responds to low-dose prednisone at 10 to 15 mg/d.



202. Reiter syndrome is a reactive polyarthritis that develops several weeks after an infection such as nongonococcal urethritis or gastrointestinal infection caused by Yersinia enterocolitica, Campylobacter jejuni, or Salmonella or Shigella species. Reiter syndrome is characterized as a triad of oligoarticular arthritis, conjunctivitis, and urethritis. The disease is most common among young men and is associated with the HLA-B27 locus. A circinate balanitis is painless and occurs in 25 to 40% of patients. Other clinical features may include waxy papules on the palms and soles called keratoderma blenorrhagicum, spondylitis, myocarditis, and thrombophlebitis. ANA and rheumatoid factor are usually negative. Gonorrhea can precipitate Reiter syndrome, but patients with the disease are culture negative.




203. Unilateral headache and visual loss in this elderly patient with polymyalgia rheumatica (PMR) symptoms lead to a clinical diagnosis of temporal arteritis. The erythrocyte sedimentation rate is high in almost all of these patients. Skull x-ray and CT scan would be normal. Carotid disease would not be expected. Temporal arteritis occurs most commonly in patients over the age of 55 and is highly associated with polymyalgia rheumatica. About 25% of patients with PMR have some features of giant cell arteritis. Thus, older patients who complain of diffuse myalgias and joint stiffness, particularly of the shoulders and hips, should be evaluated for PMR with ESR. Sudden visual loss in such a patient makes temporal arteritis an important diagnosis to make quickly.
PMR-Proximal muscle weakness of hip & shoulder.


204. The combination of fever, malar rash, and arthritis suggests systemic lupus erythematosus, and the patient’s thrombocytopenia, leukopenia, and positive antibody to native DNA provide more than four criteria for a definitive diagnosis. Other criteria for the diagnosis of lupus include discoid rash, photosensitivity, oral ulcers, serositis, renal disorders (proteinuria or cellular casts), and neurologic disorder (seizures). High-dose corticosteroids would therefore be indicated for any life-threatening complication of lupus such as glomerulonephritis, severe thrombocytopenia, or hemolytic anemia. Patients with SLE have an unpredictable course. Few patients develop all signs or symptoms. Neuropsychiatric disease occurs at some time in about half of all SLE patients, and Raynaud’s phenomenon in about 25%. Pregnancy is relatively safe in women with SLE who have controlled disease and are on less than 10 mg of prednisone.


205. The complaints (A 60-year-old female complains of dry mouth and a gritty sensation in her eyes. She states it is sometimes difficult to speak for more than a few minutes. There is no history of diabetes mellitus or neurologic disease. The patient is on no medications. On exam, the buccal mucosa appears dry and the salivary glands are enlarged bilaterally. The next step in evaluation is ?) described are characteristic of Sjögren syndrome, an autoimmune disease with presenting symptoms of dry eyes and dry mouth. The disease is caused by lymphocytic infiltration and destruction of lacrimal and salivary glands. Dry eyes can be measured objectively by the Schirmer test, which measures the amount of wetness of a piece of filter paper when exposed to the lower eyelid for 5 minutes. Most patients with Sjögren syndrome produce autoantibodies, particularly anti-Ro (SSA). Lip biopsy is needed only to evaluate uncertain cases, such as when dry mouth occurs without dry eye symptoms. Mumps can cause bilateral parotitis, but would not explain the patient’s dry eye syndrome. Corticosteroids are reserved for life-threatening vasculitis, particularly when renal or pulmonary disease is severe.



206. The clinical picture of symmetrical swelling and tenderness of the metacarpophalangeal (MCP) and wrist joints lasting longer than 6 weeks strongly suggests rheumatoid arthritis. Rheumatoid factor, an immunoglobulin directed against the Fc portion of IgG, is positive in about two-thirds of cases and is present early in the disease. The history of lethargy or fatigue is a common prodrome of RA. The inflammatory joint changes are not consistent with chronic fatigue syndrome. The MCP wrist distribution of joint symptoms makes osteoarthritis very unlikely. The x-ray changes described are characteristic of RA, but would occur later in the course of the disease.



207. The symptoms of Raynaud’s phenomenon, arthralgia, and dysphagia point toward the diagnosis of scleroderma. Scleroderma or systemic sclerosis is characterized by a systemic vasculopathy of small and medium-sized vessels, excessive collagen deposition in tissues, and an abnormal immune system. It is an uncommon multisystem disease affecting women more than men. There are two variants of scleroderma—a benign type called the CREST syndrome and a more severe diffuse disease. Antinucleolar antibody occurs in only 20 to 30% of patients with the disease, but a positive test is highly specific. Cardiac involvement may occur, and an ECG could show heart block or pericardial involvement. Renal failure can develop insidiously. Rheumatoid factor is nonspecific and present in 20% of patients with scleroderma.



208. Wegener’s granulomatosis is a granulomatous vasculitis of small arteries and veins that affects the lungs, sinuses, nasopharynx, and kidneys, where it causes a focal and segmental glomerulonephritis. Other organs can also be damaged, including the skin, eyes, and nervous system. Most patients with the disease develop antibodies to certain proteins in the cytoplasm of neutrophils called antineutrophil cytoplasmic antibodies (ANCA).



209. The 35-year-old with cough, sore throat, and fever went on to develop symptoms of myopericarditis with typical ECG findings. Coxsackievirus B infection is the most likely cause of URI symptoms that evolve into a picture of myocarditis. Myocarditis may be asymptomatic or can present with chest pain, both pleuritic and ischemic-like. Enteroviruses rarely if ever attack the pericardium alone without involving the subepicardial myocardium.



210. Gold therapy is still used in some patients with rheumatoid arthritis, especially in those who have not tolerated methotrexate. However, side effects are significant and include a dermatitis that may lead to exfoliative dermatitis if treatment is not discontinued, stomatitis, the nephrotic syndrome, and bone marrow suppression.



211. The rash of Rocky Mountain spotted fever (RMSF) occurs about 5 days into an illness characterized by fever, malaise, and headache. The rash may be macular or petechial, but almost always spreads from the ankles and wrists to the trunk. The disease is most common in spring and summer. North Carolina and East Tennessee have a relatively high index of disease. RMSF is a rickettsial disease with the tick as the vector. About 80% of patients will give a history of tick exposure. Doxycycline is considered the drug of choice, but chloramphenicol is preferred in pregnancy because of the effects of tetracycline on fetal bones and teeth. Overall mortality from the infection is now about 5%.



212. The patient has more than four of the required signs or symptoms of RA, including morning stiffness, swelling of the wrist or MCP, simultaneous swelling of joints on both sides of body, subcutaneous nodules, and positive rheumatoid factor. Subcutaneous nodules are a poor prognostic sign for the activity of the disease, and disease-modifying drugs (gold, penicillamine, antimalarials, or methotrexate) should be instituted. Methotrexate has emerged as the agent of choice. Oral corticosteroids are generally withheld unless absolutely necessary and after disease-modifying drugs are instituted. However, low-dose corticosteroids have recently been shown to reduce the progression of bony erosions. There is no value to using both aspirin and nonsteroidals together, as simultaneous usage will increase side effects.



213. Insidious back pain occurring in a young male that improves with exercise suggests one of the spondyloarthropathies—ankylosing spondylitis, Reiter syndrome, psoriatic arthritis, or enteropathic arthritis. Ankylosing spondylitis is most likely in this patient. Acute lumbosacral strain would not be relieved by exercise or worsened by rest. The prognosis in ankylosing spondylitis is generally very good, with only 6% dying of the disease itself. While pulmonary fibrosis and restrictive lung disease can occur, it is rarely a cause of death (cervical fracture, heart block, and amyloidosis are leading causes of death due to ankylosing spondylitis). Rheumatoid factor is negative in all the spondyloarthropathies. Crohn’s disease can cause an enteropathic arthritis, but this diagnosis is unlikely without gastrointestinal symptoms.



214. Felty syndrome consists of a triad of rheumatoid arthritis, splenomegaly, and leukopenia. In contrast to the lymphopenia observed in patients who have systemic lupus erythematosus, the leukopenia of Felty syndrome is related to a reduction in the number of circulating polymorphonuclear leukocytes. The mechanism of the granulocytopenia is poorly understood. Felty syndrome tends to occur in people who have had active rheumatoid arthritis for a prolonged period. These patients commonly have other systemic features of rheumatoid disease such as nodules, skin ulcerations, the sicca complex, peripheral sensory and motor neuropathy, and arteritic lesions



215. Polyarteritis nodosa- (Inflammation of small- to medium-sized muscular arteries, which may cause kidney, heart, liver, gastrointestinal, and muscular damage) is a multisystem necrotizing vasculitis that, prior to the use of steroids and cyclophosphamide, was uniformly fatal. In 30% of patients, antecedent hepatitis B virus infection can be demonstrated; immune complexes containing the virus have been found in such patients and are likely pathogenetic.




216. Howell Jolly bodies: eg post-spenlenectomy
Teardrop cells: Eg myelofibrosis and myelophthisis
Macro-ovalocytes: eg B12 deficiency
Target cells: If there is HbC or severe liver disease




217. The age and mediastinal location are typical for a lymphoblastic lymphoma involving the thymus. This lesion is in the spectrum of acute lymphoblastic !eukemia or lymphoma (ALL). Most ALL cases with lymphomatous presentation are of the pre-T cell type. This is supported by the expression of the T-cell markers CD2, CD5, and CD1. TdT is a marker of pre-T and pre-B cells. A Burkitt lymphoma is a B-cell lymphoma that may also be seen in adolescents but in the region of the jaw or abdomen. Nodular sclerosing Hodgkin disease does occur in the mediastinum, but it involves mediastinal nodes, not thymus. The histologic features of Hodgkin disease include the presence of Reed-Sternberg cells, and this variant has fibrous bands intersecting the lymphoid cells. Mantle cell lymphomas and follicular lymphomas are B-cell tumors usually seen in older patients, and they do not involve the thymus.



218. The features of gen. exfoliative erythroderma and skin biopsy showing lymphoid cells with cerebroform nucleii and them being present in blood too... implies Cutaneous T cell lymphoma... Sezary syndrome
Sezary syndrome (Cutaneous T-cell lymphoma) CD4 +ve and CD 8 -ve
A skin biopsy reveals the presence of lymphoid cells in the upper dermis and epidermis. These cells have cerebriform nuclei with marked infolding of nuclear membranes. Similar cells are seen on his peripheral blood smear.



219. Genes coding for LMP2, 3 and TAP 2 are present on chromosome: 6p
The MHC class II region also includes two alpha genes, DMA and DNA, and two beta genes, DMB and DOB, genes for the low-molecular-weight proteins (LMPs) LMP2 and LMP3 and for the transporter molecules TAP1 and TAP2.."


220. TNF alpha, beta genes are found in chromosome –6p
MHC class III region codes for complement components factor B, C2, and both C4 molecules, both tumor necrosis factor genes alpha and beta, and the heat shock proteins Hsp 1H and Hsp 70 2, and 21-hydroxylase.



221. Defect in Common variable immunodeficiency: Plasma cell absence
CVID is probably most common cause of pan-hypogammaglobulinemia in adults. Defect in terminal differentiation of B cells and hence absent plasma cells.



222.
a. Alpha heavy chain disease: Segilman disease
b. Gamma heavy chain disease: Franklin disease
c.Mu heavy chain disease is associated with CLL



223. HLA-A29 associated with birdshot retinochoroidopathy.

Rat bite lesions: punched out erosions with an overhanging rim of cortical bone. When these are adjacent to soft tissue tophi, they are pathognomonic of gout
Note: Meat, seafood are high purine
Milk, eggs are low purine
Note: Meat, seafood are high purine
Milk, eggs are low purine

But, most vegetables can be taken as low purine... EXCEPT : beans, peas, cauliflowers, mushrooms, spinach, lentils

In CPRS (complex regional pain syndrome/Reflex sympathetic dystrophy), swelling is diffuse in hands and NOT limited to joints. It is called catcher's mitt hand.


Leflunomide inhibits pyrimidine synthesis. It is carcinogenic, teratogenic, causes severe wt loss.


Still's disease = adult variant of JRA. Usually patients are 20-40 yrs old. Dramatic fever spiking upto 40degrees and then, fever may precede arthritis.
Also lymphadenopathy, pericardial effusions can happen.
An evanescent slamon-colored nonpruritic rash chiefly on the chest and abdomen is characterisitc... and it concides with fever spikes.



Note:
Cryoglobulins: main associations are Hep C and Sjogrens
Since 90% patients with cryoglobulinemia are associated with Hep C, Peg IFN alpha is standard care for mixed cryoglobulinemia
Cryoglobulins: types:
Type I -- (monoclonal proteins that lack rheumatoid factor activity) are more commonly seen in lymphoproliferative disease. (Type I cryoglobulins usually cause hyperviscosity syndromes rather than vasculitis.)
Type II --(monoclonal antibody with rheumatoid factor activity) can cause vasculitis
Type III- (polyclonal antibody with rheumatoid factor activity) cryoglobulins cause vasculitis.




Psoriatic arthritis: Assymetric sacroilitis + atypical syndesmophytes + relative lack of osteoporosis. Also pencil in cup deformity.



Causative agent for INDIAN tick typhus is : Rickettsia conorii


The main vector for rural malaria is: An. Culicifacies

(Height in cm)/(cube root of body wt in kg) is: Ponderal index



13.Which of these is correct:
a. National malaria eradication programme started in 1958
b. Modified Plan of Operation of NMEP started in 1977
c. Urban malaria scheme launched in 1971
d. All of the above


Lymph node of tongue: Jugulo-omohyoid
Lymph node of tonsil: Jugulo-digastric



Most commonly involved in raised ICT: Abducent
Most commonly involved in skull base #: Facial
Most commonly affected in spinal anesthesia: Abducent
Most thick cranial n: trigeminal
Most thin cranial n: trochlear



Note: Temperature receptors:
- Cold: End bulbs of Krause
- Warmth: Organs of Ruffini
- Heat: Organs of Golgi Mazzoni



Receptor for:
- Static balance: Macula
- Kinetic balance: Crista



Taste area (parietal operculum) in brain is: Area 43


Centre for extrapyramidal system' is: Area 6



a. Metacarpophalyngeal joints: Condylar joint
b. Interphalangeal joints: Hinge joints
c. First carpo-metacarpal joint: Saddle joint



Meckel cartilage: Malleus. ... So, Reichert cartilage : Stapes
Note: in ossicular chain embryology
Meckel cartilage (1st arch) gives malleus and incus
Reichert cartilage (2nd arch) gives stapes


Nerve of sixth arch is: Rec. laryngeal n
Note: Nerves of arches
1st: Mandibular div of CN5
2nd: CN7
3rd: CN9
4th: Sup laryngeal
5th: -
6th: Rec laryngeal




Note: larynx muscles in brief:

Adductors: (LTTE) . LTTE ppl close the glottis by adducting so that you cant breathe! How sick!
LTTE :
L - Lateral cricoarytenoids
T - Transverse arytenoids
T - Thyroarytenoids
E - c(e)ricothyroids (errr... c looks like e)


Abductors: (open glottis)
-Posterior cricoarytenoids


Tensors:
- Cricothyroids
- Thyroarytenoids


Relax vocal cords:
- Thyroarytenoids
- Vocalis



Close inlet of larynx:
- Oblique arytenoids
- Aryepiglotticus


Open inlet of larynx:
- Thyroepiglotticus



Main duct of pancreas: Wirsung
Accessory pancreatic duct: Santorini


Internal carotid artery passes through: Foramen lacerum


Nerve affected in Epicondylar Tunnel Syndrome: ulnar n
Note:
Epicondylar tunnel syndrome: Ulnar n at elbow
Carpal tunnel syndrome: Median
Tarsal tunnel syndrome: Posterior tibial n at ankle

Wrist drop: Radial n
Foot drop: deep peroneal n


Mutations in the BMPR2 gene cause pulmonary arterial hypertension.


Hering's N transmits impulses from carotid bodies to glossopharyngeal n
Note:
Arnold n / alderman nerve arises from vagus
Jacobson n arises from glossopharyngeal
Nervi erigentes are PARAsympathetic nerves



Narath's hernia is a femoral hernia associated with CDH
Note:
Laugier's femoral hernia: Hernia through gap in gimbernat's ligament
Narath's femoral hernia: Hernial sac lies between femoral vessels in Cong Dislocation of hip



224. Patients with classic Kawasaki disease must have 5 of the following symptoms, with fever an absolute criterion:
--Fever, lasting more than 5 days and refractory to appropriate antibiotic therapy
--Polymorphous erythematous rash
--Nonpurulent bilateral conjunctival injection
--Oropharyngeal changes, including diffuse hyperemia, strawberry tongue, and lip changes (eg,
swelling, fissuring, erythema, bleeding)
--Peripheral extremity changes, including erythema, edema, induration, and desquamation
--Nonpurulent cervical lymphadenopathy




225. Alkaline diuresis: Phenobarbital, Salicylate
Hemodialysis: Ethylene glycol, Lithium, Methanol, Salicylates, Theophylline
Hemoperfusion: Barbiturates, Theophylline

Further it says.. Charcoal hemoperfusion & hemodialysis have a role in barbiturate overdose for critical patients who do not respond to conservative therapy. Charcoal hemoperfusion is treatment of choice for Theophylline toxicity.


226. Piaget's theory of development of cognitive thinking in children encompasses four stages:
-Sensorimotor (18–24 months),
-Pre-operational (2 to 5–7 years),
-Concrete operational (6–11 years), and
-Formal operational (11 years to adulthood).


227. A young man is often the object of his friends’ jokes because he drops on the floor whenever he is having a good laugh. This young man suffers from :-
-Cataplexy refers to a sudden loss of muscle tone, ranging in severity from weakness in the knee to a total loss of tone, triggered by strong emotions, that takes place during full wakefulness.
-Cataplexy is thought to be due to an abnormal intrusion of REM sleep phenomena in periods of wakefulness.
-It is usually treated with medications that reduce REM sleep, such as antidepressants.
-Note that cataplexy can exist on its own... as well as a part of narcolepsy
-Then, also must not confuse cataplexy with catalepsy




228. A hemophilia patient with only 6% residual activity of factor 8 would be termed as:
Mild 6-30 %
Moderate 1-5 %
Severe <1 %




229.
ASD + PAPVR--- ASD likely to be sinus venosus defect
ASD + MR ----- ASD likely to be ostium primum defect
ASD + MS ----- ASD likely to be ostium secundum ., called Lutembacher syndrome






230. "Good ventricular function and low pulmonary vascular resistance are essential requirements for a successful Fontan procedure."
"The Fontan operation should not be performed when ventricular ejection fraction is less than 30% or ventricular end-diastolic pressure is greater than 15 mmHg"

Also note:
"Pulmonary vascular resistance in excess of 4 Woods units should also be considered an absolute contraindication for Fontan correction."
"Age at the time of Fontan procedure does not appear to be a major risk factor, provided age is greater than 2 years"




231. Defect in the following Proteins:--
MRP2- Dubin jonson
BSEP- Progressive familial intrahepatic cholestasis
CFTR- cystic fibrosis
F1C1 --Defect in Byler's disease is this protein




232. Which is the IgA type present in serum predominantly:
IgA1: primarily in serum
IgA2: more in secretions


233. Combined chemoradiation (the so-called Nigro protocol) promises to preserve continence, avoid colostomy, and offer a similar survival rate. For most lesions, chemoradiation—external-beam radiation, 5-fluorouracil, and mitomycin C—is the treatment of choice."




234.
Immunoglobulin Isotypes Mature B lymphocytes express IgM and IgD on their surfaces. They may differentiate by isotype switching (mediated by cytokines and CD40 ligand) into plasma cells that secrete IgA, IgE, or IgG.

IgG Main antibody in 2° response. Most abundant. Fixes complement, crosses the placenta,
opsonizes bacteria, neutralizes bacterial toxins and viruses.

IgA Prevents attachment of bacteria and viruses to mucous membranes, does not fix
complement. Monomer or dimer. Found in secretions. Picks up secretory component from
epithelial cells before secretion.

IgM Produced in the 1° response to an antigen. Fixes complement but does not cross the
placenta. Antigen receptor on the surface of B cells. Monomer or pentamer.

IgD Unclear function. Found on the surface of many B cells and in serum.

IgE Mediates immediate (type I) hypersensitivity by inducing the release of mediators from
mast cells and basophils when exposed to allergen. Mediates immunity to worms.
Lowest concentration in serum.



235. IL_1-------Fever
IL-2--------Stimulates T-Cells
IL-3--------Stimulates bone marrow.
IL-4--------Stimulates IgE production.
IL-5--------Stimulates IgA production.







236. The APGAR score (commonly performed at 1 and 5 minutes after birth; maximum
score is 10):

NUMBER OF POINTS GIVEN

CATEGORY 0 I 2

Heart rate Absent < 100 beats/rain > 100 beats/min
Respiratory effort None Slow, weak cry Good, strong cry
Muscle tone Limp Some flexion of extremities Active motion
Reflex irritability* None Grimace Grimace and strong cry, cough,
and sneeze
Color Pale. blue Body pink. extremities blue Completely pink

Reflex irritability usually is measured by the infant's response to stimulation of the sole of the foot or a catheter put inlo the nose.









237. Overdoses and antidotes

POISON OR MEDICATION ANTIDOTE

Acetaminophen
Cholinesterase inhibitors
Quinidine or tricyclic anti-depressants
Iron
Digoxin
Methanol/ethylene glycol
Benzodiazepines
Beta blockers
Lead
Copper or gold
Opioids
Carbon monoxide
Muscarinic blockers
Acetylcysteine
Atropine, pralidoxime
Sodium bicarbonate (cardioprotective)
Deferoxmnine
Normalize potassium and other electrolytes; digoxin Ab
Ethanol
Flumazenil
Glucagon
Edetate (EDTA); use succimer in children
Penicillamine
Naloxone
Oxygen (hyperbaric in cases of severe poisoning)
Physostigmine





238. IOLmaterial. Basically, IOLS can be divided into nonflexible and flexible types, as well as one-piece IOLs (in which the haptics and optic are made of a single material with no connecting points) and three-piece IOLs (in which the optic and haptics are made of different materials such as PMMA, polypropylene, and polyamide and connected to each other).

Nonflexible IOLs. These are mostly made of polymethylmethacrylate (PMMA). To implant a nonflexible IOL, the incision needs to be larger than the diameter of the IOL (5.5–6.5mm). Modern nonflexible IOLs are one-piece IOLs.

Flexible IOLs are folded with a forceps or an injector systemand are therefore implantable through 2.0–3.0mm incisions with the same optic size as non- flexible IOLs. Flexible IOLs are made of silicone, acrylic, hydrogel, or Collamer. The development andmodification ofmodern IOLs is a constantly ongoing process.

Cataract eyeglasses are only suitable for correcting bilateral aphakia. Cataract eyeglasses have the disadvantage of limiting the field of vision (peripheral and ring scotoma).




239. Kayser–Fleischer Ring: This golden-brown to yellowish-green corneal ring is caused by copper deposits at the level of Descemet’s membrane in Wilson’s disease (liver and lens degeneration with decreased serumlevels of ceruloplasmin). This ring is so characteristic that the ophthalmologist often is the first to diagnose this rare clinical syndrome.
In the early stages, a Kayser–Fleischer ring is best detected using gonioscopy.




240. Rigid Contact Lens: Previously, polymethylmethacrylate (PMMA) was used as a material. However, this is practically impermeable to oxygen. The lenses were fitted in small diameters with a very shallow curvature; the central area maintained contactwith the corneawhile the periphery projected. This allowed excellent tear film circulation, and patients were able to wear the lenses for surprisingly long periods.
Today, highly oxygen-permeable materials such as silicone copolymers are available. This eliminates the time limit for daily wearing. These lenses may also remain in the eye overnight in special cases, such as aphakic patients with poor coordination (prolonged wearing).

Rigid contact lenses can be manufactured as spherical lenses and toric lenses. Spherical contact lenses can almost completely compensate for corneal astigmatism of less than 2.5 diopters. This is possible because the space between the posterior surface of the spherical contact lens and the anterior surface of the astigmatic cornea is filled with tear fluid that forms a “tear lens.” Tear fluid has nearly the same refractive index as the cornea. More severe corneal astigmatism or internal astigmatism requires correction with toric contact lenses. Rigid contact lenses can even correct severe keratoconus.

Soft Contact Lenses
The material of the contact lens, such as hydrogel, is soft and pliable. Patients find these lenses significantly more comfortable. The oxygen permeability of the material depends on its water content, which may range from 36 to 85%. The higher the water content, the better the oxygen permeability. However, it is typically lower than that of rigid lenses. The material is more permeable to foreign substances, which can accumulate in it. At 12.5–16mm, flexible lenses are larger in diameter than rigid lenses. Flexible lenses are often supported by the limbus. The lens is often displaced only a few tenths of a milli-meter when the patient blinks. This greatly reduces the circulation of tear film under the lenses. This limits the maximum daily period that patients are able to wear them and requires that they be removed at night to allow regeneration of the cornea. Deviation from this principle is only possible in exceptional cases under the strict supervision of a physician.
As the lenses are almost completely in contact with the surface of the cornea, corneal astigmatism cannot be corrected with spherical soft lenses. This requires toric soft lenses.




241.Location of the extraocular muscle nuclei and gaze centers
Fig. 17.2 The oculomotor nerve (the third cranial nerve) supplies all of the extraocular muscles except the superior oblique (which is supplied by the trochlear nerve/fourth cranial nerve) and the lateral rectus (supplied by the abducent nerve/sixth cranial nerve). The rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF) is responsible for vertical eye movement and phases of rapid nystagmus. The paramedian pontine reticular formation (PPRF) is responsible for horizontal eye movement.

Notes 155-194

155. Neurogenic diabetes insipidus is treated with desmopressin, a drug that is similar to vasopressin (ADH) but a selective activator of V2 receptors in the kidney. Remember that V1 receptors are present in smooth muscle, and their activation leads to vasoconstriction and bronchoconstriction. Nephrogenic diabetes insipidus (decreased response of vasopressin receptors) is treated with thiazides except in the case of that induced by lithium, when amiloride is preferred (because thiazides increase blood levels of lithium).



156. The release of insulin from the pancreas is stimulated by insulinogens (glucose), sulfonylurea hypoglycemics (glipizide), activators of beta2 adrenoceptors (e.g., albuterol), and activators of muscarinic receptors (e.g., pilocarpine). The only receptor that, when activated, inhibits insulin release is the alpha2 receptor, which could be stimulated by clonidine or methyldopa.


157. Mifepristone (RU 486) is both a glucocorticoid and progestin receptor antagonist, the latter being responsible for its abortifacient activity. Dinoprostone is also a stimulant of uterine smooth muscle, but is a PGE2derivative, not a progestin antagonist. Flutamide is an androgen receptor antagonist, and tamoxifen is a partial agonist (or mixed agonist-antagonist) at estrogen receptors.


158. The profile of lead toxicity includes decreased heme synthesis, anemia, nephropathy, and peripheral neuropathy, the last leading to foot drop or wrist drop. Garlic breath and watery stools are associated with arsenic poisoning. Chronic gingivitis and loose teeth are features of mercury poisoning.


159. Didanosine causes pancreatitis in a significant number of patients treated for AIDS. Amantadine is used in the prevention and treatment of influenza and causes CNS stimulation and light headedness. Ribavirin is used for the treatment of respiratory syncytial virus in infants and causes dose-dependent hemolytic anemia in about 10% of patients. Ritonavir, a protease inhibitor used in AIDS, causes hepatitis. Zidovudine another drug used in AIDS, causes neutropenia as its primary dose limiting effect.


160. Acyclovir is an acyclic guanine nucleoside analog that undergoes activation by phosphorylation by herpesviral thymidine kinase (but not the host thymidine kinase) to form the acyclovir triphosphate form and causes DNA chain termination.
Amantadine is a tricyclic amine that inhibits uncoating of influenza A virus. It is also used for the treatment of parkinsonism.
Foscarnet is a pyrophosphate analog that inhibits herpesvirus nucleic acid synthesis at the level of the viral DNA polymerase.
Saquinavir is an HIV protease inhibitor.
Zidovudine is an antiretroviral thymidine analog.
The triphosphate is a competitive inhibitor of reverse transcriptase and a DNA chain terminator. The monophosphate is a competitive inhibitor of thymidine kinase.



161. Resistance to tetracyclines such as doxycycline is associated with production of an efflux pump or alteration of the 30S ribosomal-binding site. Resistance to beta lactams such as amoxicillin usually results from production of beta lactamase. Macrolides such as clarithromycin, erythromycin, and azithromycin bind to the 50S ribosome in susceptible organisms and prevent protein synthesis. Simple methylation of the binding site prevents the bacteriostatic action of these drugs and many bacteria have such mutation. Resistance to aminoglycosides such as gentamicin is usually due to synthesis of inactivating enzymes by the bacteria. Resistance to vancomycin is still unusual but can occur through the modification of the D-ala-D-ala-binding site in peptidoglycan.



162. Rifampin selectively inhibits bacterial DNA-dependent RNA polymerase. It is very useful in treating mycobacterial infections since it can penetrate cells and kill intracellular organisms. It is one of the most potent inducers of cytochrome P450 known, leading to increased hepatic clearance of many other drugs including the oral anticoagulants, cyclosporine, propranolol, digitoxin, corticos teroids, and oral contraceptives.
Ethambutol is often combined with isoniazid in antitubercular regimens. Clearance is primarily via renal excretion.
Isoniazid is the most widely used antitubercular agent. It functions by inhibiting mycolic acid biosynthesis. Isoniazid is cleared by metabolism via N-acetylase and hydrolytic activity.
Streptomycin was the first effective drug for the treatment of tuberculosis, but, because of its ototoxicity and nephrotoxicity and the development of less toxic agents, use of streptomycin is limited to more severe forms of the disease.
Sulfisoxazole may rarely be used in antitubercular regimens in combination with other drugs. Clearance is primarily via glomerular filtration.



163. Losartan causes renal damage in the fetus, and renal impairment in renovascular disease. It is contraindicated in pregnancy. Clonidine causes some sedation and rebound hypertension when stopped suddenly, but is not contraindicated in pregnancy. Hydralazine causes a reversible type of lupus erythematosus. Hydrochlorothiazide may cause hypokalemia, dilutional hyponatremia, elevated lipids, hyperuricemia, and glucose intolerance. Methyldopa causes sedation and formation of red blood cell antibodies, but has been shown to be safe in pregnancy.
Clonidine the centrally acting alpha 2-receptor agonist, produces sedation and xerostomia but not cough. The alpha-1-receptor antagonist prazosin produces postural hypotension but not cough. The beta-blocker propranolol may produce a variety of side effects including precipitating heart failure and asthma in susceptible patients.


164. Cisplatin binds to DNA where it forms intra- and interstrand crosslinks. Cisplatin is particularly effective in testicular and ovarian cancers in combination with other antitumor agents. Cisplatin exerts a renal toxicity that may be prevented by the infusion of saline to maintain a high urine flow. Ototoxicity involving high-frequency hearing loss is an effect that is not prevented by hydration.
The natural product bleomycin binds to DNA and causes single- and double-strand breaks, leading to cytotoxicity. The drug is particularly useful against Hodgkin lymphoma and testicular tumors. Bleomycin has the serious toxicity of pulmonary fibrosis.
Cyclophosphamide is widely used in combination regimens. Nausea and vomiting are the most common toxicities. Hemorrhagic cystitis may be minimized by hydration and use of the drug mesna. Note that this toxicity is not at the level of the kidney.
The pyrimidine analog 5-fluorouracil (5-FU) is used to treat a wide variety of carcinomas. Toxicity from 5-FU is expressed as GI disturbances (anorexia, nausea, stomatitis, and diarrhea) and myelosuppression.
Paclitaxel is particularly useful in treating metastatic breast and ovarian cancer. The primary toxicity of paclitaxel is bone marrow suppression.



165. The pyrimidine analog 5-fluorouracil (5-FU) is metabolized by ribosylation and phosphorylation to the nucleotide level (F-UMP). F-UMP is further metabolized to F-dUMP, an inhibitor of thymidylate synthase. Cells then become starved for TTP and incorporate F-dUTP and dUTP in its place in DNA. 5-FU also becomes incorporated in RNA, leading to inhibition of RNAprocessing.
Anastrozole is a nonsteroidal inhibitor of aromatase, an enzyme required for synthesis of estrogens. This drug is useful against advanced estrogen or progesterone receptor-positive breast cancer.
Cytarabine (cytosine arabinoside, ara-C), is an S-phase-specific antimetabolite that is metabolized to the triphosphate form, which blocks DNAsynthesis. It is used exclusively in acute myelogenous leukemia.
Doxorubicin is an anthracycline antibiotic that intercalates into DNAcausing strand breakage and blockage of both DNAand RNAsynthesis. This agent is widely used in combination regimens for breast, endometrial, ovarian, testicular, and thyroid carcinomas, and several sarcomas and lymphomas.
Imatinib is an inhibitor of the tyrosine kinase activity of the Bcr-Abl oncogene product. It is a drug of choice in chronic myelogenous leukemia with the Philadelphia chromosome translocation.

Etoposide is a semisynthetic derivative of podophyllotoxin, a constituent of the mandrake plant. Etoposide is an inhibitor of topoisomerase II, an enzyme that relaxes supercoiled DNA by breaking one strand and passing the second strand through the break before closing the break. Etoposide inhibits the closure step and results in an accumulation of DNAstrand breaks, leading to cell death. Etoposide is used to treat testicular tumors and small cell carcinoma of the lung in combination with cisplatin. Leukopenia is the dose-limiting toxicity seen with this drug.
Dacarbazine is a synthetic prodrug activated in the liver to a metabolite that alkylates DNAleading to cytotoxicity. The drug is useful against melanoma and Hodgkin lymphoma.
Lomustine (CCNU) is a lipid-soluble nitrosourea agent that acts as an alkylating agent. The nitrosoureas are unusual in having relatively good access to the CNS and are therefore useful in treating brain tumors.
Prednisone is a potent, orally active corticosteroid with good lymphotoxic potency. Its mechanism is not fully understood but may involve activation of apoptotic pathways in lymphocytes.
Vincristine is a natural product isolated from the vinca plant. It is classified as a spindle poison and inhibits mitosis by inhibiting microtubule assembly. This drug is particularly useful in treating acute leukemias in children and Hodgkin lymphoma.



166. Long-term treatment of schizophrenia with potent dopamine D2 receptor antagonists is associated with a high incidence of the irreversible extrapyramidal dystonias called tardive dyskinesia. The phenothiazines (and haloperidol) are D2 receptor antagonists in the CNS; their success in the treatment of schizophrenia resulted in the hypothesis that the antipsychotic effect requires D2 blockade. Data from newer, atypical antipsychotic agents casts some doubt on this hypothesis because drugs, such as clozapine and risperidone, have a low affinity for D2 receptors. Older drugs in the phenothiazine class (e.g., chlorpromazine) have both antimuscarinic and antiemetic action; thus diarrhea, nausea, and vomiting are very unlikely. Because prolactin secretion from the anterior pituitary is inhibited by dopamine, blockade of D2 receptors by fluphenazine increases prolactin secretion. This may result in breast engorgement and galactorrhea in women. Tourette syndrome involves tics and other involuntary movements and obscene vocalizations. The neuroleptic agent haloperidol is the current drug of choice for the treatment of this disease. Weight loss is associated with the use of selective SSRIs, not phenothiazines. In fact, the phenothiazines are often associated with weight gain.




167. Clozapine (psychotropic drug) causes agranulocytosis in a small but consistent fraction of patients; monitoring is mandatory.
Buspirone is an antianxiety agent with minimal sedative action.
Haloperidol is an older, highlypotent antipsychotic drug used in schizophrenia.
Lithium carbonate is an important antimanic drug. It apparently acts by interfering with inositol phosphate cycling and second messenger synthesis in neurons.
Mirtazapine is a third-generation antidepressant related to antihistaminics and has significant sedative action.



168. Inhaled albuterol (or other beta-2-selective receptor agonists including bitolterol metaproterenol, pirbuterol, and terbutaline) are the usual agents of choice for treating bronchoconstriction in an acute asthma attack. These beta-2-selective agonists produce bronchial relaxation by stimulating cyclic AMP (cAMP) formation in bronchiolar smooth muscle and cause less tachycardia than nonselective beta agonists. Unfortunately, they do cause some tachycardia and skeletal muscle tremor.
Aminophylline and other methylxanthines are rarely used to terminate acute episodes of asthma because they must be administered parenterally for rapid onset of effect.
Cromolyn sodium must be used prophylactically to prevent acute episodes and probably acts by stabilizing mast cells. It is not a smooth muscle relaxing agent and is not effective in reversing bronchospasm.
Inhaled ipratropium has less general efficacy in acute attacks than beta agonists.
Salmeterol is an effective beta-2-selective agonist but has a slow onset and long duration of action. Therefore, it is used for prophylaxis, not treatment of acute attacks.





169. Allopurinol and its metabolite alloxanthine inhibit xanthine oxidase, thus preventing conversion of xanthine and hypoxanthine to uric acid. Although xanthine and hypoxanthine then accumulate, these compounds are more soluble than uric acid and less likely to deposit in joints or precipitate in the urine.
Most doses of aspirin increase retention of uric acid, especially low doses.
Colchicine is an inhibitor of microtubule function that brings relief in an acute gout attack by inhibiting the motility of granulocytes and preventing the formation of mediators of inflammation by leukocytes. Because of its toxicity at higher doses, it is now used chiefly at low doses to prevent acute attacks.
Indomethacin is an NSAID that inhibits COX and reduces formation of prostaglandins and eicosanoids involved in gouty arthritis. It has no effect on the formation of uric acid and very little on its excretion.
Sulfinpyrazone and probenecid are uricosuric agents—they increase the excretion of uric acid by the kidney. Renal uric acid excretion is determined by the balance between the amount filtered plus that actively secreted and the amount undergoing passive and active reabsorption. At very low doses, these agents inhibit active secretion and thus promote retention of uric acid. At higher (clinical) doses, both active secretion and active reabsorption are inhibited, with the result that excretion is enhanced.




170. NSAIDs have long been drugs of first choice in arthritis treatment. Their primary mechanism of action in arthritis appears to be inhibition of COX, an enzyme required for the synthesis of inflammatory and other prostaglandins. Two forms of COX are present in the body: COX-1, which is required for synthesis of several useful prostaglandins (e.g., PGE1 , a cytoprotective agent in the stomach), and COX-2, the isoform responsible for synthesis of prostacyclin as well as most of the damaging prostaglandins. Celecoxib is more selective for COX-2 and thus has a lower incidence of adverse GI effects. The older NSAIDs inhibit both COX-1 and COX-2 with less selectivity and thus reduce protective prostaglandins, resulting in a high incidence of GI disorders, especially peptic ulceration.
Misoprostol is a PGE1 analog that is used with NSAIDs to reduce peptic ulceration; unfortunately it causes a high incidence of diarrhea.



171. Bethanechol is a muscarinic agonist and typically causes vasodilation, with a drop in blood pressure and a compensatory tachycardia.
Epinephrine an alpha-1-, alpha-2-, beta-1-, and beta-2-agonist, causes hypertension at high doses, but usually also causes tachycardia.
Isoproterenol is a beta-1-, beta-2-agonist, and does not cause hypertension or bradycardia.
Norepinephrine and phenylephrine can both cause hypertension and reflex bradycardia. However, nor-epinephrine has beta-1-agonist action, whereas phenylephrine has only alpha effects. Thus, in the presence of an alpha-blocking agent, norepinephrine causes a beta-1-mediated tachycardia; phenylephrine has no effect on heart rate.



172. The benzodiazepine agents, including diazepam, facilitate the actions of the inhibitory neurotransmitter GABA, which acts on GABAA receptors to open chloride ion channels.
Bupropion is probably an inhibitor of norepinephrine and dopamine uptake and does not act on GABA receptors.
Fluoxetine is a selective inhibitor of serotonin uptake.
Pentobarbital is a modulator of the same GABA-sensitive chloride channel affected by benzodiazepines, although its mechanism of action is slightly different.
Tranylcypromine is an inhibitor of MAO rather than catechol-O-methyltransferase (COMT).




173. Apatient who is anemic, neutropenic, and thrombocytopenic requires stimulation of all three major cell lines in the bone marrow. The only drug currently available that accomplishes this broad-spectrum stimulant effect is sargramostim (granulocyte–macrophage colony stimulating factor [GM-CSF]).
Epoetin is a more selective stimulant of erythrocyte production and is useful in simple anemia.
Filgrastim is a somewhat selective stimulant of leukocyte production and has much less effect on erythrocytes and platelet production than sargramostim.

174. The blood-gas partition coefficient is a measure of the solubility of the inhalation anesthetic in the blood relative to its solubility in the inspired air. Circulating blood provides the means of anesthetic delivery to the brain and the partial pressure determines the rate of transfer into the CNS. The solubility of an agent in blood determines how rapidly the partial pressure rises in the blood. Agents with high solubility (large blood-gas partition coefficients) require large amounts of the anesthetic to dissolve in the blood before the partial pressure in the blood increases enough to effe-ctively deliver them to the brain. Thus, agents with lower blood solubilities (small blood-gas partition coefficients) have more rapid rates of onset of anesthesia. Desirable properties for inhalation anesthetic agents include high potency and low blood solubility. The halogenated hydrocarbons, such as desflurane and sevoflurane, fit these criteria and are used extensively.
The MAC value (median alveolar anesthetic concentration) required for anesthesia is a measure of the potency of the agent, but does not give an indication of the rate of onset of anesthesia.
Molecular size may play a role in determining the blood-gas partition coefficient, but it is only a partial determinant.
The oil–water partition coefficient is a measure of the lipid solubility of the anesthetic agent. This correlates with the potency as measured by the MAC.
Hepatic metabolism plays no role in onset of action, but may be important in terms of possible liver and kidney damage resulting from the production of toxic metabolites from some of the halogenated inhaled anesthetic agents.



175. Treatment of Liddle syndrome consists of direct inhibition of the abnormally expressed sodium channel by either amiloride or triamterene, both of which are classified as potassium-sparing diuretics. Triamterene is less useful than amiloride because of its low potency and low solubility, which may lead to the formation of stones.
Fludrocortisone is a synthetic mineralocorticoid used for replacement therapy in hypoaldosteronism. Although aldosterone levels are reduced in this patient, administration of a mineralocorticoid will exacerbate rather than relieve the hypertension and hypokalemic metabolic alkalosis.
Hydrochlorothiazide a thiazide diuretic, will exacerbate the problem because inhibition of the Na+/Cl− symporter in the distal convoluted tubule results in delivery of more sodium to the cortical collecting duct, where the hyperactivity of the sodium channel and resulting potassium extrusion along with increased proton exchange from type A intercalated cells results in greater hypokalemia andalkalosis.
Lisinopril is an ACE inhibitor used in the treatment of essential hypertension.
Spironolactone is a selective antagonist at the aldosterone receptor. It is used as a potassium-sparing diuretic. In thecase of Liddle disease, spironolactone has no utility; aldosterone does not play a causative role and its levels are already depressed.



176. Streptokinase has no intrinsic enzymatic activity, but instead forms a stable complex with the patient’s plasminogen, making it enzymatically active in cleaving free plasminogen to plasmin. The streptokinase–plasminogen complex is not inhibited by antiplasmin. The other thrombolytic agents
t-PA, reteplase, tenecteplase, and urokinase— activate plasminogen directly.
Competitive blocking of binding of plasminogen to fibrin is a property of aminocaproic acid (AMICAR), a lysine analog used to inhibit fibrinolysis.



177. Diplopia, abnormal gait, and other signs of cerebellar dysfunction are important symptoms of phenytoin toxicity. Other manifestations of toxicity include gingival hyperplasia, nystagmus, and vertigo.
Hyperprolactinemia is an adverse effect of antipsychotic dopamine antagonists such as the phenothiazines; dopamine inhibits prolactin secretion by the anterior pituitary.
Polydipsia and polyuria are symptoms of diabetes insipidus. These symptoms may be produced by lithium toxicity during treatment of bipolar depression, and are not associated with phenytoin toxicity.
Postural hypotension often occurs with levodopa treatment of Parkinson’s disease.
Rigidity and tremor are symptoms of parkinsonism. These symptoms may be produced by dopamine antagonists such as antipsychotic agents.


178. Ethambutol causes visual dysfunction and possible retinal damage, not hearing loss.
Isoniazid causes peripheral neuropathies and hepatic damage. Fortunately, hepatitis is uncommon in children treated with this drug.
Pyrazinamide causes joint pains and swelling, GI upset, and rash.
Rifampin causes proteinuria, rash, and thrombocytopenia.


179. Vasodilators act by one of three mechanisms: increasing cyclic GMP (cGMP) levels in vascu-lar smooth muscle cells; opening potassium channels; or blocking calcium channels.
The organic nitrates and nitroprusside (nitrova- sodilators) increase cGMP synthesis by generating nitric oxide (NO), which subsequently activates a soluble form of guanylyl cyclase. Activation of muscarinic receptors on vascular endothelial cells results in formation of NO (earlier identified as endothelium-derived relaxing factor) that diffuses to smooth muscle cells and relaxes them through increased cGMP levels. Erection of the penis involves neuronally regulated formation of NO, increased cGMP levels in the corpus cavernosum, and relaxation of cavernosal and vascular smooth muscle in erectile tissue. Rather than stimulating guanylyl cyclase, sildenafil (Viagra) acts as a selective inhibitor of cGMP phosphodiesterase type 5 to increase the half-life of cGMP in the tissues. The fact that sildenafil acts downstream of NO stimulation of guanylyl cyclase accounts for the toxic interactions between it and nitrovasodilators.
The mechanism for relaxation of vascular smooth muscle by hydralazine is unknown, but may involve NO.
Minoxidil is metabolized to minoxidil sulfate, which activates an ATP-sensitive potassium channel in smooth muscle.
Nitroprusside is a nitrovasodilator that spontaneously releases NO by a mechanism distinct from that of the organic nitrates.
Prazosin produces vasodilation by inhibiting alpha-1-adrenoreceptors on arteriolar smooth muscle.




180. Excellent analgesia and significant addictive properties are associated with drugs that act at mu-type opioid receptors.
Codeine is a weak agonist at mu-receptors, whereas the other opioid analgesics (Meperidine, Methadone, Morphine) are full agonists.
Therefore codeine is less efficacious but also has the lowest addiction and abuse liability; it is therefore the agent of choice within this list.
Diphenoxylate is a congener of meperidine (and the primary component of Lomotil) that is used to control GI motility in diarrhea. At therapeutic dose levels, neither analgesia nor addiction is observed.
Meperidine is a synthetic mu-opioid receptor agonist with high-addiction liability.
Methadone is a mu-opioid receptor agonist with good oral efficacy and a long plasma half-life (15–40 h). It is used in the treatment of opioid addiction and for severe cancer pain.
Morphine is the prototype mu-opioid receptor agonist and possesses high addiction liability.


181. The current drug of choice for acute AV nodal reentrant tachycardia (a supraventricular tachycardia [SVT]) is the nucleoside adenosine. This agent, when given as a bolus, causes marked hyperpolarization of AV node tissue and transiently blocks conduction of AV node action potentials. This abolishes the reentrant impulse and allows normal sinus rhythm to be reestablished. The half-life of adenosine is about 3 seconds and the duration of action of the dose used is about 15 seconds, so toxicities from this therapy are minimal. Calcium channel blockers such as verapamil and diltiazem are also effective in SVT.
Bethanechol is a muscarinic agonist and produces hypotension and other muscarinic effects. It is ineffective in SVT. Isoproterenol is a beta-selective adrenoreceptor agonist that causes hypotension and reflex sympathetic discharge to the heart, along with direct stimulation. It is more likely to cause than to abolish arrhythmias.
Metoprolol slows AV conduction and might abolish the AV reentrant rhythm. However, beta blockers are not very effective in converting preexisting SVT.
Procainamide and related group 1A antiarrhythmic drugs are not as effective as adenosine in converting SVT to normal sinus rhythm and much more toxic.




182. Salivary glands contain muscarinic receptors, primarily of the M3 subtype, that receive parasympathetic innervation. Direct-acting agonists such as bethanechol and indirect agents such as neostigmine mimic parasympathetic nerve stimulation. Blood vessel endothelial cells contain M3 receptors that are not innervated, but respond to circulating direct-acting muscarinic agonists. When these endothelial receptors are activated, nitric oxide synthesis is stimulated and smooth muscle relaxation occurs promptly with vasodilation and a drop in blood pressure.
Because no nerve endings are present, indirect-acting cholinomimetics such as cholinesterase inhibitors do not have this vasodilating effect. In the presence of hypotension induced by a direct-acting muscarinic agonist, a strong compensatory reflex originates in the baroreceptors and results in tachycardia.
In the case of cholinesterase inhibitors, the normal heart rate slowing effect of the vagus is amplified and at normal doses, bradycardia results.
Alpha receptor ligands have little effect on salivation, although indirectly acting agents like ephedrine can cause a sensation of dry mouth. However, ephedrine causes increased blood pressure.
Aganglionic stimulant drug causes increased salivation but also increases sympathetic discharge to the blood vessels and results in increased, not decreased, blood pressure.




183. Trastuzumab is a human antibody that reacts with the epidermal growth factor receptor HER-2/neu and is effective in slowing progression of breast cancer.
Adalimumab and etanercept are IgG1 antibodies to TNF-alpha and are used in advanced rheumatoid arthritis.
Infliximab is a chimeric antibody to TNF-alpha that is used in rheumatoid arthritis and several other autoimmune diseases.
Sirolimus is an inhibitor of B lymphocyte proliferation and immunoglobulin production. It is used to prevent transplanted organ rejection.


184. Ondansetron is a 5-HT3 antagonist.
Dronabinol is a cannabinoid agonist.
Dexamethasone is a corticosteroid.
Metoclopramide is a dopamine antagonist.
Diphenhydramine is a histamine antagonist.
Ondansetron is also effective in reducing postsurgical vomiting. Several congeners of ondansetron are available (granisetron, dolasetron).
Misoprostol is an orally active PGE1 analog that is used in the treatment or prevention of NSAID-induced ulcers.

185. Baclofen is an agonist at GABAB receptors and is useful in the treatment of chronic muscle
spasm.
Glutamate is an important excitatory transmitter in the CNS; agonists are not used clinically. Antagonists at neuronal nicotinic receptors are ganglion blockers; baclofen has no effect on these receptors.
Glycine is an important spinal inhibitory transmitter, but baclofen has no effect on its receptors.
Dantrolene is an antagonist at skeletal muscle ryanodine receptors ; baclofen has no effect at this
site



186. Beta blockers such as timolol reduce intraocular pressure by reducing synthesis of aqueous by the ciliary epithelium.
Dorzolamide is a topically active carbonic anhydrase inhibitor that inhibits the synthesis, not the outflow, of aqueous humor.
Latanoprost is a PGF-2 alpha analog used topically to increase aqueous outflow.
Pilocarpine is a muscarinic cholinomimetic that increases aqueous outflow.



187. The oral anticoagulants, such as warfarin, block the vitamin K-dependent step in the hepatic synthesis of coagulation factors VII, IX, X, and prothrombin. Carboxylation of descarboxy-prothrombin to form prothrombin containing gamma-carboxyglutamate residues requires the reduced form of vitamin K as a cofactor. Vitamin K epoxide is formed as a product. KH2 must be regenerated by an NADH-dependent epoxide reductase for the next round of carboxylation. It is the epoxide reductase step that is blocked by oral anticoagulants.
Heparin exerts its anticoagulant actions by acting as a template for combining thrombin and antithrombin III.



188. Sucralfate is a sucrose aluminum-sulfate compound that polymerizes in an acid environment and is able to form a protective coating over an ulcer bed. It must be taken four times a day, so it is less convenient than H2-blockers or proton pump inhibitors.
Because strong vasodilators evoke powerful compensatory responses (salt and water retention, tachycardia), drugs like minoxidil are almost always used together with drugs such as diuretics that prevent the compensatory responses.

189. Amitriptyline, desipramine, imipramine, and trazodone are members of the tricyclic/ heterocyclic group and all have mixed effects on both norepinephrine and serotonin reuptake.
Desipramine is the most selective agent for blocking uptake of norepinephrine.
The selective serotonin uptake inhibitors offer the advantage that they do not produce sedation or autonomic side effects, in contrast to many of the tricyclic and hetero-cyclic antidepressants.
Citalopram is one of the highly selective SSRIs, as is its (S) isomer, escitalopram. Most older, tricyclic, and heterocyclic antidepressants block—to varying degrees—reuptake of both norepinephrine and serotonin amine neurotransmitters into the presynaptic nerve terminals.




190. Chronic lead poisoning results in multiple toxicities including headache, hypertension, infertility, anemia, and renal insufficiency. Mental and growth retardation occur in children.
Acute lead intoxication usually presents as encephalopathy or severe abdominal colic, sometimes masquerading as pancreatitis. When blood lead levels exceed 50 mcg/dL, chelation treatment is indicated. The calcium ion in calcium disodium edetate (EDTA) is readily displaced by lead, forming a lead chelate that is excreted in the urine.
Arsenic poisoning is treated with chelation therapy using dimercaprol, succimer, or penicillamine.
Atropine is a lipophilic muscarinic receptor antagonist that blocks parasympathetic function and at toxic levels produces hallucinations and psychosis. Treatment of atropine intoxication consists of symptomatic management or administration of the lipid-soluble anti-cholinesterase physostigmine.
Toxicity from iron may arise from ingestion of iron supplements (as with children swallowing adult preparations) or hemolytic diseases such as thalassemia. Treatment consists of the use of the iron-chelating agents deferoxamine or deferasirox.
Inorganic mercury poisoning is treated by using chelation therapy with dimercaprol, succimer, or penicillamine. Organic mercury poisoning is more difficult to treat because of the lipophilic nature of organomercury compounds.




191. Mebendazole is a broad-spectrum anti-helmintic that is effective against a variety of nematodes including ascarids, hookworm (Necator, Ancylostoma), whipworm (Trichuris), threadworm (Strongyloides), and pinworm (Enterobius). Adverse effects are rare.
Diethylcarbamazine was developed as a treatment for filariasis. Because of adverse effects that include nausea, vomiting, headache, leukocytosis, and proteinuria, it has been largely supplanted by other antifilarial agents, except in the case of Loa loa, where it remains the drug of choice.
Ivermectin is used to treat Onchocerca volvulus, the agent responsible for river blindness in west and central Africa.
Niclosamide and praziquantel are agents with primary efficacy against flukes and tapeworms.
In the case of Fasciola hepatica (sheep liver fluke), however, bithionol or triclabendazole (a veterinary drug) are drugs of choice; in cysticercosis, albendazole is the drug of choice.



192. The leukotrienes LTC4, LTD4, and LTE4 are 5’-lipoxygenase metabolites of arachidonic acid. When lung tissue is challenged with antigen in sensitive individuals, LTC4 is formed and sub-sequently metabolized to LTD4 and LTE4. These leukotrienes are not stored but produce broncho-constriction, increased capillary permeability, and increased mucus formation for an extended time because of their slow tissue clearance. Because the first enzyme in synthesis of leukotrienes from arachidonic acid is 5’-lipoxygenase rather than COX, aspirin does not inhibit their biosynthesis. Another leukotriene, LTB4, is a potent chemotactic agent for polymorphonuclear leukocytes, but the cysteine-linked leukotrienes LTC4, LTD4, and LTE4 do not share this property.
Platelets do not contain 5’-lipoxygenase (although they do contain 12’-lipoxygenase), and leukotrienes are not stored in platelet granules.
The COX product of arachidonic acid, TXA2, is critical in platelet physiology, and acetylation of COX by aspirin accounts for the effect of this drug in inhibiting platelet function.
The leukotrienes possess significant cardiovascular effects; they produce hypotension by decreasing intravascular volume and reducing cardiac contractility by constricting coronary vessels, thus reducing coronary blood flow




193. Local anesthetic agents such as lidocaine inhibit nerve conduction through state- and use-dependent blockade of voltage-dependent fast sodium channels. As a result, the threshold of excitability of the nerve is increased, and the ability of the nerve to propagate an action potential is decreased. Ultimately, transmission of sensory stimuli to the CNS is suppressed, and motor function involving small fibers in the vicinity of the injection is also lost.



194. Pancreatic beta cells are electrically polarized. Depolarization causes entry of calcium and activation of insulin exocytosis. In hypoglycemia, the negative resting potential is maintained by the activity of an ATP-sensitive hyperpolarizing potassium channel and insulin secretion is inhibited. When extracellular glucose levels are high, glucose enters the beta cells via the GLUT2 transporter and is metabolized to yield ATP. The increased ATP levels cause closure of the potassium channel, allowing the cell to depolarize and secrete insulin.
Modulation of insulin release is the mechanism of action of the meglitinides such as repaglinide. Although the details are not full understood, these drugs share one binding site with sulfonylureas and have a second, independent binding site.
Acarbose is an inhibitor of intestinal alpha-glucosidase and thus reduces absorption of glucose.
Sulfonylureas such as glipizide bind to a cell-surface protein to cause inhibition of the hyperpolar- izing potassium channel, thereby allowing the beta cell to depolarize and secrete insulin.
Metformin and other biguanides are poorly understood, but do not inhibit the potassium channel that is the target of sulfonylureas.
Rosiglitazone and pioglitazone do not act by reduction of circulating glucagon; this is one proposed mechanism for the biguanides. These thiazolidinediones or “glitazones” appear to act by a peripheral mechanism that reduces insulin resistance, probably mediated by the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) nuclear receptor.

Topic 51-114

65. The ascending limb of Henle’s loop dilutes the fluid within the nephron by reabsorbing Na+
without water. In the absence of ADH, the reabsorption of Na+ without water continues along the collecting duct, making the Na+ concentration lower and lower. In the presence of ADH, water is reabsorbed from the collecting duct making the luminal fluid isotonic in the cortical collecting duct and hypertonic in the medullary collecting duct.

Parathyroid hormone (PTH) increases Ca2+ reabsorption from the thick ascending limb and the distal convoluted tubule. Although most of the filtered Ca2+ is reabsorbed in the proximal tubule, the regulation of Ca2+ excretion occurs in the thick ascending limb and the distal convoluted tubule. PTH regulates the reabsorption of HPO42− in the proximal tubule.

Aldosterone increases the reabsorption of Na+ from the principal cells within the cortical and medullary collecting ducts. Aldosterone increases Na+ reabsorption by increasing the luminal permeability to Na+ on the apical surface and the activity of the Na-K pump on the basal lateral surface of the principal cells. Aldosterone also increases the secretion of K+ and H+ from the collecting ducts.




66. Approximately two thirds of the 40 to 150 mg of protein excreted per day by the kidney is
derived from plasma proteins. The remainder is derived from the tubular secretion of a mucoprotein, the Tamm-Horsfall protein, that is present in tubular casts appearing in urinary sediment. Not all plasma proteins are filtered equally because glomerular permeability is related to molecular size and charge. The larger and negatively charged proteins are poorly filtered. Most of the filtered protein is reabsorbed in the proximal tubule unless the filtered load exceeds the tubular capacity. Such overload would occur following damage to the glomerular basement membrane and breakdown of normal barriers, or following an increase in the plasma concentration of a small protein, such as myoglobin. Protein excretion is also increased by sympathetic stimulation, such as that occurring during exercise. In this situation, renal vasoconstriction reduces the glomerular filtration rate, which, by increasing the transit time of glomerular filtrate, favors diffusion of proteins across the basement membrane. The presence of protein in the urine indicates glomerular dysfunction. RBC casts are indicative of glomerulonephritis. A red color indicates the presence of hemoglobin, myoglobin, or red food.





67. Juxtaglomerular ( JG) cells are sensitive to changes in afferent arterial intraluminal pressure. Increased pressure within the afferent arteriole leads to a decrease in renin release, whereas decreased pressure tends to increase renin release. Angiotensin appears to inhibit renin release by initiating the flow of calcium into the JG cells. Renin release is increased in response to increased activity in the sympathetic neurons innervating the kidney. Prostaglandins, particularly PGI2 and PGE2, stimulate renin release. Stimulation of the macula densa leads to an increase in renin release, and although the mechanism is not fully understood, it appears that increased delivery of NaCl to the distal nephron is responsible for stimulating the macula densa. Aldosterone does not appear to have any direct effect on renin release.




68. The macula densa senses the chloride concentration of the fluid flowing from the ascending limb of Henle’s loop into the distal convoluted tubule. An increase in NaCl concentration occurs when the amount of fluid flowing through the ascending limb increases because there is less time available for the reabsorption of NaCl. The resulting increase in Cl− concentration results in the release of adenosine (and/or ATP) from the macula densa.Adenosine constricts the afferent arteriole, resulting in a decrease in filtraion and a return of the flow rate within the nephron toward normal. This response is referred to as tubuloglomerular feedback. If the NaCl concentration decreases (e.g., when circulating blood volume decreases), the decreased Cl− concentration results in the release of renin from granular cells of the juxtaglomerular apparatus. Spironolactone acts by competitive
inhibition of aldosterone, thereby blocking Na+ reabsorption in the distal tubules and collecting ducts. Potassium-sparing diuretics are relatively weak and therefore are most effective when administered in combination with loop and/or thiazide diuretics.


The juxtaglomerular apparatus (JGA) is responsible for releasing renin when the effective circulating blood volume is decreased. The JGA releases renin when the Cl− concentration in the luminal fluid bathing the macula densa is decreased. The decrease in Cl− (and Na+) concentration
occurs when the flow rate within the nephron decreases and ample time is available for the loop of Henle to remove NaCl from the lumen. Adenosine is released from the macula densa cells when the luminal Cl− concentration increases in response to an increase in luminal flow rate. Adenosine
decreases renal blood flow by constricting the afferent arteriole and, therefore, the blood flow through the glomerular capillary.


69. Increased renin leads to increased production of angiotensin II, which binds to AT1 receptors in the zona glomerulosa, which act via a G protein to activate phospholipase C. The resultant increase in protein kinase C fosters the conversion of cholesterol to pregnenolone and facilitates the action of aldosterone synthase, resulting in the conversion of deoxycorticosterone to aldosterone.

Increased potassium concentration directly stimulates aldosterone secretion. Like angiotensin II, K+
stimulates the conversion of cholesterol to pregnenolone and the conversion of deoxycorticosterone to aldosterone by aldosterone synthase. Potassium exerts effect on aldosterone secretion by depolarizing the the zona glomerulosa cells, which opens voltage-gated Ca2+ channels, increasing
intracellular Ca2+. Adrenocorticotropic hormone (ACTH) stimulates aldosterone synthesis and secretion via increases in cyclic AMP and protein kinase A. The stimulatory effect of ACTH on aldosterone secretion is usually transient, declining in 1–2 days, but persists in patients with
glucocorticoid-remediable aldosteronism, an autosomal dominant disorder in which the 5’ regulatory region of the 11β-hydroxylase gene is fused to the coding region of aldosterone synthase gene, producing an ACTH-sensitive aldosterone synthase.






70. Blood flow through the kidney is controlled by numerous humoral agents. Angiotensin II decreases renal blood flow. It vasoconstricts efferent arterioles more than afferent arterioles, which helps to maintain glomerular filtration rate in the face of decreases in renal perfusion pressure. This may account for the renal failure that sometimes develops in patients with decreased renal perfusion who are taking angiotensin-converting enzyme inhibitors. Nitric oxide dilates the afferent arteriole and constricts the efferent arteriole, producing a rise in glomerular capillary pressure (and glomerular filtration) without having much of an effect on renal blood flow. Dopamine synthesized in the kidney increases renal blood flow and sodium excretion. Acetylcholine and atrial natriuretic peptide also produce renal vasodilation and an increase in renal blood flow.







71. Free water clearance is the amount of water excreted in excess of that required to make the urine isotonic to plasma. It is calculated using the formula: CH2O = V − Cosm. Free water clearance is positive when the urine is dilute (more than a sufficient amount of water is excreted), and free water clearance is negative when the urine is concentrated (not enough water is excreted to make the urine isotonic to plasma). An increase in free water clearance can lead to hypernatremia; a decrease in free water clearance can lead to hyponatremia. In diabetes insipidus, very little water is reabsorbed in the distal nephron, and, therefore, the free water clearance is very high. In heart failure or renal failure, very little free water can be generated even if the urine is dilute because the glomerular filtration rate is decreased. With diuretic therapy, Na+ excretion is increased. Therefore, the increased water excretion is accompanied by an increased Na+ excretion and the amount of free water generated is limited. Although the water loss is proportionally greater than the solute loss in
diabetes mellitus, the amount of water excreted is much less and the solute concentration significantly higher than in diabetes insipidus, so the free water clearance is much less in diabetes mellitus than in diabetes insipidus.






72. Growth hormone (GH) exerts many of its effects on growth and metabolism by stimulating the production and release of polypeptide growth factors called somatomedins from the liver, cartilage, and other tissues. In humans, the principal circulating somatomedins are insulin-like growth factor I (IGF-I, somatomedinC) and IGF-II. GH release is stimulated by growth hormone-releasing hormone (GHRH) and ghrelin and inhibited by somatostatin. All of these peptides are synthesized and released by the hypothalamus, though the main site of ghrelin synthesis and secretion is the stomach. GH increases lipolysis; the resultant increase in free fatty acids, which takes several hours to develop, provides a ready source of energy for the tissues during hypoglycemia, fasting, and stressful stimuli. GH also has a protein anabolic effect. GH is metabolized rapidly; the half-life of circulating GH in humans is 6 to 20 minutes.





73. Hormone-sensitive lipase is a cytoplasmic enzyme in adipocytes that catalyzes the complete hydrolysis of triglyceride to fatty acids and glycerol. It is activated by a cyclic AMP-dependent protein kinase that phosphorylates the enzyme, converting it to its active form. Because no accumulation of monoglycerides or diglycerides is detected in adipocytes following the action of hormone-sensitive lipase, it is the initial hydrolysis of triglyceride to fatty acid and diglyceride that is the rate-limiting step. Hormone-sensitive lipase is sensitive to several hormones in vitro, but it appears to be regulated in vivo primarily by epinephrine and glucagon, which activate it by increasing cyclic AMP, and insulin, which inhibits it by preventing cyclic AMP-dependent phosphorylation. Cortisol enhances lipolysis indirectly by promoting increased enzyme synthesis.





74. Synthesis and secretion of growth hormone (GH) by the anterior pituitary is regulated by a variety of metabolic factors, many of which act to alter the balance between release of growth hormone-releasing hormone (GRH) and somatostatin (SS) from the hypothalamus. Among the stimuli that increase GH secretion are: (1) conditions in which there is a deficiency of energy substrate (e.g., hypoglycemia, exercise, and fasting); (2) stressful stimuli (e.g., fever, various psychological stresses); (3) an increase in arginine and some other amino acids (e.g., protein meal, infusion of arginine); (4) glucagon; (5) L-Dopa and dopamine receptor agonists; (6) estrogens
and androgens; and (7) going to sleep. Stimuli that decrease GH secretion include somatostatin, REM sleep, glucose, cortisol, free fatty acids, and GH itself.




75. The primary action of glucagon is to increase blood glucose concentration, which it accomplishes by promoting gluconeogenesis and glycogenolysis in the liver but not in muscle. These effects are mediated by cyclic AMP, which is produced by hepatic adenylate cyclase
following interaction of glucagon with its plasma membrane receptor. Interaction of glucagon with different hepatic plasma membrane receptors activates phospholipase C, which results in a rise in concentration of intra-cellular Ca2+, which further stimulates glycogenolysis. Although glucagon
opposes the action of insulin, it does not directly affect insulin secretion.





76. Removal of the adrenal glands produces the clinical picture known as Addison’s disease, a disorder associated with deprivation of adrenocortical hormones. A lack of glucocorticoids diminishes the body’s ability to synthesize glucose by gluconeogenesis. Mineralocorticoid deprivation produces diuresis, natriuresis, and decreased potassium secretion leading to
excessive potassium plasma levels and acidosis.



77. Insulin does not promote glucose uptake by most brain cells. Insulin does increase glucose uptake in skeletal muscle, cardiac muscle, smooth muscle, adipose tissue, leukocytes, and the liver. In most insulin-sensitive tissues, insulin acts to promote glucose transport by enhancing facilitated diffusion of glucose down a concentration gradient. In the liver, where glucose freely permeates the
cell membrane, glucose uptake is increased as a result of its phosphorylation by glucokinase. Formation of glucose-6-phosphate reduces the intra-cellular concentration of free glucose and maintains the concentration gradient favoring movement of glucose into the cell.



78. Thyroid storm is an exaggerated manifestation of hyperthyroidism. Thyroid storm is a medical emergency and mortality is high (20–50%) even with the correct treatment. After primary stabilization of the airway, breathing and oxygenation, circulation, and fluid balance, treatment
includes propylthiouracil (PTU) or methimazole to block the synthesis of new thyroid hormone and β-blockers to block adrenergic effects. Iodine should not be given until after PTU has taken effect (~1.5) or more thyroid hormone will be produced. Aspirin displaces T4 from thyroid binding pro-
tein, and therefore should not be used to treat fever. T3 and T4 inhibit the release of thyrotropin-releasing hormone (TRH) from the hypothalamus, which regulates thyroid-stimulating hormone (TSH) secretion from the anterior pituitary gland.



79. Synthesis and secretion of melatonin are increased in the dark via input from norepinephrine
secreted by postganglionic sympathetic neurons. Melatonin is synthesized in the pineal gland from the amino acid tryptophan. Pinealomas (tumors of the pineal gland) that destroy the pineal gland and reduce secretion of melatonin and cause hypothalamic damage may cause precocious puberty
by removing the inhibitory effect of melatonin on the pituitary response to gonadotropin-releasing hormone. Melatonin causes amphibian skin to become lighter in color but has no role in the regulation of skin color in humans.




80. The islets of Langerhans, which constitute 1 to 2% of the pancreatic weight, secrete insulin, glucagon, somatostatin, and pancreatic polypeptide. Each is secreted from a distinct cell type, A, B, D, and F, respectively. The islets are scattered throughout the pancreas, but are more plentiful in the tail than in the body or head....



81. As a result of insulin deficiency-->Decreased intracellular α-glycerophosphate in liver and fat cells---α-Glycerophosphate is produced in the course of normal use of glucose. In the absence of adequate quantities of α-glycerophosphate, a normal acceptor of free fatty acids in triglyceride synthesis, lipolysis will be the predominant process in adipose tissue. As a result, fatty acids will be released into the blood. The prevailing insulin level is decisive in the selection of substrate by a tissue for the production of energy. Insulin promotes use of carbohydrate, and a lack of the hormone causes use of fat mainly to the exclusion of uptake and use of glucose, except by brain tissue. Indirect depression of glucose utilization due to excess fatty acids is a result, and not a contributing cause, of increased use of fat.



82. Thyroxin-binding globulin (TBG) is increased in estrogen-treated patients and during pregnancy, increasing the total plasma levels of T3 and T4, but with a normal level of the free thyroid hormones, such that the clinical state is euthyroid. Cortisol levels also increase during pregnancy and parturition due to increased production of corticotropin-releasing hormone (CRH) by
the placenta (as well as the fetal hypothalamus). Although tissue renin contributes little to the circulating renin pool, pregnancy is associated with increased renin levels that may arise from components of the tissue renin-angiotensin system found in the uterus, the placenta, and the fetal membranes. Amniotic fluid contains large amounts of prorenin.


Secretion of TSH is regulated primarily by the pituitary levels of T3. As plasma thyroid hormone levels increase, pituitary T3 levels rise and lead to inhibition of TSH synthesis and secretion. TSH stimulates thyroid gland function by binding to specific cell membrane receptors and increasing the
intracellular levels of cAMP. The thyroid gland secretes thyroxine (T4) and triiodothyronine (T3); the latter is the physiologically active hormone. The majority of T3 is formed in the peripheral tissues by deiodination of T4.


84. Growth hormone activates many different intracellular enzyme cascades, including the
JAK2-STAT pathway, which also mediates the effects of various growth factors and prolactin. Secretion of insulin-like growth factor I (IGF-I) increases throughout childhood and stimulate cell proliferation and growth in many different cell types, including chondrocytes within growth plates.
Linear growth ends earlier in girls than in boys. IGF-II is largely independent of growth hormone and plays a role in the growth of the fetus before birth. Thyroid hormones are essential for normal linear growth and skeletal development. The growth-promoting effects of thyroid hormones occur
via a synergistic effect with growth hormone.

Patients with acromegaly have insulin resistance. In addition, they manifest increased lipolysis and increased gluconeogenesis due to their high growth hormone levels. The combination of enhanced glucose production and insulin resistance can produce hyperglycemia and diabetes mellitus.
Protein synthesis increases to support tissue growth and proliferation.



85. Due to their relatively low solubility within the lipid portions of the cell membrane, peptide hormones and catecholamines (epinephrine) must interact with receptors located on the cell membrane. Activation of the receptor is followed by the generation of intracellular second messengers that ultimately mediate the biological response to the hormone. Steroid hormones and thyroid hormones readily pass through the cell surface membrane and interact with intracellular
receptors to produce their effects by regulating gene expression within the nucleus.

Cortisol, like other steroid hormones, diffuses into target cells and interacts with intracellular
receptors. The steroid-receptor complex has a high affinity for the steroid-responsive element of DNA. Once bound to DNA, the hormone-receptor complex acts as a transcription factor to regulate gene expression and formation of specific messenger RNAs.





86. Glucocorticoids lower plasma Ca2+ levels by inhibiting osteoclast formation and activity. Over long periods of time, glucocorticoids cause osteoporosis by decreasing bone formation and
increasing bone resorption. They decrease bone formation by inhibiting protein synthesis in osteoblasts. Glucocorticoids also decrease the absorption of Ca2+ and PO4 3–from the intestine and increase the renal excretion of these ions. Vitamin D formation is facilitated when plasma Ca2+
levels are low.

Cortisol is defined as a glucocorticoid because it promotes the conversion of amino acids to glucose (gluconeogenesis). It also decreases glucose uptake by muscle and adipocytes by decreasing the sensitivity of the cells to insulin. The net result is to provide more glucose to non-insulin-requiring cells. Cortisol retards wound healing. It also decreases CRH and ACTH secretion by feedback inhibition.





87. Phenylethanolamine-N-methyltransferase (PNMT), the enzyme that catalyzes the formation of epinephrine from norepinephrine, is found in appreciable quantities only in the brain and the adrenal medulla. Adrenal medullary PNMT is induced by glucocorticoiods and glucocorticoids are necessary for the normal development of the adrenal medulla. Circumstances that increase sympathetic nerve input to the adrenal medulla increase catecholamine secretion. Major stressors include decreased intravascular volume or pressure, fear or rage, a change in posture from supine to standing, and hypoglycemia.




88. Atrial natriuretic peptide (ANP) is synthesized, stored, and secreted by cardiac atrial muscle, the latter in response to increased central venous pressure or increased plasma sodium concentrations. ANP increases glomerular filtration by simultaneous dilation of afferent and constriction of efferent renal arterioles. It decreases salt and water reabsorption along the entire length of the kidney. The excretion of water is enhanced by inhibition of ADH.






ANATOMY



89. The maximum number of oogonia occurs at about the fifth month of development. Primordial germ cells arrive in the embryonic gonad of a genetic female during the 7th to 12th week where they differentiate into oogonia. After undergoing a number of mitotic divisions, those fetal cells
form clusters in the cortical part of the ovary. Some of those oogonia differentiate into the larger primary oocytes (not to be confused with primary follicles). The primary oocytes begin meiosis. At the same time, the number of oogonia continues to increase to about 6,000,000 by the fifth month. At this time, most of the surviving oogonia and some of the oocytes become atretic. However, the surviving primary oocytes (400,000 to1,000,000) become surrounded by epithelial cells and form the primordial follicles by the seventh month. During childhood there is continued atresia, so that by puberty only about 40,000 primary oocytes remain.



90. On fusion of the first sperm with the oocyte cell membrane, the contents of secretory granules stored just beneath the oocyte membrane (cortical granules) are released (the zona reaction). Enzymes stored in those granules cause biochemical and electrical changes in the zona pellucida and the oocyte membrane that prevent the binding of additional sperm.

Primitive female germ cells (oogonia) enter the first meiotic division during fetal development . This process becomes arrested in prophase I until individual primary oocytes are hormonally induced to resume the first meiotic division during puberty and early adulthood (menarche to menopause). Fusion of the sperm and oocyte membranes initiates the resumption of the second meiotic division, resulting in the formation of a haploid pronucleus in the oocyte and extrusion of the second polar body .

Capacitation is a process by which enzymatic secretions of the uterus and oviducts strip glycoproteins from the sperm cell membrane. This is required for penetration of the layer of cells surrounding the oocyte (corona radiata). The release of enzymes from the sperm acrosomal cap (an enlarged lysosome) results in digestion of the zona pellucida surrounding the oocyte, allowing penetration by sperm.

Primary oocytes have developed by the time of birth. From puberty to menopause, these germ cells remain suspended in meiotic prophase I (diplotene or dictyate stage). A midcycle surge of LH triggers the resumption of meiosis and causes the FSH-primed follicle to rupture and discharge the ovum. Under the influence of LH, the ruptured follicle is transformed into a corpus luteum, which
produces progesterone. FSH and LH produced in the adenohypophysis result in growth and maturation of the ovarian follicle. Under FSH stimulation, the theca cells proliferate, hypertrophy, and begin to produce estrogen.


The secondary oocyte enters the second meiotic division just before ovulation and arrests at metaphase. Fertilization by a spermatozoon provides the stimulation for the division of chromatin to the haploid number. By the time the fertilized ovum reaches the uterus, the progesterone produced by the corpus luteum has initiated the secretory phase in the endometrium. Once implantation occurs and the chorion develops, human chorionic gonadotropin (hCG) is synthesized and the corpus luteum is maintained . Expulsion from the follicle and the environment of the oviduct and
uterus do not induce the second meiotic division



91. Capacitation, the acrosome reaction and penetration are required for the hamster sperm penetration assay (SPA). Capacitation prepares the sperm for fertilization and requires an increase in fluidity of the sperm plasma membrane. Sperm must reside in the female reproductive tract or under appropriate in vitro conditions for about 1 hour for capacitation to occur. During capacitation there is a loss of decapacitation factors that have been added to the sperm by epididymal cells and accessory male reproductive organs. Cholesterol is removed from the sperm plasma membrane during this period, which results in the increased fluidity of this membrane that is required for the fusion of the acrosomal membrane with the sperm plasma membrane. Next, there is release of the acrosomal enzymes , which are required for the breakdown of the corona radiata and the zona pel-
lucida of the oocyte to facilitate sperm penetration. Sperm formation and maturation occur in the testis and epididymis.


The formation of the acrosome, a specialized secretory granule, is one of many maturation events
occurring during spermiogenesis (the process by which mature sperm are formed from the spermatids). Acrosome formation involves lytic enzyme maturation and occurs after division of secondary spermatocytes. It involves no mitotic or meiotic activity . The acrosome develops from
Golgi vesicles just like any other secretory granules. It contains acrosin, a serine protease, hyaluronidase, and neuraminidase, responsible for the penetration ability of the sperm. The developing cells are in contact with Sertoli cells for all of the stages of spermiogenesis. At the end of spermiogenesis, spermatids are released by Sertoli cells in a process called spermiation .
Decapacitation factors are not involved in acrosomal maturation.

Spermatogenesis, the processby which spermatogonia undergo mitotic division to produce primary spermatocytes, occurs at 1°C (2°F) below normal body temperature. Subsequent meiotic divisions produce secondary spermatocytes with a bivalent haploid chromosome number and then spermatids with a monovalent haploid chromosome number. Spermiogenesis, the maturation of the spermatid, results in spermatozoa. Morphologically, adult spermatozoa are moved to the epididymis, where they become fully motile.


92. Cells of the inner cell mass (embryoblast) of the blastocyst differentiate into the epiblast and hypoblast. Cells of the epiblast migrate toward the primitive streak during the second week and
become internalized, forming the mesodermal and endodermal germ layers. Remaining cells of the epiblast become the ectodermal germ layer (epidermis, epidermal appendages, and the nervous system). Cells of the hypoblast will contribute to the yolk sac. Cells of the outer cell mass of the blastocyst will differentiate into the cytotrophoblast and syncytiotrophoblast , which will contribute to formation of the placenta. The yolk sac is incorporated into the embryo as the primitive gut during embryonic folding.
Formation of most internal organs occurs during the second month, the period of organogenesis. The first month of embryonic development generally is concerned with cleavage, formation of the germ layers, and establishment of the embryonic body. The period from the ninth week to the end of intrauterine life, known as the fetal period, is characterized by maturation of tissues and rapid growth of the fetal body.

93. During the second week of fetal development, lacunar spaces develop between cells of the syncytiotrophoblast, particularly in the region of the embryonic pole as the conceptus invades the endometrium. Endometrial capillaries in this region become dilated and engorged with blood to form sinusoids. The syncytial cells direct erosion of the endothelium of the maternal capillaries, allowing maternal blood to enter the lacunae and bathe the syncytial cells. During the second week, primary villi consist of projections of syncytial cells surrounding a core of cytotrophoblast cells. During the third week , the villus core is invaded by mesodermal cells to form a secondary villus. Cells of the mesodermal core will then differentiate to form capillaries and blood cells by the end of the third week (tertiary villus). Those vessels become connected to the fetal circulation early in the fourth week establishing the functional uteroplacental circulation.



94. The presence of a murmur could be indicative of any of the conditions. The presence of a continuous machine-like murmur is indicative of a patent ductus arteriosus (PDA). The ventilator requirements are increased due to increasing pCO2 (as the lungs become “wet,” the pCO2 increases). The diastolic blood pressure usually drops and there is a widened pulse pressure (usually greater than 20). The PDA was always there, it is just that her pulmonary vascular resistance relaxed enough to allow more left-to-right shunting and more blood flow to the lungs (less to the body).

An atrial septal defect (ASD), such as a persistent foramen ovale, could be eliminated from the diagnosis because the murmur would be heard as an abnormal splitting of the second sound during expiration.

A patent foramen ovale is a common echo finding in premature babies and is usually not followed up unless it appears remarkable to the pediatric cardiologist or there is a persistent murmur. A patent foramen ovale might result in only minimal or intermittent cyanosis during crying or straining to pass stool.

A murmur caused by a ventricular septal defect (VSD, answer c), occurs between the first and second heart sounds (S1 and S2) and is described as holosystolic (pansystolic) because the amplitude is high throughout systole.

Pulmonary stenosis would be heard as a harsh systolic ejection murmur. Coarctation of the aorta would result in a systolic murmur.

PDA refers to the maintenance of the ductus arteriosus, a normal fetal structure. In the fetus, the ductus arteriosus allows blood to bypass the pulmonary circulation, since the lungs are not involved in CO2/O2 exchange until after birth. The placenta subserves the function of gas exchange during fetal development. The ductus arteriosus shunts flow from the left pulmonary artery to the aorta. High oxygen levels after birth and the absence of prostaglandins from the placenta cause the ductus arteriosus to close in most cases within 24 hours. A PDA most often corrects itself within several months of birth, but may require infusion of indomethacin (a prostaglandin inhibitor) as a treatment, insertion of surgical plugs during catheterization, or actual surgical ligation.



95. IgA deficiency, the most common immunoglobulin deficiency. IgA functions in several ways, one of which is to coat pathogens with a negative charge that repels the polyanionic charge on the cell surface. In IgA deficiency, pathogens can more easily attach to the cell surface leading to persistent infections. The carbohydrate of biological membranes is found in the form of glycoproteins and glycolipids rather than as free saccharide groups. The polyanionic charge of the membrane is produced by the sugar side chains on the glycoproteins and glycolipids. Glycoproteins often terminate in sialic acid side chains, which impart a negative (polyanionic) charge to the mem-
brane. Similarly, the glycolipids (also called glycosphingolipids), particularlythe gangliosides, terminate in sialic acid residues with a strong negative charge. Cholesterol alters membrane fluidity (see figure below and question 34) and is amphipathic (hydrophilic and hydrophobic properties). It
reduces the packing of lipid acyl groups through its steroid ring structure and hydrocarbon tail and cements hydrophilic regions of the membrane through interactions with its hydroxyl (OH) region. Peripheral membrane proteins are found primarily on the cytosolic leaflet of the membrane
bilayer. Integrins (answer e) are heterodimeric receptors that bind with extra-cellular matrix (ECM) molecules such as laminin and fibronectin.




96. In its anion exchanger role, band 3 protein exchanges bicarbonate ion for chloride ion. Bicarbonate is transported by band 3 out of the RBC in exchange for chloride, permitting the highly efficient transport of CO2 to the lungs as bicarbonate. In the absence of band 3 protein, the bicar-
bonate buffering of the blood is reduced, leading to acidosis or lowering of blood pH. The result is reduced capacity to carry CO2. In addition to its functional, bidirectional anion exchanger role, band 3 plays a key membrane structural role, since the cytoplasmic domain of the protein interacts with spectrin through an ankyrin bridge. Spectrin exists as dimers and trimers; the trimers are bound together by actin, thus providing a connection to the cytoskeleton maintaining the shape and stability of the RBC. The result of a null mutation in band 3 is the formation of erythrocytes that are small and round instead of biconcave (spherocytosis). Spherocytes are osmotically fragile because of their decreased surface area per unit volume. The defective RBCs do not readily pass through the small sinusoids of the spleen, resulting in destruction and further membrane conditioning, which leads to accelerated destruction and, eventually, enlargement of the spleen (splenomegaly). The
accelerated hemolysis leads to increased bile production and jaundice. Hemoglobin production is also increased, as exemplified by an increase in mean corpuscular hemoglobin concentration (MCHC) by about 35 to 40%. The bone marrow compensates for the increased destruction of RBCs with hyperplasia of erythroid precursors in the bone marrow and increase in the number of reticulocytes (polychromasia)





97. The patient in the scenario is suffering from cirrhosis in which there are alterations in plasma
lipoproteins. Binding of an antibody to a cell surface receptor results in lateral diffusion of protein in the lipid bilayer, resulting in increased membrane fluidity—patching and capping. Rotational and lateral movements of both proteins and lipids contribute to membrane fluidity. Restriction reduces
membrane fluidity. Phospholipids are capable of lateral diffusion, rapid rotation around their long axis, and flexion of their hydrocarbon (fatty acyl) tails. They undergo transbilayer movement, known as “flip-flop,” between bilayers in the endoplasmic reticulum; however, in general thisdoes not occur in the plasma membrane. Other factors reduce membrane fluidity. An increase in the amount of cholesterol relative to phospholipid has been shown by a variety of physicochemical techniques to decrease fluidity in both biological and artificial membranes by interacting with the hydrophobic regions near the polar head groups and stiffening this region of the membrane. Association or binding of integral membrane proteins with cytoskeletal elements on the interior of the cell and peripheral membrane proteins on the extracellular surface limit membrane mobility and fluidity.


Asymmetry of the lipid bilayer is established during membrane synthesis in the endoplasmic retic-
ulum before reaching the Golgi apparatus. Carbohydrates are associated with the N terminals of transmembrane proteins that extend from the extracellular surface, not the cytoplasmic surface. Cholesterol is different from proteins and phospholipids that are asymmetrically distributed within the bilayer. Cholesterol is found on both sides of the bilayer. The small polar head group structure
of cholesterol allows it to flip-flop from leaflet to leaflet and respond to changes in shape. In contrast to cholesterol, most proteins and phospholipids are capable of only rare flip-flop. For example, transbilayer movement of phospholipid is limited mostly to the endoplasmic reticulum.


98. Albuterol binds to β-receptors, which are multipass G-protein-linked receptors. Binding to G-protein-linked receptors activates or inactivates enzymes bound to the plasma membrane (adenylyl cyclase or phospholipase C) or opens or closes ion channels using G proteins. A table of G proteins and their functions appears below. The β-receptors, as well as muscarinic cholinergic receptors and rhodopsin, are multipass transmembrane proteins consisting specifically of seven hydrophobic
spanning segments of the single polypeptide chain. The peptide bonds of the spanning segments are polar. In the hydrophobic environment of the lipid bilayer, in the absence of water, they form hydrogen bonds with eachother. There is a remarkable homology between the cell-surface receptors
linked to the G proteins. Ligand binding occurs on the extracellular surface. Receptors with intrinsic enzyme activity belong to a separateclass of single-pass transmembrane proteins. All of these trans-
membrane proteins show a carboxyl terminus on the cytosolic side and N-linked glycosylation sites on the extracellular surface.







99. Anti-vimentin is specific for mesenchymal cells such as fibroblasts, macrophages, endothelial cells, and smooth muscle of the vasculature. In the salivary glands fibrous stromal tissue is derived from mesenchyme.
The acini and ducts are derived from epithelium.
The parasympathetic ganglia will stain with pan-neuronal markers such as peripherin.
The type of intermediate filament protein is relatively specific for cells derived from the three embryonic germ layers. Antibodies to intermediate filament proteins have been used by pathologists to determine the origin of tumors. Intermediate filament proteins have a structural role but also are involved in the anchorage of the proteins that form ion channels.
Cytokeratins (also known as keratins) are specific for epithelial cells.
Neurofilament proteins (NFL, NFM, and NFH) are found in neurons. In Alzheimer’s disease, extensive plaques of neurofilament proteins occur.
Desmin is found in striated and most smooth muscle, except vascular smooth muscle.
Glial fibrillary acidic protein, GFAP, is specific for astrocytes, not microglia or oligodendrocytes





100. The large subunit of the ribosome catalyzes peptide bond formation by activation of peptidyl transferase. The small ribosomal subunit contains the peptidyl-tRNA-binding (P) site that binds the tRNA molecule attached to the carboxyl end of the growing end of the polypeptide chain.
The small subunit also contains the aminoacyl-tRNA-binding (A) site that holds the incoming tRNA and amino acid. The initiation factors are loaded on the small ribosomal subunit that must locate the AUG (start) codon to initiate protein synthesis. This occurs before binding of the large subunit. In addition, the initiator tRNA containing methionine provides the amino acid necessary to start protein synthesis. The initiator tRNA is also located on the small subunit. It resides at the P site (the normal peptidyl site) even though it is an aminoacyl-tRNA. This occurs before binding to the mRNA. Therefore, the initiation phase of protein synthesis is regulated by the small subunit of the ribosome.
Ribosomes are composed of both protein and RNA (predominantly rRNA, but also mRNA and
tRNA). Single ribosomes are involved in synthesis of cytosolic proteins. Polyribosomes, linked by mRNA, synthesize proteins that are translocated into the cisternal space of the rough endoplasmic reticulum (RER) and destined for export or specific organelles.



101. Histochemical stains, such as acid phosphatase and nucleoside diphosphates, show that the Golgi apparatus is topologically compartmentalized. It presents two faces: a cis face, which is the point of entry of transport vesicles (COP-II-coated), in transit from the rough endoplasmic reticulum (RER) to the Golgi, and a trans face, which is the exit point associated with
granule formation and the maturation of proteins. Both proteins and lipids are transported from the transitional elements of the ER to the Golgi apparatus. Packaging is not the sole function of the
Golgi. This organelle is also involved in the processing of proteins (e.g.,addition and trimming of oligosaccharide chains) that was initiated in the RER as well as sulfation.


102. Oxidative metabolism by cytochrome p450 enzymes in hepatocytes is a primary mechanism for drug metabolism. Barbiturates are modified in the liver by oxidative demethylation through the P450 oxidase system found in the smooth endoplasmic reticulum (SER) (the structure shown in the electron micrograph). The SER in hepatocytes responds to Phenobarbital ingestion by increasing its volume. The proliferation (hypertrophy) of the SER facilitates metabolism of drugs. There is a concomitant increase in enzymatic activity, however, the synthesis of those enzymes occurs in the
rough endoplasmic reticulum (RER) not in the SER (answer d). The purpose of drug metabolism is to make drugs more water soluble so they can be more easily excreted from the liver through the bile. Increase in enzymatic activity following Phenobarbital ingestion catalyzes reactions that increase the solubility of various xenobiotics including toxins, alcohol, steroids, eicosanoids, carcinogens, insecticides, and other environmental pollutants. Lysosomes not the SER contain acid hydrolases. The P450 system and the SER are involved in drug interactions. Hepatocytes adapted to metabolize one drug may develop increased capability to metabolize other drugs. For example, if patients taking Phenobarbital for epilepsy increase their alcohol intake they may be ingesting subtherapeutic levels of the antiseizure medication because of induction of smooth ER in
response to the alcohol.



103. The woman in the sce nario suffers from retinitis pigmentosa. Vesicles and organelles move
unidirectionally along microtubules from the inner segment to the outer segment of the photoreceptor. Opsin, which is needed to sense light, is transported to sites of utilization in the disks of the outer segment. Transport occurs through the connecting, non-motile cilium, driven by the microtubule motor, kinesin, an ATPase. Microtubules are composed of tubulin and are involved in motility as the principal protein in the composition of the axoneme (the core of the cilium or flagellum). Micro-filaments (thin filaments) are composed of actin, the most abundant protein in cells of eukaryotes. They are involved in cell motility and changes in cell shape. Myosin is the main constituent of the thick filament that binds to actin and functions as an ATPase activated by actin. Intermediate filaments that are “intermediate” in diameter (8 to 10 nm) between thin and thick filaments are of five different types. Type I and type II are the acidic and basic keratins (cytokeratins) respectively and are found specifically in epithelial cells. Type III intermediate filaments are composed of vimentin, desmin, and glial fibrillary acidic protein (GFAP). Vimentin is found in cells of mesenchymal origin, desmin in muscle cells, and glial fibrillary acidic protein in astrocytes. Type IV intermediate filaments are neurofilament proteins found in neurons. Type V intermediate filaments include the nuclear lamins A, B, and C and are associated with nuclear lamina of all cells. Spectrin heterodimers stabilize the plasma membrane and connect the membrane to actin.





104.














105. The common fibular (peroneal) nerve bifurcates into superficial and deep branches. The deep fibular nerve innervates all muscles of the anterior compartment of the leg. The lateral sural cutaneous is a cutaneous branch of the common fibular nerve. The superficial fibular nerve
emerges from the deep fascia and descends in the lateral compartment, where it innervates the fibularis (peroneus) longus and brevis muscles before dividing into median dorsal cutaneous and intermediate dorsal cutaneous nerves, which supply the distal third of the leg, dorsum of the
foot, and all the toes. The saphenous nerve [ the terminal branch of the common femoral nerve] distributes cutaneous branches to the anterior and medial aspects of the leg as well as to the dorsomedial aspect of the foot. The sural nerve follows the course of the lesser saphenous vein and becomes the lateral sural cutaneous nerve to supply the anterolateral aspect of the foot.



106. All of the listed choices are branches of the internal iliac artery. The inferior vesical artery in the male supplies the seminal vesicle, prostate, fundus of the bladder, distal ureter, and the vas deferens. In the female, the vaginal artery supplies the vagina, urinary bladder, and pelvic portion of the urethra. The obturator artery (Br of post division) gives off muscular and nutrient branches within the pelvis and then leaves the pelvis via the obturator canal to supply the thigh. The internal pudendal artery crosses the piriformis muscle, exits the pelvic cavity via the greater sciatic foramen, and enters the ischiorectal fossa via the lesser sciatic foramen. It supplies the external genitalia (penis and clitoris). The middle rectal artery supplies the inferior rectum and forms important anastomoses with other rectal arteries. The umbilical artery (Br of Ant division of Internal iliac artery) gives off the superior vesical artery in both sexes. Its distal portion degenerates to form the medial umbilical ligament.





107. The Celiac Plexus (Plexus Cœliacus; Solar Plexus) —The celiac plexus, the largest of the three sympathetic plexuses, is situated at the level of the upper part of the first lumbar vertebra and is composed of two large ganglia, the celiac ganglia, and a dense net-work of nerve fibers uniting them together. It surrounds the celiac artery and the root of the superior mesenteric artery. It lies behind the stomach and the omental bursa, in front of the crura of the diaphragm and the commencement of the abdominal aorta, and between the suprarenal glands. The plexus and the ganglia receive the greater and lesser splanchnic nerves of both sides and some filaments from the right vagus, and give off numerous secondary plexuses along the neighboring arteries

The Celiac Ganglia (ganglia cæliaca; semilunar ganglia) are two large irregularlyshaped masses having the appearance of lymph glands and placed one on either side of the middle line in front of the crura of the diaphragm close to the suprarenal glands, that on the right side being placed behind the inferior vena cava. The upper part of each ganglion is joined by the greater splanchnic nerve, while the lower part, which is segmented off and named the aorticorenal ganglion, receives the lesser splanchnic nerve and gives off the greater part of the renal plexus.
The secondary plexuses springing from or connected with the celiac plexus are the
Phrenic.

Renal.
Hepatic.

Spermatic.
Lienal.

Superior mesenteric.
Superior gastric.

Abdominal aortic.
Suprarenal.

Inferior mesenteric.




The Hypogastric Plexus (Plexus Hypogastricus)—The hypogastric plexus is situated in front of the last lumbar vertebra and the promontory of the sacrum, between the two common iliac arteries, and is formed by the union of numerous filaments, which descend on either side from the aortic plexus, and from the lumbar ganglia; it divides, below, into two lateral portions which are named the pelvic plexuses.

The Pelvic Plexuses—The pelvic plexuses supply the viscera of the pelvic cavity, and are situated at the sides of the rectum in the male, and at the sides of the rectum and vagina in the female. They are formed on either side by a continuation of the hypogastric plexus, by the sacral sympathetic efferent fibers from the second, third, and fourth sacral nerves, and by a few filaments from the first two sacral ganglia. At the points of junction of these nerves small ganglia are found. From these plexuses numerous branches are distributed to the viscera of the pelvis. They accompany the branches of the hypogastric artery.

The superior mesenteric plexus (plexus mesentericus superior) is a continuation of the lower part of the celiac plexus, receiving a branch from the junction of the right vagus nerve with the plexus. It surrounds the superior mesenteric artery, accompanies it into the mesentery, and divides into a number of secondary plexuses, which are distributed to all the parts supplied by the artery, viz., pancreatic branches to the pancreas; intestinal branches to the small intestine; and ileocolic, right colic, and middle colic branches, which supply the corresponding parts of the great intestine. The nerves composing this plexus are white in color and firm in texture; in the upper part of the plexus close to the origin of the superior mesenteric artery is a ganglion (ganglion mesentericum superius).


The inferior mesenteric plexus (plexus mesentericus inferior) is derived chiefly from the aortic plexus. It surrounds the inferior mesenteric artery, and divides into a number of secondary plexuses, which are distributed to all the parts supplied by the artery, viz., the left colic and sigmoid plexuses, which supply the descending and sigmoid parts of the colon; and the superior hemorrhoidal plexus, which supplies the rectum and joins in the pelvis with branches from the pelvic plexuses.



The Hypogastric Plexus (Plexus Hypogastricus)—The hypogastric plexus is situated in front of the last lumbar vertebra and the promontory of the sacrum, between the two common iliac arteries, and is formed by the union of numerous filaments, which descend on either side from the aortic plexus, and from the lumbar ganglia; it divides, below, into two lateral portions which are named the pelvic plexuses.

The superior gastric plexus (plexus gastricus superior; gastric or coronary plexus) accompanies the left gastric artery along the lesser curvature of the stomach, and joins with branches from the left vagus.

The suprarenal plexus (plexus suprarenalis) is formed by branches from the celiac plexus, from the celiac ganglion, and from the phrenic and greater splanchnic nerves, a ganglion being formed at the point of junction with the latter nerve. The plexus supplies the suprarenal gland, being distributed chiefly to its medullary portion; its branches are remarkable for their large size in comparison with that of the organ they supply.

The renal plexus (plexus renalis) is formed by filaments from the celiac plexus, the aorticorenal ganglion, and the aortic plexus. It is joined also by the smallest splanchnic nerve. The nerves from these sources, fifteen or twenty in number, have a few ganglia developed upon them. They accompany the branches of the renal artery into the kidney; some filaments are distributed to the spermatic plexus and, on the right side, to the inferior vena cava.

The spermatic plexus (plexus spermaticus) is derived from the renal plexus, receiving branches from the aortic plexus. It accompanies the internal spermatic artery to the testis. In the female, the ovarian plexus (plexus arteriæ ovaricæ) arises from the renal plexus, and is distributed to the ovary, and fundus of the uterus.




108. Preganglionic parasympathetic neurons to the lower colon arise from the spinal cord at sacral levels two to four and reach the wall of the colon via pelvic splanchnic nerves. The nucleus ambiguus is the source of preganglionic parasympathetic neurons that innervate the heart via the vagus nerve and cardiac plexus. Neurons arising in the cervical intermediolateral cell column are sympathetic preganglionics. Preganglionic parasympathetic neurons arising from the motor nucleus of the vagus innervate the upper GI tract. Neurons arising from the ventral horn are primary somatic motor neurons to skeletal muscle.

Sensation produced by distention of the rectum travels along the pelvic splanchnic nerves to sacral
levels S2–S4. Fecal continence is affected by nerves from the S2–S4 segments of the spinal cord. The principal effector, the puborectalis portion of the levator ani muscle, is innervated by somatic twigs from the sacral plexus. The external anal sphincter is controlled by the pudendal nerve, which also carries pain sensation associated with external hemorrhoids. The lumbar and sacral sympathetic chain would provide motor innervation to the rectum. The vagus nerve does not innervate the rectum.


109. The lower thoracic and upper lumbar portion of the spinal cord tend to receive a single major
radicular artery (of Adamkiewicz), which supplies blood to the anterior longitudinally running spinal artery. The anterior spinal artery mainly supplies the anterior two-thirds of the spinal cord in this region, which includes motor neurons that control the lower limbs. Because the metabolic needs of the spinal cord nerves are so great, the lack of blood during the surgery can lead to nerve cell death and thus paraplegia. Both muscle and peripheral nerves generally can survive the temporary disruption in blood flow. A process of cooling the spinal cord, by perfusing ice cold saline into the extradural space (called epidural cooling), is often performed to reduce the metabolic needs of the spinal nerves, thus often preventing central nervous system cell death during the surgical procedure. Muscles and nerves of the lower limb can survive reduced blood flow for an hour.





110. The lateral umbilical folds are produced by the underlying inferior epigastric arteries as they course from the external iliac artery in the inguinal region toward the rectus sheath. A direct inguinal hernia starts medial to the lateral ambilical fold and an indirect inguinal hernia starts lateral to the same fold. The medial umbilical folds are peritoneal elevations produced by the obliterated umbilical arteries. In the midline, the median umbilical ligament is formed by the underlying urachus, a remnant of the embryonic allantois. The Falx inguinalis represents infero-medial attachment of transversus abdominis with some fibers of internal abdominal oblique, also known as: conjoint tendon. The lateral border of the rectus sheath forms the medial edge of the inguinal triangle.




111. The kidney forms in three stages. The pronephric, metanephric, and mesonephric kidneys all form from the urogenital ridge, an extension of intermediate mesoderm into the coelomic cavity. Mesoderm derived from the somites gives rise to components of the axial skeleton and associated muscle and connective tissues. Splanchnic lateral plate mesoderm gives rise to the smooth muscle and connective tissue tunics of the abdominal viscera. Somatic lateral plate mesoderm contributes substantially to the skeleton, connective tissue, and muscle mass of the appendages. Neural crest forms the sensory and sympathetic chain ganglia and other structures.




112. Abdominal Aorta & its branches:


The celiac artery (a. cæliaca; celiac axis) (Figs. 532, 533) is a short thick trunk, about 1.25 cm. in length, which arises from the front of the aorta, just below the aortic hiatus of the diaphragm, and, passing nearly horizontally forward, divides into three large branches, the left gastric, the hepatic, and the splenic; it occasionally gives off one of the inferior phrenic arteries.

Relations.—The celiac artery is covered by the lesser omentum. On the right side it is in relation with the right celiac ganglion and the caudate process of the liver; on the left side, with the left celiac ganglion and the cardiac end of the stomach. Below, it is in relation to the upper border of the pancreas, and the lienal vein.

1.The Left Gastric Artery (a. gastrica sinistra; gastric or coronary artery), the smallest of the three branches of the celiac artery, passes upward and to the left, posterior to the omental bursa, to the cardiac orifice of the stomach. Here it distributes branches to the esophagus, which anastomose with the aortic esophageal arteries; others supply the cardiac part of the stomach, anastomosing with branches of the lienal artery. It then runs from left to right, along the lesser curvature of the stomach to the pylorus, between the layers of the lesser omentum; it gives branches to both surfaces of the stomach and anastomoses with the right gastric artery.
2.2. The Hepatic Artery (a. hepatica) in the adult is intermediate in size between the left gastric and lienal; in the fetus, it is the largest of the three branches of the celiac artery. It is first directed forward and to the right, to the upper margin of the superior part of the duodenum, forming the lower boundary of the epiploic foramen (foramen of Winslow). It then crosses the portal vein anteriorly and ascends between the layers of the lesser omentum, and in front of the epiploic foramen, to the porta hepatis, where it divides into two branches, right and left, which supply the corresponding lobes of the liver, accompanying the ramifications of the portal vein and hepatic ducts. The hepatic artery, in its course along the right border of the lesser omentum, is in relation with the common bile-duct and portal vein, the duct lying to the right of the artery, and the vein behind.

Its branches are:

Right Gastric.

Gastroduodenal
Right Gastroepiploic.

Superior Pancreaticoduodenal.
Cystic.



The right gastric artery (a. gastrica dextra; pyloric artery) arises from the hepatic, above the pylorus, descends to the pyloric end of the stomach, and passes from right to left along its lesser curvature, supplying it with branches, and anastomosing with the left gastric artery.

The gastroduodenal artery (a. gastroduodenalis) (Fig. 533) is a short but large branch, which descends, near the pylorus, between the superior part of the duodenum and the neck of the pancreas, and divides at the lower border of the duodenum into two branches, the right gastroepiploic and the superior pancreaticoduodenal. Previous to its division it gives off two or three small branches to the pyloric end of the stomach and to the pancreas.

The right gastroepiploic artery (a. gastroepiploica dextra) runs from right to left along the greater curvature of the stomach, between the layers of the greater omentum, anastomosing with the left gastroepiploic branch of the lienal artery. Except at the pylorus where it is in contact with the stomach, it lies about a finger's breadth from the greater curvature. This vessel gives off numerous branches, some of which ascend to supply both surfaces of the stomach, while others descend to supply the greater omentum and anastomose with branches of the middle colic.

The superior pancreaticoduodenal artery (a. pancreaticoduodenalis superior) descends between the contiguous margins of the duodenum and pancreas. It supplies both these organs, and anastomoses with the inferior pancreaticoduodenal branch of the superior mesenteric artery, and with the pancreatic branches of the lienal artery.
The celiac artery and its branches; the stomach has been raised and the peritoneum removed.

The cystic artery (a. cystica) (Fig. 532), usually a branch of the right hepatic, passes downward and forward along the neck of the gall-bladder, and divides into two branches, one of which ramifies on the free surface, the other on the attached surface of the gall-bladder.

1.The Lienal or Splenic Artery (a. lienalis), the largest branch of the celiac artery, is remarkable for the tortuosity of its course. It passes horizontally to the left side, behind the stomach and the omental bursa of the peritoneum, and along the upper border of the pancreas, accompanied by the lienal vein, which lies below it; it crosses in front of the upper part of the left kidney, and, on arriving near the spleen, divides into branches, some of which enter the hilus of that organ between the two layers of the phrenicolienal ligament to be distributed to the tissues of the spleen; some are given to the pancreas, while others pass to the greater curvature of the stomach between the layers of the gastrolienal ligament.
Its branches are:
Pancreatic.

Short Gastric.

Left Gastroepiploic.


The pancreatic branches (rami pancreatici) are numerous small vessels derived from the lienal as it runs behind the upper border of the pancreas, supplying its body and tail. One of these, larger than the rest, is sometimes given off near the tail of the pancreas; it runs from left to right near the posterior surface of the gland, following the course of the pancreatic duct, and is called the arteria pancreatica magna. These vessels anastomose with the pancreatic branches of the pancreaticoduodenal and superior mesenteric arteries.

The superior mesenteric artery and its branches
The short gastric arteries (aa. gastricæ breves; vasa brevia) consist of from five to seven small branches, which arise from the end of the lienal artery, and from its terminal divisions. They pass from left to right, between the layers of the gastrolienal ligament, and are distributed to the greater curvature of the stomach, anastomosing with branches of the left gastric and left gastroepiploic arteries.

The left gastroepiploic artery (a. gastroepiploica sinistra) the largest branch of the lienal, runs from left to right about a finger’s breadth or more from the greater curvature of the stomach, between the layers of the greater omentum, and anastomoses with the right gastroepiploic. In its course it distributes several ascending branches to both surfaces of the stomach; others descend to supply the greater omentum and anastomose with branches of the middle colic.

The superior mesenteric artery (a. mesenterica superior) (Fig. 534) is a large vessel which supplies the whole length of the small intestine, except the superior part of the duodenum; it also supplies the cecum and the ascending part of the colon and about one-half of the transverse part of the colon. It arises from the front of the aorta, about 1.25 cm. below the celiac artery, and is crossed at its origin by the lienal vein and the neck of the pancreas. It passes downward and forward, anterior to the processus uncinatus of the head of the pancreas and inferior part of the duodenum, and descends between the layers of the mesentery to the right iliac fossa, where, considerably diminished in size, it anastomoses with one of its own branches, viz., the ileocolic. In its course it crosses in front of the inferior vena cava, the right ureter and Psoas major, and forms an arch, the convexity of which is directed foward and downward to the left side, the concavity backward and upward to the right. It is accompanied by the superior mesenteric vein, which lies to its right side, and it is surrounded by the superior mesenteric plexus of nerves.
Branches.—Its branches are:
Inferior Pancreaticoduodenal.

Ileocolic.
Intestinal.

Right Colic.
Middle Colic.

The Inferior Pancreaticoduodenal Artery (a. pancreaticoduodenalis inferior) is given off from the superior mesenteric or from its first intestinal branch, opposite the upper border of the inferior part of the duodenum. It courses to the right between the head of the pancreas and duodenum, and then ascends to anastomose with the superior pancreaticoduodenal artery. It distributes branches to the head of the pancreas and to the descending and inferior parts of the duodenum.

The Intestinal Arteries (aa. intestinales; vasa intestini tenuis) arise from the convex side of the superior mesenteric artery. They are usually from twelve to fifteen in number, and are distributed to the jejunum and ileum. They run nearly parallel with one another between the layers of the mesentery, each vessel dividing into two branches, which unite with adjacent branches, forming a series of arches, the convexities of which are directed toward the intestine (Fig. 535). From this first set of arches branches arise, which unite with similar branches from above and below and thus a second series of arches is formed; from the lower branches of the artery, a third, a fourth, or even a fifth series of arches may be formed, diminishing in size the nearer they approach the intestine. In the short, upper part of the mesentery only one set of arches exists, but as the depth of the mesentery increases, second, third, fourth, or even fifth groups are developed. From the terminal arches numerous small straight vessels arise which encircle the intestine, upon which they are distributed, ramifying between its coats. From the intestinal arteries small branches are given off to the lymph glands and other structures between the layers of the mesentery.

The Ileocolic Artery (a. ileocolica) is the lowest branch arising from the concavity of the superior mesenteric artery. It passes downward and to the right behind the peritoneum toward the right iliac fossa, where it divides into a superior and an inferior branch; the inferior anastomoses with the end of the superior mesenteric artery, the superior with the right colic artery.

The inferior branch of the ileocolic runs toward the upper border of the ileocolic junction and supplies the following branches (Fig. 536):
(a) colic, which pass upward on the ascending colon; (b) anterior and posterior cecal, which are distributed to the front and back of the cecum; (c) an appendicular artery, which descends behind the termination of the ileum and enters the mesenteriole of the vermiform process; it runs near the free margin of this mesenteriole and ends in branches which supply the vermiform process; and (d) ileal, which run upward and to the left on the lower part of the ileum, and anastomose with the termination of the superior mesenteric.



The Right Colic Artery (a. colica dextra) arises from about the middle of the concavity of the superior mesenteric artery, or from a stem common to it and the ileocolic. It passes to the right behind the peritoneum, and in front of the right internal spermatic or ovarian vessels, the right ureter and the Psoas major, toward the middle of the ascending colon; sometimes the vessel lies at a higher level, and crosses the descending part of the duodenum and the lower end of the right kidney. At the colon it divides into a descending branch, which anastomoses with the ileocolic, and an ascending branch, which anastomoses with the middle colic. These branches form arches, from the convexity of which vessels are distributed to the ascending colon.

The inferior mesenteric artery and its branches.
The Middle Colic Artery (a. colica media) arises from the superior mesenteric just below the pancreas and, passing downward and forward between the layers of the transverse mesocolon, divides into two branches, right and left; the former anastomoses with the right colic; the latter with the left colic, a branch of the inferior mesenteric. The arches thus formed are placed about two fingers’ breadth from the transverse colon, to which they distribute branches.

The inferior mesenteric artery (a. mesenterica inferior) (Fig. 537) supplies the left half of the transverse part of the colon, the whole of the descending and iliac parts of the colon, the sigmoid colon, and the greater part of the rectum. It is smaller than the superior mesenteric, and arises from the aorta, about 3 or 4 cm. above its division into the common iliacs and close to the lower border of the inferior part of the duodenum. It passes downward posterior to the peritoneum, lying at first anterior to and then on the left side of the aorta. It crosses the left common iliac artery and is continued into the lesser pelvis under the name of the superior hemorrhoidal artery, which descends between the two layers of the sigmoid mesocolon and ends on the upper part of the rectum.
Branches.—Its branches are:
Left Colic.

Sigmoid.

Superior Hemorrhoidal.


The Left Colic Artery (a. colica sinistra) runs to the left behind the peritoneum and in front of the Psoas major, and after a short, but variable, course divides into an ascending and a descending branch; the stem of the artery or its branches cross the left ureter and left internal spermatic vessels. The ascending branch crosses in front of the left kidney and ends, between the two layers of the transverse mesocolon, by anastomosing with the middle colic artery; the descending branch anastomoses with the highest sigmoid artery. From the arches formed by these anastomoses branches are distributed to the descending colon and the left part of the transverse colon.

The Sigmoid Arteries (aa. sigmoideæ) (Fig. 538), two or three in number, run obliquely downward and to the left behind the peritoneum and in front of the Psoas major, ureter, and internal spermatic vessels. Their branches supply the lower part of the descending colon, the iliac colon, and the sigmoid or pelvic colon; anastomosing above with the left colic, and below with the superior hemorrhoidal artery.

The Superior Hemorrhoidal Artery (a. hæmorrhoidalis superior) (Fig. 538), the continuation of the inferior mesenteric, descends into the pelvis between the layers of the mesentery of the sigmoid colon, crossing, in its course, the left common iliac vessels. It divides, opposite the third sacral vertebra, into two branches, which descend one on either side of the rectum, and about 10 or 12 cm. from the anus break up into several small branches. These pierce the muscular coat of the bowel and run downward, as straight vessels, placed at regular intervals from each other in the wall of the gut between its muscular and mucous coats, to the level of the Sphincter ani internus; here they form a series of loops around the lower end of the rectum, and communicate with the middle hemorrhoidal branches of the hypogastric, and with the inferior hemorrhoidal branches of the internal pudendal.

The middle suprarenal arteries (aa. suprarenales media; middle capsular arteries; suprarenal arteries) are two small vessels which arise, one from either side of the aorta, opposite the superior mesenteric artery. They pass lateralward and slightly upward, over the crura of the diaphragm, to the suprarenal glands, where they anastomose with suprarenal branches of the inferior phrenic and renal arteries. In the fetus these arteries are of large size.

The renal arteries (aa. renales) (Fig. 531), are two large trunks, which arise from the side of the aorta, immediately below the superior mesenteric artery. Each is directed across the crus of the diaphragm, so as to form nearly a right angle with the aorta. The right is longer than the left, on account of the position of the aorta; it passes behind the inferior vena cava, the right renal vein, the head of the pancreas, and the descending part of the duodenum. The left is somewhat higher than the right; it lies behind the left renal vein, the body of the pancreas and the lienal vein, and is crossed by the inferior mesenteric vein. Before reaching the hilus of the kidney, each artery divides into four or five branches; the greater number of these lie between the renal vein and ureter, the vein being in front, the ureter behind, but one or more branches are usually situated behind the ureter. Each vessel gives off some small inferior suprarenal branches to the suprarenal gland, the ureter, and the surrounding cellular tissue and muscles. One or two accessory renal arteries are frequently found, more especially on the left side they usually arise from the aorta, and may come off above or below the main artery, the former being the more common position. Instead of entering the kidney at the hilus, they usually pierce the upper or lower part of the gland.

The internal spermatic arteries (aa. spermaticæ internæ; spermatic arteries) (Fig. 531) are distributed to the testes. They are two slender vessels of considerable length, and arise from the front of the aorta a little below the renal arteries. Each passes obliquely downward and lateralward behind the peritoneum, resting on the Psoas major, the right spermatic lying in front of the inferior vena cava and behind the middle colic and ileocolic arteries and the terminal part of the ileum, the left behind the left colic and sigmoid arteries and the iliac colon. Each crosses obliquely over the ureter and the lower part of the external iliac artery to reach the abdominal inguinal ring, through which it passes, and accompanies the other constituents of the spermatic cord along the inguinal canal to the scrotum, where it becomes tortuous, and divides into several branches. Two or three of these accompany the ductus deferens, and supply the epididymis, anastomosing with the artery of the ductus deferens; others pierce the back part of the tunica albuginea, and supply the substance of the testis. The internal spermatic artery supplies one or two small branches to the ureter, and in the inguinal canal gives one or two twigs to the Cremaster.

Sigmoid colon and rectum, showing distribution of branches of inferior mesenteric artery and their anastomoses

The ovarian arteries (aa. ovaricæ) are the corresponding arteries in the female to the internal spermatic in the male. They supply the ovaries, are shorter than the internal spermatics, and do not pass out of the abdominal cavity. The origin and course of the first part of each artery are the same as those of the internal spermatic, but on arriving at the upper opening of the lesser pelvis the ovarian artery passes inward, between the two layers of the ovariopelvic ligament and of the broad ligament of the uterus, to be distributed to the ovary. Small branches are given to the ureter and the uterine tube, and one passes on to the side of the uterus, and unites with the uterine artery. Other offsets are continued on the round ligament of the uterus, through the inguinal canal, to the integument of the labium majus and groin.

At an early period of fetal life, when the testes or ovaries lie by the side of the vertebral column, below the kidneys, the internal spermatic or ovarian arteries are short; but with the descent of these organs into the scrotum or lesser pelvis, the arteries are gradually lengthened.

The inferior phrenic arteries (aa. phrenicæ inferiores) (Fig. 531) are two small vessels, which supply the diaphragm but present much variety in their origin. They may arise separately from the front of the aorta, immediately above the celiac artery, or by a common trunk, which may spring either from the aorta or from the celiac artery. Sometimes one is derived from the aorta, and the other from one of the renal arteries; they rarely arise as separate vessels from the aorta. They diverge from one another across the crura of the diaphragm, and then run obliquely upward and lateralward upon its under surface. The left phrenic passes behind the esophagus, and runs forward on the left side of the esophageal hiatus. The right phrenic passes behind the inferior vena cava, and along the right side of the foramen which transmits that vein. Near the back part of the central tendon each vessel divides into a medial and a lateral branch. The medial branch curves forward, and anastomoses with its fellow of the opposite side, and with the musculophrenic and pericardiacophrenic arteries. The lateral branch passes toward the side of the thorax, and anastomoses with the lower intercostal arteries, and with the musculophrenic. The lateral branch of the right phrenic gives off a few vessels to the inferior vena cava; and the left one, some branches to the esophagus. Each vessel gives off superior suprarenal branches to the suprarenal gland of its own side. The spleen and the liver also receive a few twigs from the left and right vessels respectively.

The lumbar arteries (aa. lumbales) are in series with the intercostals. They are usually four in number on either side, and arise from the back of the aorta, opposite the bodies of the upper four lumbar vertebræ. A fifth pair, small in size, is occasionally present: they arise from the middle sacral artery. They run lateralward and backward on the bodies of the lumbar vertebræ, behind the sympathetic trunk, to the intervals between the adjacent transverse processes, and are then continued into the abdominal wall. The arteries of the right side pass behind the inferior vena cava, and the upper two on each side run behind the corresponding crus of the diaphragm. The arteries of both sides pass beneath the tendinous arches which give origin to the Psoas major, and are then continued behind this muscle and the lumbar plexus. They now cross the Quadratus lumborum, the upper three arteries running behind, the last usually in front of the muscle. At the lateral border of the Quadratus lumborum they pierce the posterior aponeurosis of the Transversus abdominis and are carried forward between this muscle and the Obliquus internus. They anastomose with the lower intercostal, the subcostal, the iliolumbar, the deep iliac circumflex, and the inferior epigastric arteries.
Branches.—In the interval between the adjacent transverse processes each lumbar artery gives off a posterior ramus which is continued backward between the transverse processes and is distributed to the muscles and skin of the back; it furnishes a spinal branch which enters the vertebral canal and is distributed in a manner similar to the spinal branches of the posterior rami of the intercostal arteries (page 601). Muscular branches are supplied from each lumbar artery and from its posterior ramus to the neighboring muscles.

The middle sacral artery (a. sacralis media) (Fig. 531) is a small vessel, which arises from the back of the aorta, a little above its bifurcation. It descends in the middle line in front of the fourth and fifth lumbar vertebræ, the sacrum and coccyx, and ends in the glomus coccygeum (coccygeal gland). From it, minute branches are said to pass to the posterior surface of the rectum. On the last lumbar vertebra it anastomoses with the lumbar branch of the iliolumbar artery; in front of the sacrum it anastomoses with the lateral sacral arteries, and sends offsets into the anterior sacral foramina. It is crossed by the left common iliac vein, and is accompanied by a pair of venæ comitantes; these unite to form a single vessel, which opens into the left common iliac vein.
The arteries of the pelvis





113. The rectum receives blood from three different arteries, which come from three different major branches: superior rectal artery off the inferior mesenteric artery; middle rectal artery off the internal iliac artery, and inferior rectal artery off the internal pudendal artery. There are also three sets of veins: superior rectal veins, which drain into the hepatic portal system; middle rectal veins, which drain into the internal iliac veins (part of the systemic venous system); and inferior rectal veins, which drain into internal pudendal veins (also part of the systemic venous system). Because the internal rectal venous plexus is a potential site of portal-systemic anastomoses, internal hemorrhoids may be an indication of liver pathology.

114. The diaphragm possesses three principal hiatuses shown in the diagram accompanying the question: the hiatus for the inferior vena cava(a), the esophageal hiatus(c), and the aortic hiatus (e). Potential diaphragmatic developmental defects include the foramen of Morgagni (b), just lateral to the xiphoid attachment of the diaphragm, and the pleuroperitoneal canal of Bochdalek (d), which is the most common site for congenital hernias.
The inferior vena cava and frequently small branches of the right phrenic nerve pass through a hiatus (A) slightly to the right of the midline at the T8 level. The left phrenic nerve usually passes through the central tendon of the diaphragm on the left side to innervate the left hemidiaphragm from below. The esophageal hiatus (C) just to the left of the midline at the T10 level transmits the esophagus, the left and right vagus nerves, and the esophageal branches of the left gastric artery and vein. An acquired hiatal hernia usually is the consequence of a short esophagus or of a weakened esophageal hiatus. The two diaphragmatic crura are joined superiorly by the median arcuate ligament to form an opening (E) at the T12 level. The aortic hiatus transmits the aorta, thoracic duct, and a continuation of the azygos vein into the abdomen. The splanchnic nerves penetrate the crura on each side of the aortic hiatus to reach the abdomen.



115. Risk factors for the development of an abdominal aortic aneurysm include hypertension, excessive weight and smoking. Males are about five times more likely to have an aortic aneurysm than females. About 5% of men over 60 years of age have abdominal aortic aneurysms. Ninety percent of the time abdominal aortic aneurysms develop inferior to the renal arteries. About two-third of the time they extend inferiorly to include one of the common iliac arteries. (What blood vessel comes off the aorta inferior to the renal arteries and superior to the bifurcation into common iliac arteries? Answer: gonadal and inferior mesenteric arteries.) Despite the retroperitoneal location of the abdominal aorta, the high-pressure in the vessel typically makes ruptures of abdominal aortic aneurysms fatal. Blood fills the peritoneal cavity and the individual bleeds to death. If discovered prior to rupture they are typically repaired if greater than about 5.5 cm in diameter. Currently they tend to be repaired intravascularly by placing a 6-inch Dacron tube with metal-mesh cylinder into the aorta via the femoral artery. Anecdotally, abdominal aortic aneurysms have been known to rupture with straining, such as during defecation.


116. The Ciliary Ganglion (ophthalmic or lenticular ganglion) (Figs. 775, 777).—The ciliary ganglion is a small, sympathetic ganglion, of a reddish-gray color, and about the size of a pin’s head; it is situated at the back part of the orbit, in some loose fat between the optic nerve and the Rectus lateralis muscle, lying generally on the lateral side of the ophthalmic artery.
Its roots are three in number, and enter its posterior border. One, the long or sensory root, is derived from the nasociliary nerve, and joins its postero-superior angle. The second, the short or motor root, is a thick nerve (occasionally divided into two parts) derived from the branch of the oculomotor nerve to the Obliquus inferior, and connected with the postero-inferior angle of the ganglion. The motor root is supposed to contain sympathetic efferent fibers (preganglionic fibers) from the nucleus of the third nerve in the mid-brain to the ciliary ganglion where they form synapses with neurons whose fibers (postganglionic) pass to the Ciliary muscle and to Sphincter muscle of the pupil. The third, the sympathetic root, is a slender filament from the cavernous plexus of the sympathetic; it is frequently blended with the long root. According to Tiedemann, the ciliary ganglion receives a twig of communication from the sphenopalatine ganglion.
Its branches are the short ciliary nerves. These are delicate filaments, from six to ten in number, which arise from the forepart of the ganglion in two bundles connected with its superior and inferior angles; the lower bundle is the larger. They run forward with the ciliary arteries in a wavy course, one set above and the other below the optic nerve, and are accompanied by the long ciliary nerves from the nasociliary. They pierce the sclera at the back part of the bulb of the eye, pass forward in delicate grooves on the inner surface of the sclera, and are distributed to the Ciliaris muscle, iris, and cornea. Tiedemann has described a small branch as penetrating the optic nerve with the arteria centralis retinæ.


Distribution of the maxillary and mandibular nerves, and the submaxillary ganglion





Nerves of the orbit, and the ciliary ganglion. Side view
Nerves of the orbit. Seen from above.

117. There are four blood vessels that supply blood to this area: ( Kiesselbach’s area)- 1) anterior ethmoid artery (a branch off the ophthalmic artery); 2)sphenopalatine artery (a branch off the maxillary artery that came through the sphenopalatine foramen; 3) greater palatine artery (a branch also off the maxillary artery, but has run through both the greater foramen and the incisive foramen to get to the nose); and 4) septal branch artery (a branch off the superior labial artery which comes off the facial artery). While the lay press often suggests holding the bridge of the nose, this would only block blood within the infratrochlear artery, which mainly serves the exterior dorsal surface of the nose. Holding both sides of the nose at the junction of the nasal bones with the lateral nasal cartilages would tend to block blood flow within the external branch of the anterior ethmoid. This might actually increase the blood coming from an artery in Kiesselbach’s area. Thus holding both sides of the upper lip between his fingers will cut off blood to the septal branch of the superior labial artery and apply pressure from the oral cavity over the incisive foramen would cut off blood coming from the greater palatine arteries. Note, it is difficult to stop blood within either the sphenoid palatine artery or anterior ethmoid arteries by applying any external pressure.



118. The superior ophthalmic vein drains the region of the paranasal sinuses and is directly connected with the cavernous sinus although blood flow is normally away from the brain. The pterygoid venous plexus (answer a) communicates with the cavernous sinus via the ophthalmic veins. The frontal emissary vein (answerc) communicates with the superior sagittal sinus via the foramen cecum. The basilar venous plexus (answer d) communicates with the inferior petrosal sinus. The parietal emissary vein (answer e) also communicates with the superior sagittal sinus.



119. A lesion of the spinal canal that compresses the ventral commissure (syringomyelia) would interrupt ascending fibers crossing there, but would not interfere with already crossed fibers ascending in the lateral spinothalamic tracts. Pain and temperature sensation above and below the level of the cord lesion would be preserved. The cell bodies of first-order afferent (sensory) neurons are located in the dorsal root ganglia. Their central processes enter the spinal cord and ascend one segment before synapsing with a second-order neuron in the dorsal horn. The central processes of second-order neurons cross in the ventral white commissure to the opposite side of the cord and ascend in the lateral spinothalamic tract to the ventral posterior lateral nucleus of the thalamus where they synapse with third-order neurons, which relay the message to cortical neurons of the postcentral gyrus of the parietal lobe. Lesions occurring unilaterally in a peripheral nerve would result in an ipsilateral deficit, whereas lesions in a crossed ascending pathway, in the thalamus, or in the cortex would result in contralateral deficits.



120. The palatine tonsil sits in the lateral wall of the oropharynx in the palatine arch posterior to the palatoglossus muscle and anterior to the palatopharyngeus muscle. The glossopharyngeal CN (IX) traverses the bed of the pelatine tonsil and carries afferent information to the brain regarding both general sensation and the special sense of taste from the posterior one-third of the tongue. The glossopharyngeal nerve is at risk for being cut during tonsillectomy. The ability to taste in the anterior two-thirds of the tongues not at risk because that information is carried by the lingual nerve, below the tongue. The ability to protrude your tongue is provided by innervation from the hypoglossal nerve, which innervates all the intrinsic tongue muscles and lies below the tongue and is not a risk. The mandibular division of the trigeminal CN (V3) does not course near the palatine arch and would not be at risk. It aids in the opening of the mouth and movement of the mandible from side-to-side.




121. The vertebral arteries usually arise from the subclavian arteries and ascend through the transverse foramina of the sixth to the first cervical vertebrae, but not the seventh. They enter the cranium through the foramen magnum after which they join to form the basilar artery. The basilar artery terminates by bifurcating into the posterior cerebral arteries. The hypoglossal nerves (CN XII) leave the cranium via the anterior condylar (hypoglossal) canals, whereas the posterior condylar canals transmit emissary veins. The vertebral arteries form the basilar artery which in turn feeds the posterior cerebral arteries.


122. The nucleus ambiguus, along with special visceral efferent (SVE) components of CN IX, X, and XI, is a column of lower motor neurons that innervate muscles of the pharynx, larynx, and palate. Damage to this nucleus results in loss of the gag reflex, difficulty in swallowing, and hoarseness. The lateral spinothalamic tract passes through the medulla and carries sensory information (pain and temperature) from the contralateral extremities and trunk. Similarly, the spinal tract of CN V carries pain and temperature sensation from the ipsilateral face. Descending sympathetic pathways course through the medulla to reach the intermediolateral cell column of the spinal gray matter. Damage to those fibers would result in loss of ability to dilate the pupil (meiosis), drooping eyelid (ptosis), and loss of sweating ipsilaterally (hemianhydrosis). Damage to nerve fibers passing to and from the cerebellum via the inferior cerebellar peduncle would result in intention tremor and lack of coordination.



123. The symptoms indicate that the lesion is at the level of the midbrain. The spastic paralysis, hyperreflexia, and positive Babinski reflect an upper motor neuron lesion. The corticobulbar and corticospinal tracts pass through the cerebral peduncles (basis pedunculi). Those originating in the right cortex will pass through the right peduncle and then cross to the contralateral side in the pyramidal decussation, resulting in left-side hemiplegia. It is of interest that the lower motor neurons innervating muscles of facial expression located below the eye receive upper motor neurons (corticobulbar tract) only from the contralateral cortex, whereas lower motor neurons innervating facial muscles above the eye (e.g., frontalis) receive input from both sides of the cortex. This explains why only the lower portion of the left face was paralyzed. The deficit in movement of the right eye indicates damage to the ipsilateral oculomotor nerve (CN III), which passes through the cerebral peduncle en route to the interpeduncular fossa. The “down and out” direction of the right eye is explained by unopposed contraction of the lateral rectus (CN VI) and superior oblique (CN IV) muscles. Because there were no sensory deficits, neither the thalamus nor sensory cortex were involved. The sensory tracts are arranged dorso-laterally in the midbrain and do not pass through the affected area.

124. The middle cerebral artery supplies a large portion of cerebral cortex, including portions of the frontal, parietal, and temporal lobes. These regions include the Broca’s and Wernicke’s areas and the precentral motor and postcentral sensory regions. Decreased blood flow in these regions explains the observed motor and sensory deficits. The anterior choroidal artery (answer a) is a branch of the internal carotid artery and is primarily distributed to the basal ganglia, hippocampus, and choroid plexus of the lateral ventricle. The posterior communicating artery (answer c) connects the internal carotid and vertebral arterial systems. The ophthalmic artery (answer d) is a direct branch of the internal carotid artery that enters the orbit along with the optic nerve. Although the anterior cerebral artery (answer e) has a wide distribution and anastomoses with branches of both the middle and posterior cerebral arteries, it primarily supplies medial and superior portions of the cortex.



125. The patient has facial paralysis, which indicates injury to the facial nerve. A problem in the internal auditory meatus usually affects hearing and balance. That the superior salivatory nucleus is normal is indicated by normal lacrimation. Hence, the lesion must be distal to the origin of the greater superficial nerve at the genu of the facial nerve. However, absence of hyperacusis indicates that the branch to the stapedius muscle is functioning normally, and this fact suggests that the lesion is close to the stylomastoid foramen. Loss of taste and diminished salivation locate the lesion proximal to the origin of the chorda tympani nerve. If the lesion were distal to the stylomastoid foramen, taste and salivation would have been normal, with facial paralysis as the only sign.



126. The tensor veli palatini and levator veli palatini, which arise from opposite sides of the auditory tube and base of the skull, insert into the soft palate. They are innervated, respectively, by the trigeminal nerve and the pharyngeal branch of the vagus nerve. The anterior palatoglossal arch, or anterior faucial pillar, is formed by the mucosa overlying the palatoglossal muscle. The posterior faucial pillar, or palatopharyngeal arch, likewise is formed by the palatopharyngeus muscle. The palatoglossus and palatopharyngeus muscles insert into the tongue and pharynx, respectively, and both are innervated by the pharyngeal branch of the vagus nerve (CN X). The salpingopharyngeus muscle, also innervated by the pharyngeal branch of the vagus nerve, arises from the torus tubarius at the opening of the auditory tube and inserts into the pharyngeal musculature. The superior and middle pharyngeal constrictors are innervated by the pharyngeal branch of the vagus nerve. The stylopharyngeus and styloglossus muscles originate from the styloid process and insert onto the lesser horn of the hyoid and into the tongue, respectively. They are innervated by the glossopharyngeal and hypoglossal nerves, respectively. Levator veli palatini and tensor veli palatini muscles are above the soft palate.


127. Spina bifida usually occurs near the caudal end of the neural tube. If there is no projection of the spinal cord or its covering through the bony defect, the condition is generally hidden (spina bifida occulta). However, it is termed spina bifida cystica when spinal material traverses the defect. In a meningocele, this is a saclike projection formed only by the meninges. If the projection contains neural material, it is a meningomyelocele, which is the case for this new born. Rachischisis is an extreme example of spina bifida cystica in which the neural folds underlying the vertebral defect fail to fuse, leaving an exposed neural plate. Anencephaly occurs when the cranial neural tube fails to fuse, thus resulting in lack of formation of forebrain structures and a portion of the enclosing cranium. Hydrocephaly results from blockage of the narrow passageways between the ventricles or between the ventricles and the subarachnoid space. Resultant swelling of the ventricles compresses the brain against the cranial vault and may cause serious mental deficits.



128. The styloglossus muscle is innervated by the hypoglossal nerve, which leaves the posterior cranial fossa by way of the anterior condylar canal.
In addition to the internal jugular vein, the jugular foramen contains the glossopharyngeal nerve (innervating the stylopharyngeus muscle), the vagus nerve (innervating palatal, pharyngeal, and laryngeal musculature), and the spinal accessory nerve [innervating the sternocleidomastoid and trapezius muscles].
The foramen ovale--It transmits the mandibular division of the trigeminal cranial nerve (CN V3), which is responsible for innervating the muscles of mastication. The patient would also likely suffer from loss of sensation along the mandible due to loss of sensation within the mandibular division of the trigeminal cranial nerve.
Weakened facial expressions wouldresult from compromising the stylomastoid foramen, which transmits part of the facial cranial nerve (CN VII).
Weakened ability to turn one’s head and shrug would be the result of damage to the accessory cranial nerve (CN XI), which exits the skull out the jugular foramen. The vagus cranial nerve (CN X) passes out the jugular foramen along with CN IX and XI.

The mandibular division of the trigeminal cranial nerve exits the skull through the foramen ovale. This division provides general sensation to the tongue (via the lingual nerve) and mandibular teeth (via the inferior alveolar nerve) and area over the mandible (via the buccal nerve). In addition the mandibular division of the trigeminal also innervates 8 muscles (the four muscles of mastication [temporalis, masseter, medial and lateral pterygoid muscles], two associated with the floor of the mouth [the mylohyoid and anterior belly of the digastric muscles] and two tensors [tensor tympani in the middle ear and tensor palati in the soft palate]). In addition preganglionic nerves from cranial nerve IX (via the lesser petrosal nerve) also pass through the foramen ovale on their way to stimulate the parotid salivary gland.
A tumor at the superior orbital fissure would affect eye movements and forehead sensation.
A tumor at the foramen rotundum would affect sensation under the eye on the face and maxillary teeth pain.
A tumor at the internal acoustic meatus would affect the facial nerve, hearing and balance.



129. The posterior cricoarytenoid muscles rotate the arytenoids laterally, which swings the vocal process of that cartilage outward to abduct the vocal cords and open the glottis. These are the sole abductors of the vocal folds. The lateral cricoarytenoid muscles and the unpaired transverse arytenoid muscle adduct the vocal folds. The thyroarytenoid muscle and its innermost portion, the vocalis muscle, act to tense the cords. The cricothyroid muscle lengthens the vocal cords.


130. The medial pterygoid muscle, which originates on the medial side of the lateral pterygoid plate, and the masseter muscle, which originates from the zygomatic arch, pass medially and laterally to the ramus of the mandible to form a sling about the angle of the mandible. These muscles are powerful elevators of the jaw. The muscle bundles of the anterior portion of the temporalis muscle run nearly vertically into the coronoid process of the mandible, acting as a jaw elevator.
The lateral pterygoid muscles run from the lateral side of the pterygoid plate and from the infratemporal fossa to the head of the mandible and the articular disk of the temporomandibular joint. Contraction of the lateral pterygoid muscles bilaterally protrudes the jaw. Unilateral contraction swings the jaw toward the opposite side.
The submental muscles, assisted by gravity, are the primary depressors of the jaw. These include the geniohyoid and mylohyoid muscles as well as the anterior belly of the digastric muscle, all of which function in conjunction with the infrahyoid strap muscles.
The posterior muscle bundles of the temporalis originate over the temporal region and pass nearly horizontally into the coronoid process of the mandible and, therefore, function as jaw retractors.
The buccinator muscle fibers are horizontal between the maxilla and mandible so that they cannot act on the mandible. This is a muscle of facial expression and assists mastication by working with the tongue to keep food on the occlusive surfaces of the teeth.

131. The ciliary ganglion receives preganglionic parasympathetic nerves from the Edinger-Westphal nucleus (cranial nerve III) that synapse in the ciliary ganglion. Those collections of postganglionic parasympathetic nerve cell bodies innervate the sphincter pupillae muscles, which constrict the pupil, closing it during bright-light conditions.
The geniculate ganglion houses the pseudounipolar cell bodies that receive taste information from the presulcal (anterior 2/3) of the tongue.
The otic ganglia is a parasympathetic ganglia that contains postganglionic parasympathetic nerves to stimulate the parotid salivary gland (preganglionic fibers from cranial nerve IX).
The pterygopalatine (sphenopalatine) ganglion contains postganglionic parasympathetic nerves to stimulate the lacrimal gland and glands of the nose and paranasal sinuses (preganglionic parasympathetic fibers from cranial nerve VII).
The semilunar (trigeminal) ganglion contains pseudounipolar cell bodies that receive pain, touch and temperature information from the face via the trigeminal nerve.
The submandibular ganglion contains postganglionic parasympathetic nerves to stimulate the submandibular and sublingual salivary glands (preganglionic parasympathetic fibers from cranial nerve VII).


132. An acoustic neuroma is a benign tumor of the Schwann cells that myelinate the vestibular portion of the VIII cranial nerve. Even though the tumor arises on the vestibular portion of the VIII cranial nerve, hearing loss is usually the first reported symptom. Tinnitus or ringing in the ear and headaches are also frequently reported. Normally, while the vestibular system may be disrupted (this patient reported a couple of days of dizziness) since the vestibular system on the right side is functioning normally and provides enough information once one is use to the loss. In this case the tumor has started to also affect the VII cranial nerve which controls the muscles of facial expression. Her symptoms go beyond conductive hearing loss [she is also young (53) to be suffering from conductive hearing loss].
Meniere’s disease is an excess accumulation of endolymph, which is usually associated with hearing loss, tinnitus and vertigo (all reported in this woman), but would not be associated with any facial paralysis

133. The inferior aspect of the genioglossus and the geniohyoid muscles contract in order to pull the hyoid bone forward allowing one to stick their tongue out of their mouth. All the intrinsic and three quarters of the extrinsic muscles of the tongue are innervated by the hypoglossal nerve (XII CN). Shortening the posterior belly of the digastric would worsen the problem by pulling the tongue up and back within the mouth.



134. The inner nuclear layer is responsible for the integration of data from adjacent photoreceptors. The retina consists of 10 layers:
1.The retinal pigment epithelium (RPE) is derived from the outer wall of the optic cup. The RPE functions in the phagocytosis of rod disks.
2.The photoreceptor layer consisting of the rods and cones is the outer layer of the retina.
3.The outer limiting membrane is formed by the junctional complexes between Müller’s cells and the membranes of photoreceptor cells.
4.The outer nuclear layer contains the nuclei of rod and cone cells and the surrounding cytoplasm (perikarya).
5.The outer plexiform layer contains rod and cone synapses as well as the cell processes of bipolar, horizontal, and photoreceptor cells.
6.The inner nuclear (bipolar) layer is composed of the nuclei and perikarya of the bipolar and amacrine cells as well as the nuclei of Müller’s cells.
7.The inner plexiform layer consists of amacrine cells dispersed between the processes of bipolar and ganglion cells. This layer is responsible for modulation of signals from the ganglion to the photoreceptor cells.
8.The ganglion cell layer contains the ganglion cells separated by the cytoplasm of astrocyte-like glia (Müller’s cells).
9.The nerve fiber layer consists of axons of the ganglion cells that will form the optic nerve.
10.The internal limiting membrane is located between the vitreous body and the retina.
The photoreceptors are of two types: rods and cones.
The nuclei of the rods and cones are found in the outer nuclear layer and extend across the outer limiting membrane in one direction and toward the outer plexiform layer in the other direction. The outer segment is the photon-sensitive portion of the rod and cone and contains membranous disks. Rhodopsin is composed of opsin and retinal. It is responsible for transduction of light (photons) into hyperpolarization of the cell membrane. Rhodopsin is present in the disks of the outer segment of the rod. The inner segment contains numerous mitochondria, glycogen, and protein synthetic apparatus. Rods are responsible for night vision, whereas the cones are responsible for color vision, which is best resolved at the fovea. The fovea, which is the center of the macula, is composed exclusively of cones and is the site of optimal resolution.
The choroid is a highly vascular layer that consists of three parts:
stroma, choriocapillaris, and Bruch’s membrane. Blood supply to the retina is derived from the choriocapillaris of the choroid. The sclera is a layer of relatively avascular dense connective tissue.


135. The scala tympani contains perilymph. Endolymph is similar to extracellular fluid (high K+, lowNa+). It is found in the utricle, saccule, semicircular canals, and scala media (cochlear duct), which are parts of the membranous labyrinth. Endolymph is synthesized by the highly vascular stria vascularis in the lateral wall of the scala media. The endolymphatic sac and duct are responsible for absorption of endolymph and the endocytosis of molecules from the endolymph.

136. The stria vascularis (D) is found in the lateral wall of the cochlear duct (scala media, I) and is responsible for the ionic composition of the endolymph. The organ of Corti is found within the cochlear duct and contains the hair cells that are responsible for transduction of the sound to a nerve impulse. It rests on the basilar membrane, which separates it from the epithelial lining of the tympanic cavity. The inner tunnel (H) of the organ of Corti separates the outer from the inner hair cells. The outer hair cells possess microvilli that are attached to the tectorial membrane (C). In contrast, the inner hair cells are unattached. Supportive cells include the phalangeal and pillar cells, which are not labeled on the figure. The spiral lamina is a bony structure that protrudes from the modiolus. The spiral limbus (B) is a connective tissue structure superior to the unattached edge of the spiral lamina. Along the outer wall of the canal of the organ of Corti is a thickened projection of periosteum known as the spiral ligament (F). The spiral ganglion is labeled A on the figure and contains bipolar cells. Peripheral processes of spiral ganglion cells reach the organ of Corti, whereas central processes terminate in nuclei located in the medulla. The internal spiral tunnel is labeled E in the figure.


137. The afferent arterioles contain the juxtaglomerular cells, modified arterial smooth muscle cells that produce renin, a major factor in blood pressure regulation. The thin loop of Henle is responsible for the production of the countercurrent multiplier, which allows the kidneys to produce a hyperosmotic medulla. The multiplier moves Na+ and Cl− out of the ascending limb (which is impermeable to water) and into the medullary interstitial fluid. Subsequently, the descending limb, which is permeable to water, takes up the Na+ and Cl− from the interstitium. The vasa rectae adjust their osmolarity to that of the medulla. The distal convoluted tubule (DCT) has the highest concentration of Na+, K+ -ATPase. The DCT pumps Na+ against a concentration gradient and is relatively impermeable to water, leading to the production of a hypotonic tubular fluid. The distal tubules empty into the connecting and collecting ducts, which are permeable to water under the regulation of ADH.ADH stimulation increases collecting duct permeability to water, allowing the production of hyperosmotic urine. Without ADH, the urine leaving the kidney would be hyposmotic. The collecting duct principal cells are the ADH responsive cells and contain fewer mitochondria and basal infoldings than occur in the cells of the distal convoluted tubule. Aldosterone also acts on the principal cells and secondarily on the thick ascending limb of Henle to increase reabsorption of Nacl.

138. In patients who have suffered from diabetes mellitus for many years glycation (nonenzymatic addition of sugar to proteins and other molecules) occurs in response to high blood glucose levels. The critical renal changes are the thickening of the glomerular basement membrane, elimination of the separation of laminae rarae and densa, loss of anionic repulsion of sugar groups, and obliteration of the filtration slits. These renal changes are known as nephrotic syndrome and lead to loss of selectivity of the filtration barrier and increased permeability to proteins. This causes the loss of protein from the blood to the urine (proteinuria). The liver adjusts to the proteinuria by producing more proteins (e.g., albumin). After continued proteinuria, the liver is unable to produce sufficient protein, which results in hypoalbuminemia leading to an overall decrease in osmotic pressure. Edema then occurs as fluid leaves the vasculature to enter the tissues. The movement of fluid from the vasculature to the tissues results in reduced plasma volume and decreased glomerular filtration rate [GFR]. The overall effect is further edema because of compensatory release of aldosterone coupled with reduced GFR and the already existing edema. Glycation results in the production of advanced glycation end-products (AGE, see figure on the next page), which alters the properties of the glomerular basement membrane. The cellular receptor for AGE is called RAGE and is a multiligand member of the immunoglobulin superfamily of cell surface molecules. In addition, to its role in diabetes, RAGE interacts with molecular pathways that regulate homeostasis, development, and inflammation and plays a role in pathological conditions such as Alzheimer’s disease and diabetes mellitus. Binding of a ligand to RAGE activates key cell signaling pathways, such as p21 (ras), MAP kinases, and NF-kappa-B (NFκB), thereby reprogramming cellular characteristics. The interactions and terminology are further complicated by the presence of ENRAGE (extracellular newly identified RAGE-binding protein) that interacts with cellular RAGE on endothelial cells, macrophages, lymphocytes, and other cells to activate proinflammatory mediators. Interactions between AGE, RAGE, and ENRAGE may explain many diabetic complica- tions including delayed wound healing. AGE derivatization is probably nonspecific and involves not only basal lamina-specific molecules, but also a vast array of extracellular and intracellular proteins (transcription factors, structural proteins, and membrane transporters). Hence, cellular coordination/communication becomes slowly but progressively hampered in the kidney and other organs.





139. Estrogen levels increase during the maturation of ovarian follicles, which results in a concomitant increase in ciliation and height of the oviductal lining cells. Increases in the number of cilia serve to facilitate movement of the ovum. Increased estrogen levels also decrease FSH levels and cause an LH surge. Elevated estrogen levels result in increased secretion of lytic enzymes, prostaglandins, plasminogen activator, and collagenase to facilitate the rupture of the ovarian wall and the release of the ovum and the attached corona radiata. Following ovulation, during the luteal phase of the cycle, the theca and granulosa cells are transformed into the corpus luteum under the influence of LH. Ovulation occurs near the middle of the menstrual cycle and is associated with an increase in basal body temperature that appears to be indirectly regulated by elevated estrogen levels, with IL-1 functioning as the endogenous pyrogen. Estrogen also upregulates FSH receptors on granulosa cell membranes and enhances synthesis and storage of glycogen in the vaginal epithelium.
Graafian follicle are granulosa cells that produce plasminogen activator and collagenase. Those molecules, along with plasmin and prostaglandins, facilitate the rupture of the ovarian follicle, leading to ovulation. The increase in LH in midcycle induces production of collagenase and plasminogen activator. Those proteases facilitate ovulation by initiating connective tissue remodeling, including the breakdown of the basement membrane between thecal and granulosa layers.
Development of ovarian follicles begins with a primordial follicle that consists of flattened follicular cells surrounding a primary oocyte. During the follicular phase, those cells undergo mitosis to form multiple granulosa layers (primary follicle) in response to elevated levels of FSH and LH from the anterior pituitary. A glycoproteinaceous coat surrounds the oocyte and is called the zona pellucida. The connective tissue around the follicle differentiates into two layers: theca externa (D) and theca interna (E). The theca externa is closest to the ovarian stroma and consists of a highly vascular connective tissue. The theca interna synthesizes androgens (e.g., androstenedione) in response to LH. Androgens are converted to estradiol by the action of an aromatase enzyme synthesized by the granulosa cells under the influence of FSH. Increased levels of estrogen from the ovary feed back to decrease FSH secretion from gonadotrophs in the anterior pituitary. Liquor folliculi is produced by the granulosa cells and is secreted between the cells. When cavities are first formed by the development of follicular fluid between the cells, the follicle is called secondary. When the antrum is completely formed, the follicle is called a mature (Graafian) follicle, and the antrum is completely filled with liquor folliculi. The granulosa cells form two structures. The corona radiata (C) represents those granulosa cells that remain attached to the zona pellucida. The cumulus oophorus (not labeled) represents those granulosa cells that surround the oocyte (B) and connect it to the wall.



140. Leydig cell (i.e., interstitial cell) is regulated by luteinizing hormone (LH), formerly known as interstitial cell–stimulating hormone (ICSH), secreted by gonadotrophs in the anterior pituitary. Leydig cells are located between seminiferous tubules and are responsible for the production of testosterone. The star delineates a cluster of Leydig cells, found between the seminiferous tubules. The Leydig cells normally synthesize and release testosterone in response to LH that is produced by gonadotrophs in the anterior pituitary. Leydig cell tumors develop in males between 20 and 60 years of age and produce androgens, estrogens, and sometimes glucocorticoids. Calcitonin is synthesized by C cells in the thyroid. Progesterone is synthesized by corpora lutea under the influence of LH. FSH (follicle- stimulating hormone) plays a key physiological role in both males (spermatogenesis) and females (regulation of follicular growth) and is produced and released by gonadotrophs in the anterior pituitary. FSH stimulates the maturation of ovarian follicles. FSH treatment of humans results in development of more than the usual number of mature follicles and an increased number of mature gametes. FSH is also critical for sperm production. It supports the function of Sertoli cells, which serve a nutritive role in sperm cell maturation. Parathyroid hormone is synthesized and released from the principal cells of the parathyroid gland.
Sertoli cells function in a nutritive and supportive role somewhat analogous to the glial cells of the CNS. The Sertoli cells produce inhibin, which feeds back on the anterior pituitary and hypothalamus to regulate FSH release. Testosterone binds to androgen-binding protein (ABP), which is synthesized by the Sertoli cells. Testosterone is necessary for maintenance of spermatogenesis as well as the male ducts and accessory glands. ABP is regulated by FSH, testosterone, and inhibin. Sertoli cells have extensive tight (occluding) junctions between them that form the blood-testis barrier. Sertoli cells communicate with adjacent cells through gap junctions and extend from outside the blood-testis barrier (basal portion) to luminal (apical portion). During spermatogenesis, preleptotene spermatocytes cross from the basal to the adluminal compartment across the zonula occludens between adjacent Sertoli cells. Each Sertoli cell is, therefore, associated with multiple spermatogenic cells. The testis is composed of seminiferous tubules containing a number of spermatogenic cells undergoing spermatogenesis and spermiogenesis. The cells labeled with the arrowheads are spermatogonia, the derivatives of the embryonic primordial germ cells. These cells comprise the basal layer and undergo mitosis (spermatocytogenesis) to form primary spermatocytes, which have distinctive clumped or coarse chromatin (marked by arrows). Secondary spermatocytes are formed during the first meiotic division and exist for only a short period of time because there is no lag period before entry into the second meiotic division that results in the for-
mation of spermatids. The spermatids begin as round structures and elongate with the formation of the flagellum. This last part of seminiferous tubule function is the differentiation of sperm from spermatids (spermiogenesis) and is complete with the release of mature sperm into the lumen
of the tubule.



141. Seventy percent of carcinomas of the prostate arise from the main (external gland), also known as the outer (peripheral) glands. The prostate consists of three parts: (1) a small mucosal (inner periurethral) gland, (2) a transition zone that consists of a submucosal (outer periurethral) gland, and (3) a peripheral portion known as the main, or external, gland. Because of the peripheral location, most prostatic carcinomas (primarily adenocarcinomas) remain undiagnosed until the later symptoms of back pain or blockage of the urethra are detected. Digital rectal examination can identify some tumors earlier. Benign prostatic hypertrophy, also known as benign nodular hyperplasia, occurs in the mucosal and submucosal glands, which are rarely sites of carcinoma. Benign hyperplasia causes urethral obstruction in its early stages because of its location in the mucosal and submucosal glands surrounding the urethra. The main gland is sensitive to androgens, whereas the periurethral glands are sensitive to androgens and estrogens. Acid phosphatase and prostatic-specific antigen (PSA) levels are used in the diagnosis of prostatic carcinoma and its metastasis. By definition, a carcinoma is ductal in origin. Carcinoma of the breast metastasizes to the brain, lungs, and bones. The easy access of tumor cells to the extensive axillary blood supply and lymphatic drainage facilitates the spread of the cancer into the blood and lymph supplies. Self-examination and mammography are urged in an attempt to increase early diagnosis, which has reduced mortality of this disease. Germ cell tumors of the testes (testicular neoplasms) are classified as seminomas (germinomas) of pure germ cells and more heterogeneous cell types (e.g.teratomas and embryonal carcinomas).



142. Seminal vesicle produces fructose, ascorbic acid, prostaglandins, and proteins responsible for semen coagulation. The seminal vesicle produces about 50% of the seminal fluid on a volume basis and comprises most of the ejaculate. The wall consists of smooth muscle and the mucosa of anastomosing “villus-like” folds. In comparison, the prostate is composed of 15 to 30 tubuloalveolar glands surrounded by fibromuscular tissue with concretions in the lumina. The prostate secretes a thin, opalescent fluid that contributes primarily to the first part of the ejaculate and includes acid phosphatase, spermine (a polyamine), fibrolysin, amylase, and zinc. Spermine oxidation results in the musky odor of semen, and fibrolysin is responsible for the liquefaction of semen after ejaculation. Acid phosphatase and prostatic-specific antigen are important for the diagnosis of metastases.
Epididymis functions in the storage, maturation, and phagocytosis of sperm. In addition, the epididymis is involved in the absorption of testicular fluid and the secretion of glycoproteins involved in the inhibition of capacitation. The epithelium of the epididymis is pseudostratified with stereocilia (long microvilli), and the wall contains extensive connective tissue.
The development of the testis from an indifferent gonad depends on the presence of the testis-determining factor, a gene on the short arm of the Y chromosome. During fetal development, the production of androgens by the developing testis results in masculinization of the indifferent gonadal ducts and the indifferent genitalia. In the absence of androgens, female genitalia and female ducts (vagina, oviducts, and uterus) develop. In the mature male, testosterone is required for the initiation and maintenance of spermatogenesis as well as the structural and functional integrity of the accessory glands and ducts of the


143. Patients with Graves’ disease produce autoantibodies to
TSH receptors. CD8+
-T cells are also generated against the TSH receptors,
leading to their destruction. The result is an increase in TSH produced by
the anterior pituitary with a concomitant increase in thyroid hormone pro-
duction [T4 (tetraiodothyronine, thyroxine) and T3 (tetraiodothyronine)]
from the thyroid. The elevated thyroid hormone secretion leads to the ner-
vousness, weight loss, and extreme mood changes experienced by the
patient.
The thyroid gland is shown in the photomicrograph and is most often
confused histologically with lactating mammary gland, which differs from
the thyroid in the presence of an elaborate duct system. The thyroid is
composed of follicles filled with colloidal material and surrounded by fol-
licular cells with a cuboidal-to-columnar epithelium. The C cells are found
outside the follicular cells and produce calcitonin, synthesized by the inter-
follicular “C” (parafollicular) cells derived embryologically from the ulti-
mobranchial bodies (fourth and possibly fifth pair of branchial pouches).
Calcitonin decreases elevated serum calcium levels by transiently inhibit-
ing osteoclastic activity through receptors on osteoclasts. In Graves’ disease
there are no autoantibodies to the C cells (answer a). Destruction of C cells
would lead to an absence of calcitonin and high serum calcium levels.
Autoantibodies to principal cells of the parathyroid (answer b) would lead
to decreased serum calcium levels as parathyroid hormone (PTH) synthe-
sis and secretion would be reduced. PTH increases osteoclastic resorption
and also stimulates Ca2+
uptake from the gut and Ca2+
reabsorption by
the kidneys. The thyroid gland is under the direct regulation of TSH
(thyrotropin) production by the anterior pituitary, which in turn is regu-
lated by TSH-releasing factor (TSH-RF) released from the hypothalamus.
TSH-RF is transported by the hypothalamic-hypophyseal (pituitary)-portal
system to the anterior pituitary. Autoantibodies to TSH-RF (answer c)
would result in elevated TSH and T3 and T4, but the receptors would be
located in the anterior pituitary on thyrotrophs. Autoantibodies to thy-
roglobulin and thyroid peroxidase result in Hashimoto’s thyroiditis
[answer d (see question 233)].
Asthenia is loss of strength and tachycardia is accelerated heart rate.
Pretibial myxedema presents as an orange-peel-like rash on the shins in
some patients with Graves’ disease.
The thyroid follicular epithelial cells import iodide and amino acids
from the capillary lumen. The follicular cells synthesize thyroglobulin from
352 Anatomy,Histology, and Cell Biology amino acids. When iodide enters the follicular cells, it undergoes oxida-
tion. Thyroglobulin is iodinated while in the colloid, and iodinated thy-
roglobulin (not the thyroid hormones) is the storage product in the thyroid
colloid. The thyroid follicular cells process iodinated thyroglobulin, and
the activity of lysosomes breaks down the colloid to form thyroxine (T4),
triiodothyronine (T3), diiodotyrosine (DIT), and monoiodotyrosine (MIT).
Most of the secretion of the human thyroid gland is composed of thyrox-
ine, although triiodothyronine is more potent.


144. The
neurohypophysis containing the Herring bodies is formed from neuroecto-
derm as an extension of the developing diencephalon. The pars nervosa
consists of pituicytes (supportive glia) and the Herring bodies, dilated
axons that originate in the supraoptic and paraventicular nuclei. These
nuclei produce oxytocin and vasopressin that are stored in the Herring
bodies.
Overall, the pituitary gland (hypophysis cerebri) is formed from two
types of ectoderm. An outgrowth of the oral ectoderm, Rathke’s pouch,
forms the structures that compose the adenohypophysis: pars distalis, pars
intermedia, and pars tuberalis. The pars distalis includes the classic histo-
logic cell types: chromophils (acidophils and basophils) and chromophobes
(acidophils and basophils that are depleted of secretory product). Aci-
dophils include: lactotrophs (prolactin), somatotrophs (growth hor-
mone); basophils include: corticotrophs (ACTH, α-lipotropin, β-MSH,
and α-endorphin), thyrotrophs (TSH), and gonadotrophs (FSH and LH).
The pars intermedia is also formed from the oral ectoderm, is rudimentary
in humans, and may produce preproopiomelanocortic peptide. The pars
tuberalis forms a collar around the pituitary stalk and is also derived from
the oral ectoderm. The pars nervosa (including Herring bodies) and the
remainder of the pituitary stalk (infundibular stem and median eminence)
are formed from a downgrowth of the diencephalon. The posterior pituitary
(pars nervosa and stalk) retains this close relationship with the brain (i.e.,
hypothalamus) throughout life.
The region labeled A is the posterior pituitary that stores oxytocin and
vasopressin in dilated axonal terminals. Overall, the pituitary is derived
from the ectoderm of the oral cavity (Rathke’s pouch) and the floor of the
diencephalon. The anterior (C) and intermediate (H) lobes and pars tuber-
alis (G) are derived from the oral cavity, whereas the remainder of the pitu-
itary [pars nervosa (A) and the pituitary stalk (D)] is derived from a
neuroepithelial origin. The cleft of Rathke’s pouch (B) represents the lumen
of the structure formed originally from the oral cavity. The pars distalis (C)
contains acidophils and basophils regulated by stimulatory and inhibitory
hormones produced by the hypothalamus. In the pars nervosa (A), the
major cell type present is the pituicyte, a supportive glial cell. Structure E is the
median eminence; F represents the cavity of the third ventricle.




145. Pancreatic exocrine tissue is found throughout
the pancreas with round aggregation of lighter staining cells forming the
islets of Langerhans. There are several endocrine cell types within the islets.
The more numerous (70% of total) B or β cells are centrally located and
secrete insulin that is secreted after a meal and results in a lowering of
blood sugar. The smaller population of A or α cells located at the periph-
ery of the islet (∗) secrete glucagon. Glucagon is secreted in response to low
blood sugar and raises blood sugar levels. A glucagonoma produces exces-
sive amounts of glucagon that results in hyperglycemia and diabetes. The
interaction of β and α cells is based on the blood supply. Blood entering the
islet initially bypasses the α cells. The result is that blood reaching the α
cells already contains insulin, which regulates glucagon production. The
absence of normal glucagon regulation by insulin is a further complication
in type I diabetes in which insulin is not produced. Other cell types [D (δ)
and F] are variable in location and secrete somatostatin and pancreatic
polypeptide, respectively. Somatostatin regulates insulin and glucagon
release, whereas pancreatic polypeptide appears to regulate exocrine pro-
tein and bicarbonate secretion. The exocrine portion of the pancreas con-
sists of acinar and ductal cells. The acinar cells are pyramidal in shape and
possess a very basophilic basal cytoplasm, indicating the presence of abun-
dant rough ER and an acidophilic apical cytoplasm due to the presence of
numerous secretory (zymogen) granules.


146. Addison’s
disease, in which there is a progressive destruction (hypotrophy) of the
adrenal cortex (zones A, B, and C). The result in the patient is asthenia
(lack of strength, overall weakness, and fatigue), anorexia, nausea, vom-
iting, weight loss, hypotension, and low blood sugar. The hyperpigmen-
tation results from elevated ACTH stimulation of melanocytes.
The
adrenal cortex originates from the intermediate mesoderm, whereas the
adrenal medulla forms from neural crest. Adrenocortical cells are under
the influence of corticotrophs in the anterior pituitary. Adrenocortical
cells import cholesterol and acetate and produce the hormones shown in
the table below. The zona glomerulosa (A) is found immediately beneath
the capsule (E) and is followed by the zona fasciculata (B) and zona retic-
ularis (C) as one moves toward the medulla (D). However, in all zones
the cells do not store appreciable quantities of hormones, there is an
absence of secretory granules, and the steroid hormones are released by
diffusion through the plasma membrane without use of the exocytotic
process used by most glands, including the adrenal medulla. The cells of
the adrenal medulla (D) may be considered as modified postganglionic
sympathetic neurons. Adrenal medullary cells synthesize and secrete nor-
epinephrine, epinephrine, and enkephalins in response to stimulation of
preganglionic sympathetic fibers that travel through the abdomen in the
splanchnic nerves and innervate the gland. The adrenal cortical hor-
mones are viewed as essential for life because of their regulation of
metabolism.




147. T4 (thyroxine) is the primary serum thyroid hormone and is produced only by the thyroid gland. In contrast, only about 20% of T3 (triiodothyronine) is produced by
the thyroid gland. T3 is formed in the liver and kidney by the action of a
specific enzyme, 5’-deiodinase enzyme that converts T4 to T3. That enzyme
also converts T4 to metabolically inactive thyroid hormone, rT3 (reverse
T3). T3 is three to five times more physiologically active than T4. Both T4
and T3 are bound to thyroxine-binding globulin (TBG), transthyretin, and
albumin (answer a), with only about 1% of free circulating hormone. Lev-
els of available binding proteins affect measurable levels of total T4 and T3.
When those binding proteins are found in high concentrations, total T4 and
T3 levels are also high, but free T4 and T3 values remain normal. The free
fractions of T4 and T3 are responsible for the feedback mechanism at the
level of the hypothalamus and the thyrotrophs in the anterior pituitary. T3
and T4 are regulated by TSH from the thyrotrophs


148. Mallory bodies are derived from keratin intermediate filaments within hepatocytes.
Hepatic stellate cells secrete the collagen that replaces normal liver parenchyma in cirrhosis. Kupffer cells are the macrophages of the liver.
Vimentin is the intermediate filament protein found in cells of mesenchymal origin; the liver and hepatocytes are epithelial in origin.
Desmin is the intermediate filament protein associated with muscle.



149. In the resting parietal cell, the pro-
ton pump (H+
,K+
-ATPase) is found in the tubulovesicle membranes that are
located intracellularly (answer a). The sequestration of the proton pump in
intracellular tubulovesicles in the resting state prohibits secretion. On acti-
vation of the parietal cell through Ca2+
and diacylglycerol second messen-
gers, the tubulovesicle membranes fuse with the plasma membrane by
exocytosis. Histamine (answer e), along with gastrin and acetylcholine,
activate the parietal cell. Na+
,K+
-ATPase located in the basal membrane, and
the chloride channel (answer b) of the apical plasma membrane maintain
the appropriate ionic gradients to facilitate acid secretion. Carbonic anhy-
drase, a cytoplasmic enzyme, catalyzes the formation of carbonic acid
(H2CO3) from carbon dioxide, which is the source of protons in the parietal
cell and other cell types, such as the osteoclast, that also depend on a pro-
ton pump (answer d). After dissipation of the stimulus (i.e., gastrin, acetyl-
choline, or histamine) or exposure to an H2 blocker, the parietal cell returns
to the resting state. This involves the recycling (endocytosis) of membrane
to reform the tubulovesicular arrangement within the cytoplasm.

150. Piercing of the tongue can result in complaints
of pain, numbness, and loss of taste when eating. The loss of taste is asso-
ciated with damage to the taste buds, which are shown in the photomicro-
graph. Taste from the anterior two-thirds of the tongue as shown in the
accompanying photomicrograph are innervated by the VIIth (facial) cranial
nerve. The Vth (trigeminal) cranial nerve (answer a) is responsible for
transmitting general sensation from the anterior two-thirds of the tongue.
The taste buds from the posterior one-third of the tongue are innervated by
the IXth (glossopharyngeal) cranial nerve (answer c) specifically by the chorda tympani. The Xth (vagus) cranial nerve (answer d) innervates taste
buds on the epiglottis and palate. The XIIth (hypoglossal) cranial nerve
innervates the intrinsic musculature of the tongue.


151. Hirschsprung’s disease (congenital megacolon) and Chagas’ disease have
different etiologies, but both inhibit intestinal motility by affecting the
myenteric (Auerbach’s) plexus located between the layers of the muscularis
externa (layer e) in the figure. The submucosal (Meissner’s) plexus is more
involved in regulation of lumenal size and, therefore, will affect defecation,
but will be less involved in peristalsis. Vascular smooth muscle, the mus-
cularis mucosa, and enteroendocrine cells do not play a major role in the
regulation of peristalsis, which is observed even after removal of the gut
and placement in a nutrient solution. Hirschsprung’s disease, also known
as aganglionic megacolon, results from failure of normal migration of
neural crest cells to the colon, resulting in an aganglionic segment.
Although both the myenteric and submucosal plexuses are affected, the pri-
mary regulator of intrinsic gut rhythmicity is the myenteric plexus. Chagas’
disease is caused by the protozoan Trypanosoma cruzi. Severe infection
results in extensive damage to the myenteric neurons.
The wall of the GI tract contains four layers: mucosa, submucosa,
muscularis externa, and serosa.



152. Sjögren’s syndrome, which like other autoimmune diseases (presence of ANA and RF), is much more common in women than men. The striated ducts resorb Na+ and secrete K+ from the isotonic saliva converting it to a hypotonic state.Na+ -independent chloride-bicarbonate anion exchangers appear to be involved in these processes by generating ion fluxes into the salivary secretion. The striated duct is the primary region for electrolyte transport in the salivary gland duct system. The primary secretion produced by the acinar cells is comprised of amylase, mucus, and ions in the same concentrations as those of the extracellular fluid. In the duct system, Na+ is actively absorbed from the lumen of the ducts, Cl− is passively absorbed [although the tight junctions between striated duct cells inhibit Cl− from following Na+]. HCO3− is secreted ; Ca2+ transport is not a factor (e). The resultis a hypotonic sodium and chloride concentration and a hypertonic potassium concentration.
The autonomic nervous system is the primary regulator of salivary gland function in contradistinction to the pancreas, which is regulated primarily by hormones [(cholecystokinin and secretin]. Parasympathetic fibers carry neural signals that originate in the salivatory nuclei of the medulla and pons. The sympathetic nervous system originates from the superior cervical ganglion of the sympathetic chain and stimulates acinar enzyme production. Elevated aldosterone levels affect the amount and ionic concentration of the saliva, resulting in decreased NaCl secretion and increased K+ concentration



153. Digestion of lipids occurs through the action of bile (from the liver and
bile duct) and lipase (from the pancreas). Bile serves to emulsify the lipid
to form micelles, whereas lipase breaks down the lipid from triglycerides to
fatty acids, glycerol, and monoglycerides (answers d and e). Those three
breakdown products diffuse freely across the microvilli to enter the apical
portion of the enterocyte by passive diffusion. Triglycerides are resynthe-
sized in the smooth endoplasmic reticulum. Proteins are synthesized in the
RER and are combined with sugar and lipid portions in the Golgi to form
glycoproteins and lipoproteins. Those two types of molecules form the cov-
erings of the triglyceride cores of the chylomicra. The chylomicra are
released at the basolateral membranes by exocytosis into the lacteals. From
the lacteals, the chylomicra travel into the cisterna chyli and eventually into
the venous system by way of the thoracic duct. Digestion of fat occurs to a
greater extent in the duodenum and jejunum than in the ileum.
Sugars are broken down by amylase in the oral cavity, with continued
digestion by brush border monosaccharidases. Proteins are broken down
by pepsinogen in the stomach with continued breakdown in the small
intestine by the enzymes of the pancreatic juice (e.g., trypsin, chy-
motrypsin, and carboxypeptidases). The products of protein digestion are
amino acids that are actively transported by transporters also located in the
brush border.


154.
The facial nerve (Figs. 788, 790) consists of a motor and a sensory part, the latter being frequently described under the name of the nervus intermedius (pars intermedii of Wrisberg)(Fig. 788). The two parts emerge at the lower border of the pons in the recess between the olive and the inferior peduncle, the motor part being the more medial, immediately to the lateral side of the sensory part is the acoustic nerve.
The motor part supplies somatic motor fibers to the muscles of the face, scalp, and auricle, the Buccinator and Platysma, the Stapedius, the Stylohyoideus, and posterior belly of the Digastricus; it also contains some sympathetic motor fibers which constitute the vasodilator nerves of the submaxillary and sublingual glands, and are conveyed through the chorda tympani nerve. These are preganglionic fibers of the sympathetic system and terminate in the submaxillary ganglion and small ganglia in the hilus of the submaxillary gland. From these ganglia postganglionic fibers are conveyed to these glands. The sensory part contains the fibers of taste for the anterior two-thirds of the tongue and a few somaticsensory fibers from the middle ear region. A few splanchnic sensory fibers are also present.
The motor root arises from a nucleus which lies deeply in the reticular formation of the lower part of the pons. This nucleus is situated above the nucleus ambiguus, behind the superior olivary nucleus, and medial to the spinal tract of the trigeminal nerve. From this origin the fibers pursue a curved course in the substance of the pons. They first pass backward and medialward toward the rhomboid fossa, and, reaching the posterior end of the nucleus of the abducent nerve, run upward close to the middle line beneath the colliculus fasciculus. At the anterior end of the nucleus of the abducent nerve they make a second bend, and run downward and forward through the pons to their point of emergence between the olive and the inferior peduncle.
The sensory root arises from the genicular ganglion, which is situated on the geniculum of the facial nerve in the facial canal, behind the hiatus of the canal. The cells of this ganglion are unipolar, and the single process divides in a T-shaped manner into central and peripheral branches. The central branches leave the trunk of the facial nerve in the internal acoustic meatus, and form the sensory root; the peripheral branches are continued into the chorda tympani and greater superficial petrosal nerves. Entering the brain at the lower border of the pons between the motor root and the acoustic nerve, the fibers of the sensory root pass into the substance of the medulla oblongata and end in the upper part of the terminal nucleus of the glossopharyngeal nerve and in the fasciculus solitarius.
From their superficial attachments to the brain, the two roots of the facial nerve pass lateralward and forward with the acoustic nerve to the internal acoustic meatus. In the meatus the motor root lies in a groove on the upper and anterior surface of the acoustic nerve, the sensory root being placed between them.
At the bottom of the meatus, the facial nerve enters the facial canal, which it traverses to its termination at the stylomastoid foramen. It is at first directed lateralward between the cochlea and vestibule toward the medial wall of the tympanic cavity; it then bends suddenly backward and arches downward behind the tympanic cavity to the stylomastoid foramen. The point where it changes its direction is named the geniculum; it presents a reddish gangliform swelling, the genicular ganglion (ganglion geniculi; geniculate ganglion; nucleus of the sensory root of the nerve)(Fig. 789). On emerging from the stylomastoid foramen, the facial nerve runs forward in the substance of the parotid gland, crosses the external carotid artery, and divides behind the ramus of the mandible into branches, from which numerous offsets are distributed over the side of the head, face, and upper part of the neck, supplying the superficial muscles in these regions. The branches and their offsets unite to form the parotid plexus.
Branches of Communication.—The branches of communication of the facial nerve may be arranged as follows:

In the internal acoustic meatus………………
With the acoustic nerve.

At the genicular ganglion……………………
With the sphenopalatine ganglion by the greater superficial petrosal nerve.

With the otic ganglion by a branch which joins the lesser superficial petrosal nerve.

With the sympathetic on the middle meningeal artery.

In the facial canal……………………………
With the auricular branch of the vagus.

At its exit from the stylomastoid foramen……
With the glossopharyngeal.

With the vagus.

With the great auricular.

With the auriculotemporal.

Behind the ear………………………………
With the lesser occipital.
On the face…………………………………
With the trigeminal.
In the neck…………………………………
With the cutaneous cervical.
In the internal acoustic meatus some minute filaments pass from the facial to the acoustic nerve.

The greater superficial petrosal nerve (large superficial petrosal nerve) arises from the genicular ganglion, and consists chiefly of sensory branches which are distributed to the mucous membrane of the soft palate; but it probably contains a few motor fibers which form the motor root of the sphenopalatine ganglion. It passes forward through the hiatus of the facial canal, and runs in a sulcus on the anterior surface of the petrous portion of the temporal bone beneath the semilunar ganglion, to the foramen lacerum. It receives a twig from the tympanic plexus, and in the foramen is joined by the deep petrosal, from the sympathetic plexus on the internal carotid artery, to form the nerve of the pterygoid canal which passes forward through the pterygoid canal and ends in the sphenopalatine ganglion. The genicular ganglion is connected with the otic ganglion by a branch which joins the lesser superficial petrosal nerve, and also with the sympathetic filaments accompanying the middle meningeal artery. According to Arnold, a twig passes back from the ganglion to the acoustic nerve. Just before the facial nerve emerges from the stylomastoid foramen, it generally receives a twig from the auricular branch of the vagus.
After its exit from the stylomastoid foramen, the facial nerve sends a twig to the glossopharyngeal, and communicates with the auricular branch of the vagus, with the great auricular nerve of the cervical plexus, with the auriculotemporal nerve in the parotid gland, and with the lesser occipital behind the ear; on the face with the terminal branches of the trigeminal, and in the neck with the cutaneous cervical nerve.
Branches of Distribution.—The branches of distribution (Fig. 788) of the facial nerve may be thus arranged:

With the facial canal…………………………..
Nerve to the Stapedius muscle.

Chorda tympani.

At its exit from the stylomastoid foramen………
Posterior auricular.

Digastric.

Stylohyoid.

On the face……………………………………
Temporal.

Zygomatic.

Buccal.

Mandibular.

Cervical.
The Nerve to the Stapedius (n. stapedius; tympanic branch) arises opposite the pyramidal eminence (page 1042); it passes through a small canal in this eminence to reach the muscle.

The Chorda Tympani Nerve is given off from the facial as it passes downward behind the tympanic cavity, about 6 mm. from the stylomastoid foramen. It runs upward and forward in a canal, and enters the tympanic cavity, through an aperture (iter chordæ posterius) on its posterior wall, close to the medial surface of the posterior border of the tympanic membrane and on a level with the upper end of the manubrium of the malleus. It traverses the tympanic cavity, between the fibrous and mucous layers of the tympanic membrane, crosses the manubrium of the malleus, and emerges from the cavity through a foramen situated at the inner end of the petrotympanic fissure, and named the iter chordæ anterius (canal of Huguier). It then descends between the Pterygoideus externus and internus on the medial surface of the spina angularis of the sphenoid, which it sometimes grooves, and joins, at an acute angle, the posterior border of the lingual nerve. It receives a few efferent fibers from the motor root; these enter the submaxillary ganglion, and through it are distributed to the submaxillary and sublingual glands; the majority of its fibers are afferent, and are continued onward through the muscular substance of the tongue to the mucous membrane covering its anterior two-thirds; they constitute the nerve of taste for this portion of the tongue. Before uniting with the lingual nerve the chorda tympani is joined by a small branch from the otic ganglion.
The Posterior Auricular Nerve (n. auricularis posterior) arises close to the stylo-mastoid foramen, and runs upward in front of the mastoid process; here it is joined by a filament from the auricular branch of the vagus, and communicates with the posterior branch of the great auricular, and with the lesser occipital. As it ascends between the external acoustic meatus and mastoid process it divides into auricular and occipital branches. The auricular branch supplies the Auricularis posterior and the intrinsic muscles on the cranial surface of the auricula. The occipital branch, the larger, passes backward along the superior nuchal line of the occipital bone, and supplies the Occipitalis.
The Digastric Branch (ramus digastricus) arises close to the stylomastoid foramen, and divides into several filaments, which supply the posterior belly of the Digastricus; one of these filaments joins the glossopharyngeal nerve.
The Stylohyoid Branch (ramus stylohyoideus) frequently arises in conjunction with the digastric branch; it is long and slender, and enters the Stylohyoideus about its middle.
The Temporal Branches (rami temporales) cross the zygomatic arch to the temporal region, supplying the Auriculares anterior and superior, and joining with the zygomaticotemporal branch of the maxillary, and with the auriculotemporal branch of the mandibular. The more anterior branches supply the Frontalis, the Orbicularis oculi, and the Corrugator, and join the supraorbital and lacrimal branches of the ophthalmic.
The Zygomatic Branches (rami zygomatici; malar branches) run across the zygomatic bone to the lateral angle of the orbit, where they supply the Orbicularis oculi, and join with filaments from the lacrimal nerve and the zygomaticofacial branch of the maxillary nerve.
The Buccal Branches (rami buccales; infraorbital branches), of larger size than the rest, pass horizontally forward to be distributed below the orbit and around the mouth. The superficial branches run beneath the skin and above the superficial muscles of the face, which they supply: some are distributed to the Procerus, joining at the medial angle of the orbit with the infratrochlear and nasociliary branches of the ophthalmic. The deep branches pass beneath the Zygomaticus and the Quadratus labii superioris, supplying them and forming an infraorbital plexus with the infraorbital branch of the maxillary nerve. These branches also supply the small muscles of the nose. The lower deep branches supply the Buccinator and Orbicularis oris, and join with filaments of the buccinator branch of the mandibular nerve.
The Mandibular Branch (ramus marginalis mandibulæ) passes forward beneath the Platysma and Triangularis, supplying the muscles of the lower lip and chin, and communicating with the mental branch of the inferior alveolar nerve.
The Cervical Branch (ramus colli) runs forward beneath the Platysma, and forms a series of arches across the side of the neck over the suprahyoid region. One branch descends to join the cervical cutaneous nerve from the cervical plexus; others supply the Platysma.

Notes-Conti..

64. The rise in H+and fall in HCO3− that occurs in type I (distal) renal tubular acidosis (RTA) does not increase the anion gap because the decrease in HCO3−is accompanied by an increase in Cl−. The failure of the distal nephron H+ ATPase causes a reduction in net acid excretion and a reduced H+ secretion, which causes less ammonium to be excreted in the urine. The low HCO3− in the glomerular filtrate reduces Na+ reabsorption by the Na-H exchanger and therefore more Na+
is delivered to the distal nephron. The increased Na+ delivery results in salt wasting and a secondary hyperaldosteronism which, in turn, causes K+ concentration to fall.





65. The ascending limb of Henle’s loop dilutes the fluid within the nephron by reabsorbing Na+
without water. In the absence of ADH, the reabsorption of Na+ without water continues along the collecting duct, making the Na+ concentration lower and lower. In the presence of ADH, water is reabsorbed from the collecting duct making the luminal fluid isotonic in the cortical collecting duct and hypertonic in the medullary collecting duct.

Parathyroid hormone (PTH) increases Ca2+ reabsorption from the thick ascending limb and the distal convoluted tubule. Although most of the filtered Ca2+ is reabsorbed in the proximal tubule, the regulation of Ca2+ excretion occurs in the thick ascending limb and the distal convoluted tubule. PTH regulates the reabsorption of HPO42− in the proximal tubule.

Aldosterone increases the reabsorption of Na+ from the principal cells within the cortical and medullary collecting ducts. Aldosterone increases Na+ reabsorption by increasing the luminal permeability to Na+ on the apical surface and the activity of the Na-K pump on the basal lateral surface of the principal cells. Aldosterone also increases the secretion of K+ and H+ from the collecting ducts.




66. Approximately two thirds of the 40 to 150 mg of protein excreted per day by the kidney is
derived from plasma proteins. The remainder is derived from the tubular secretion of a mucoprotein, the Tamm-Horsfall protein, that is present in tubular casts appearing in urinary sediment. Not all plasma proteins are filtered equally because glomerular permeability is related to molecular size and charge. The larger and negatively charged proteins are poorly filtered. Most of the filtered protein is reabsorbed in the proximal tubule unless the filtered load exceeds the tubular capacity. Such overload would occur following damage to the glomerular basement membrane and breakdown of normal barriers, or following an increase in the plasma concentration of a small protein, such as myoglobin. Protein excretion is also increased by sympathetic stimulation, such as that occurring during exercise. In this situation, renal vasoconstriction reduces the glomerular filtration rate, which, by increasing the transit time of glomerular filtrate, favors diffusion of proteins across the basement membrane. The presence of protein in the urine indicates glomerular dysfunction. RBC casts are indicative of glomerulonephritis. A red color indicates the presence of hemoglobin, myoglobin, or red food.





67. Juxtaglomerular ( JG) cells are sensitive to changes in afferent arterial intraluminal pressure. Increased pressure within the afferent arteriole leads to a decrease in renin release, whereas decreased pressure tends to increase renin release. Angiotensin appears to inhibit renin release by initiating the flow of calcium into the JG cells. Renin release is increased in response to increased activity in the sympathetic neurons innervating the kidney. Prostaglandins, particularly PGI2 and PGE2, stimulate renin release. Stimulation of the macula densa leads to an increase in renin release, and although the mechanism is not fully understood, it appears that increased delivery of NaCl to the distal nephron is responsible for stimulating the macula densa. Aldosterone does not appear to have any direct effect on renin release.




68. The macula densa senses the chloride concentration of the fluid flowing from the ascending limb of Henle’s loop into the distal convoluted tubule. An increase in NaCl concentration occurs when the amount of fluid flowing through the ascending limb increases because there is less time available for the reabsorption of NaCl. The resulting increase in Cl− concentration results in the release of adenosine (and/or ATP) from the macula densa.Adenosine constricts the afferent arteriole, resulting in a decrease in filtraion and a return of the flow rate within the nephron toward normal. This response is referred to as tubuloglomerular feedback. If the NaCl concentration decreases (e.g., when circulating blood volume decreases), the decreased Cl− concentration results in the release of renin from granular cells of the juxtaglomerular apparatus. Spironolactone acts by competitive
inhibition of aldosterone, thereby blocking Na+ reabsorption in the distal tubules and collecting ducts. Potassium-sparing diuretics are relatively weak and therefore are most effective when administered in combination with loop and/or thiazide diuretics.


The juxtaglomerular apparatus (JGA) is responsible for releasing renin when the effective circulating blood volume is decreased. The JGA releases renin when the Cl− concentration in the luminal fluid bathing the macula densa is decreased. The decrease in Cl− (and Na+) concentration
occurs when the flow rate within the nephron decreases and ample time is available for the loop of Henle to remove NaCl from the lumen. Adenosine is released from the macula densa cells when the luminal Cl− concentration increases in response to an increase in luminal flow rate. Adenosine
decreases renal blood flow by constricting the afferent arteriole and, therefore, the blood flow through the glomerular capillary.


69. Increased renin leads to increased production of angiotensin II, which binds to AT1 receptors in the zona glomerulosa, which act via a G protein to activate phospholipase C. The resultant increase in protein kinase C fosters the conversion of cholesterol to pregnenolone and facilitates the action of aldosterone synthase, resulting in the conversion of deoxycorticosterone to aldosterone.

Increased potassium concentration directly stimulates aldosterone secretion. Like angiotensin II, K+
stimulates the conversion of cholesterol to pregnenolone and the conversion of deoxycorticosterone to aldosterone by aldosterone synthase. Potassium exerts effect on aldosterone secretion by depolarizing the the zona glomerulosa cells, which opens voltage-gated Ca2+ channels, increasing
intracellular Ca2+. Adrenocorticotropic hormone (ACTH) stimulates aldosterone synthesis and secretion via increases in cyclic AMP and protein kinase A. The stimulatory effect of ACTH on aldosterone secretion is usually transient, declining in 1–2 days, but persists in patients with
glucocorticoid-remediable aldosteronism, an autosomal dominant disorder in which the 5’ regulatory region of the 11β-hydroxylase gene is fused to the coding region of aldosterone synthase gene, producing an ACTH-sensitive aldosterone synthase.






70. Blood flow through the kidney is controlled by numerous humoral agents. Angiotensin II decreases renal blood flow. It vasoconstricts efferent arterioles more than afferent arterioles, which helps to maintain glomerular filtration rate in the face of decreases in renal perfusion pressure. This may account for the renal failure that sometimes develops in patients with decreased renal perfusion who are taking angiotensin-converting enzyme inhibitors. Nitric oxide dilates the afferent arteriole and constricts the efferent arteriole, producing a rise in glomerular capillary pressure (and glomerular filtration) without having much of an effect on renal blood flow. Dopamine synthesized in the kidney increases renal blood flow and sodium excretion. Acetylcholine and atrial natriuretic peptide also produce renal vasodilation and an increase in renal blood flow.







71. Free water clearance is the amount of water excreted in excess of that required to make the urine isotonic to plasma. It is calculated using the formula: CH2O = V − Cosm. Free water clearance is positive when the urine is dilute (more than a sufficient amount of water is excreted), and free water clearance is negative when the urine is concentrated (not enough water is excreted to make the urine isotonic to plasma). An increase in free water clearance can lead to hypernatremia; a decrease in free water clearance can lead to hyponatremia. In diabetes insipidus, very little water is reabsorbed in the distal nephron, and, therefore, the free water clearance is very high. In heart failure or renal failure, very little free water can be generated even if the urine is dilute because the glomerular filtration rate is decreased. With diuretic therapy, Na+ excretion is increased. Therefore, the increased water excretion is accompanied by an increased Na+ excretion and the amount of free water generated is limited. Although the water loss is proportionally greater than the solute loss in
diabetes mellitus, the amount of water excreted is much less and the solute concentration significantly higher than in diabetes insipidus, so the free water clearance is much less in diabetes mellitus than in diabetes insipidus.






72. Growth hormone (GH) exerts many of its effects on growth and metabolism by stimulating the production and release of polypeptide growth factors called somatomedins from the liver, cartilage, and other tissues. In humans, the principal circulating somatomedins are insulin-like growth factor I (IGF-I, somatomedinC) and IGF-II. GH release is stimulated by growth hormone-releasing hormone (GHRH) and ghrelin and inhibited by somatostatin. All of these peptides are synthesized and released by the hypothalamus, though the main site of ghrelin synthesis and secretion is the stomach. GH increases lipolysis; the resultant increase in free fatty acids, which takes several hours to develop, provides a ready source of energy for the tissues during hypoglycemia, fasting, and stressful stimuli. GH also has a protein anabolic effect. GH is metabolized rapidly; the half-life of circulating GH in humans is 6 to 20 minutes.





73. Hormone-sensitive lipase is a cytoplasmic enzyme in adipocytes that catalyzes the complete hydrolysis of triglyceride to fatty acids and glycerol. It is activated by a cyclic AMP-dependent protein kinase that phosphorylates the enzyme, converting it to its active form. Because no accumulation of monoglycerides or diglycerides is detected in adipocytes following the action of hormone-sensitive lipase, it is the initial hydrolysis of triglyceride to fatty acid and diglyceride that is the rate-limiting step. Hormone-sensitive lipase is sensitive to several hormones in vitro, but it appears to be regulated in vivo primarily by epinephrine and glucagon, which activate it by increasing cyclic AMP, and insulin, which inhibits it by preventing cyclic AMP-dependent phosphorylation. Cortisol enhances lipolysis indirectly by promoting increased enzyme synthesis.





74. Synthesis and secretion of growth hormone (GH) by the anterior pituitary is regulated by a variety of metabolic factors, many of which act to alter the balance between release of growth hormone-releasing hormone (GRH) and somatostatin (SS) from the hypothalamus. Among the stimuli that increase GH secretion are: (1) conditions in which there is a deficiency of energy substrate (e.g., hypoglycemia, exercise, and fasting); (2) stressful stimuli (e.g., fever, various psychological stresses); (3) an increase in arginine and some other amino acids (e.g., protein meal, infusion of arginine); (4) glucagon; (5) L-Dopa and dopamine receptor agonists; (6) estrogens
and androgens; and (7) going to sleep. Stimuli that decrease GH secretion include somatostatin, REM sleep, glucose, cortisol, free fatty acids, and GH itself.




75. The primary action of glucagon is to increase blood glucose concentration, which it accomplishes by promoting gluconeogenesis and glycogenolysis in the liver but not in muscle. These effects are mediated by cyclic AMP, which is produced by hepatic adenylate cyclase
following interaction of glucagon with its plasma membrane receptor. Interaction of glucagon with different hepatic plasma membrane receptors activates phospholipase C, which results in a rise in concentration of intra-cellular Ca2+, which further stimulates glycogenolysis. Although glucagon
opposes the action of insulin, it does not directly affect insulin secretion.





76. Removal of the adrenal glands produces the clinical picture known as Addison’s disease, a disorder associated with deprivation of adrenocortical hormones. A lack of glucocorticoids diminishes the body’s ability to synthesize glucose by gluconeogenesis. Mineralocorticoid deprivation produces diuresis, natriuresis, and decreased potassium secretion leading to
excessive potassium plasma levels and acidosis.



77. Insulin does not promote glucose uptake by most brain cells. Insulin does increase glucose uptake in skeletal muscle, cardiac muscle, smooth muscle, adipose tissue, leukocytes, and the liver. In most insulin-sensitive tissues, insulin acts to promote glucose transport by enhancing facilitated diffusion of glucose down a concentration gradient. In the liver, where glucose freely permeates the
cell membrane, glucose uptake is increased as a result of its phosphorylation by glucokinase. Formation of glucose-6-phosphate reduces the intra-cellular concentration of free glucose and maintains the concentration gradient favoring movement of glucose into the cell.



78. Thyroid storm is an exaggerated manifestation of hyperthyroidism. Thyroid storm is a medical emergency and mortality is high (20–50%) even with the correct treatment. After primary stabilization of the airway, breathing and oxygenation, circulation, and fluid balance, treatment
includes propylthiouracil (PTU) or methimazole to block the synthesis of new thyroid hormone and β-blockers to block adrenergic effects. Iodine should not be given until after PTU has taken effect (~1.5) or more thyroid hormone will be produced. Aspirin displaces T4 from thyroid binding pro-
tein, and therefore should not be used to treat fever. T3 and T4 inhibit the release of thyrotropin-releasing hormone (TRH) from the hypothalamus, which regulates thyroid-stimulating hormone (TSH) secretion from the anterior pituitary gland.



79. Synthesis and secretion of melatonin are increased in the dark via input from norepinephrine
secreted by postganglionic sympathetic neurons. Melatonin is synthesized in the pineal gland from the amino acid tryptophan. Pinealomas (tumors of the pineal gland) that destroy the pineal gland and reduce secretion of melatonin and cause hypothalamic damage may cause precocious puberty
by removing the inhibitory effect of melatonin on the pituitary response to gonadotropin-releasing hormone. Melatonin causes amphibian skin to become lighter in color but has no role in the regulation of skin color in humans.




80. The islets of Langerhans, which constitute 1 to 2% of the pancreatic weight, secrete insulin, glucagon, somatostatin, and pancreatic polypeptide. Each is secreted from a distinct cell type, A, B, D, and F, respectively. The islets are scattered throughout the pancreas, but are more plentiful in the tail than in the body or head....



81. As a result of insulin deficiency-->Decreased intracellular α-glycerophosphate in liver and fat cells---α-Glycerophosphate is produced in the course of normal use of glucose. In the absence of adequate quantities of α-glycerophosphate, a normal acceptor of free fatty acids in triglyceride synthesis, lipolysis will be the predominant process in adipose tissue. As a result, fatty acids will be released into the blood. The prevailing insulin level is decisive in the selection of substrate by a tissue for the production of energy. Insulin promotes use of carbohydrate, and a lack of the hormone causes use of fat mainly to the exclusion of uptake and use of glucose, except by brain tissue. Indirect depression of glucose utilization due to excess fatty acids is a result, and not a contributing cause, of increased use of fat.



82. Thyroxin-binding globulin (TBG) is increased in estrogen-treated patients and during pregnancy, increasing the total plasma levels of T3 and T4, but with a normal level of the free thyroid hormones, such that the clinical state is euthyroid. Cortisol levels also increase during pregnancy and parturition due to increased production of corticotropin-releasing hormone (CRH) by
the placenta (as well as the fetal hypothalamus). Although tissue renin contributes little to the circulating renin pool, pregnancy is associated with increased renin levels that may arise from components of the tissue renin-angiotensin system found in the uterus, the placenta, and the fetal membranes. Amniotic fluid contains large amounts of prorenin.


Secretion of TSH is regulated primarily by the pituitary levels of T3. As plasma thyroid hormone levels increase, pituitary T3 levels rise and lead to inhibition of TSH synthesis and secretion. TSH stimulates thyroid gland function by binding to specific cell membrane receptors and increasing the
intracellular levels of cAMP. The thyroid gland secretes thyroxine (T4) and triiodothyronine (T3); the latter is the physiologically active hormone. The majority of T3 is formed in the peripheral tissues by deiodination of T4.


84. Growth hormone activates many different intracellular enzyme cascades, including the
JAK2-STAT pathway, which also mediates the effects of various growth factors and prolactin. Secretion of insulin-like growth factor I (IGF-I) increases throughout childhood and stimulate cell proliferation and growth in many different cell types, including chondrocytes within growth plates.
Linear growth ends earlier in girls than in boys. IGF-II is largely independent of growth hormone and plays a role in the growth of the fetus before birth. Thyroid hormones are essential for normal linear growth and skeletal development. The growth-promoting effects of thyroid hormones occur
via a synergistic effect with growth hormone.

Patients with acromegaly have insulin resistance. In addition, they manifest increased lipolysis and increased gluconeogenesis due to their high growth hormone levels. The combination of enhanced glucose production and insulin resistance can produce hyperglycemia and diabetes mellitus.
Protein synthesis increases to support tissue growth and proliferation.



85. Due to their relatively low solubility within the lipid portions of the cell membrane, peptide hormones and catecholamines (epinephrine) must interact with receptors located on the cell membrane. Activation of the receptor is followed by the generation of intracellular second messengers that ultimately mediate the biological response to the hormone. Steroid hormones and thyroid hormones readily pass through the cell surface membrane and interact with intracellular
receptors to produce their effects by regulating gene expression within the nucleus.

Cortisol, like other steroid hormones, diffuses into target cells and interacts with intracellular
receptors. The steroid-receptor complex has a high affinity for the steroid-responsive element of DNA. Once bound to DNA, the hormone-receptor complex acts as a transcription factor to regulate gene expression and formation of specific messenger RNAs.





86. Glucocorticoids lower plasma Ca2+ levels by inhibiting osteoclast formation and activity. Over long periods of time, glucocorticoids cause osteoporosis by decreasing bone formation and
increasing bone resorption. They decrease bone formation by inhibiting protein synthesis in osteoblasts. Glucocorticoids also decrease the absorption of Ca2+ and PO4 3–from the intestine and increase the renal excretion of these ions. Vitamin D formation is facilitated when plasma Ca2+
levels are low.

Cortisol is defined as a glucocorticoid because it promotes the conversion of amino acids to glucose (gluconeogenesis). It also decreases glucose uptake by muscle and adipocytes by decreasing the sensitivity of the cells to insulin. The net result is to provide more glucose to non-insulin-requiring cells. Cortisol retards wound healing. It also decreases CRH and ACTH secretion by feedback inhibition.





87. Phenylethanolamine-N-methyltransferase (PNMT), the enzyme that catalyzes the formation of epinephrine from norepinephrine, is found in appreciable quantities only in the brain and the adrenal medulla. Adrenal medullary PNMT is induced by glucocorticoiods and glucocorticoids are necessary for the normal development of the adrenal medulla. Circumstances that increase sympathetic nerve input to the adrenal medulla increase catecholamine secretion. Major stressors include decreased intravascular volume or pressure, fear or rage, a change in posture from supine to standing, and hypoglycemia.




88. Atrial natriuretic peptide (ANP) is synthesized, stored, and secreted by cardiac atrial muscle, the latter in response to increased central venous pressure or increased plasma sodium concentrations. ANP increases glomerular filtration by simultaneous dilation of afferent and constriction of efferent renal arterioles. It decreases salt and water reabsorption along the entire length of the kidney. The excretion of water is enhanced by inhibition of ADH.






ANATOMY



89. The maximum number of oogonia occurs at about the fifth month of development. Primordial germ cells arrive in the embryonic gonad of a genetic female during the 7th to 12th week where they differentiate into oogonia. After undergoing a number of mitotic divisions, those fetal cells
form clusters in the cortical part of the ovary. Some of those oogonia differentiate into the larger primary oocytes (not to be confused with primary follicles). The primary oocytes begin meiosis. At the same time, the number of oogonia continues to increase to about 6,000,000 by the fifth month. At this time, most of the surviving oogonia and some of the oocytes become atretic. However, the surviving primary oocytes (400,000 to1,000,000) become surrounded by epithelial cells and form the primordial follicles by the seventh month. During childhood there is continued atresia, so that by puberty only about 40,000 primary oocytes remain.



90. On fusion of the first sperm with the oocyte cell membrane, the contents of secretory granules stored just beneath the oocyte membrane (cortical granules) are released (the zona reaction). Enzymes stored in those granules cause biochemical and electrical changes in the zona pellucida and the oocyte membrane that prevent the binding of additional sperm.

Primitive female germ cells (oogonia) enter the first meiotic division during fetal development . This process becomes arrested in prophase I until individual primary oocytes are hormonally induced to resume the first meiotic division during puberty and early adulthood (menarche to menopause). Fusion of the sperm and oocyte membranes initiates the resumption of the second meiotic division, resulting in the formation of a haploid pronucleus in the oocyte and extrusion of the second polar body .

Capacitation is a process by which enzymatic secretions of the uterus and oviducts strip glycoproteins from the sperm cell membrane. This is required for penetration of the layer of cells surrounding the oocyte (corona radiata). The release of enzymes from the sperm acrosomal cap (an enlarged lysosome) results in digestion of the zona pellucida surrounding the oocyte, allowing penetration by sperm.

Primary oocytes have developed by the time of birth. From puberty to menopause, these germ cells remain suspended in meiotic prophase I (diplotene or dictyate stage). A midcycle surge of LH triggers the resumption of meiosis and causes the FSH-primed follicle to rupture and discharge the ovum. Under the influence of LH, the ruptured follicle is transformed into a corpus luteum, which
produces progesterone. FSH and LH produced in the adenohypophysis result in growth and maturation of the ovarian follicle. Under FSH stimulation, the theca cells proliferate, hypertrophy, and begin to produce estrogen.


The secondary oocyte enters the second meiotic division just before ovulation and arrests at metaphase. Fertilization by a spermatozoon provides the stimulation for the division of chromatin to the haploid number. By the time the fertilized ovum reaches the uterus, the progesterone produced by the corpus luteum has initiated the secretory phase in the endometrium. Once implantation occurs and the chorion develops, human chorionic gonadotropin (hCG) is synthesized and the corpus luteum is maintained . Expulsion from the follicle and the environment of the oviduct and
uterus do not induce the second meiotic division



91. Capacitation, the acrosome reaction and penetration are required for the hamster sperm penetration assay (SPA). Capacitation prepares the sperm for fertilization and requires an increase in fluidity of the sperm plasma membrane. Sperm must reside in the female reproductive tract or under appropriate in vitro conditions for about 1 hour for capacitation to occur. During capacitation there is a loss of decapacitation factors that have been added to the sperm by epididymal cells and accessory male reproductive organs. Cholesterol is removed from the sperm plasma membrane during this period, which results in the increased fluidity of this membrane that is required for the fusion of the acrosomal membrane with the sperm plasma membrane. Next, there is release of the acrosomal enzymes , which are required for the breakdown of the corona radiata and the zona pel-
lucida of the oocyte to facilitate sperm penetration. Sperm formation and maturation occur in the testis and epididymis.


The formation of the acrosome, a specialized secretory granule, is one of many maturation events
occurring during spermiogenesis (the process by which mature sperm are formed from the spermatids). Acrosome formation involves lytic enzyme maturation and occurs after division of secondary spermatocytes. It involves no mitotic or meiotic activity . The acrosome develops from
Golgi vesicles just like any other secretory granules. It contains acrosin, a serine protease, hyaluronidase, and neuraminidase, responsible for the penetration ability of the sperm. The developing cells are in contact with Sertoli cells for all of the stages of spermiogenesis. At the end of spermiogenesis, spermatids are released by Sertoli cells in a process called spermiation .
Decapacitation factors are not involved in acrosomal maturation.

Spermatogenesis, the processby which spermatogonia undergo mitotic division to produce primary spermatocytes, occurs at 1°C (2°F) below normal body temperature. Subsequent meiotic divisions produce secondary spermatocytes with a bivalent haploid chromosome number and then spermatids with a monovalent haploid chromosome number. Spermiogenesis, the maturation of the spermatid, results in spermatozoa. Morphologically, adult spermatozoa are moved to the epididymis, where they become fully motile.


92. Cells of the inner cell mass (embryoblast) of the blastocyst differentiate into the epiblast and hypoblast. Cells of the epiblast migrate toward the primitive streak during the second week and
become internalized, forming the mesodermal and endodermal germ layers. Remaining cells of the epiblast become the ectodermal germ layer (epidermis, epidermal appendages, and the nervous system). Cells of the hypoblast will contribute to the yolk sac. Cells of the outer cell mass of the blastocyst will differentiate into the cytotrophoblast and syncytiotrophoblast , which will contribute to formation of the placenta. The yolk sac is incorporated into the embryo as the primitive gut during embryonic folding.
Formation of most internal organs occurs during the second month, the period of organogenesis. The first month of embryonic development generally is concerned with cleavage, formation of the germ layers, and establishment of the embryonic body. The period from the ninth week to the end of intrauterine life, known as the fetal period, is characterized by maturation of tissues and rapid growth of the fetal body.

93. During the second week of fetal development, lacunar spaces develop between cells of the syncytiotrophoblast, particularly in the region of the embryonic pole as the conceptus invades the endometrium. Endometrial capillaries in this region become dilated and engorged with blood to form sinusoids. The syncytial cells direct erosion of the endothelium of the maternal capillaries, allowing maternal blood to enter the lacunae and bathe the syncytial cells. During the second week, primary villi consist of projections of syncytial cells surrounding a core of cytotrophoblast cells. During the third week , the villus core is invaded by mesodermal cells to form a secondary villus. Cells of the mesodermal core will then differentiate to form capillaries and blood cells by the end of the third week (tertiary villus). Those vessels become connected to the fetal circulation early in the fourth week establishing the functional uteroplacental circulation.



94. The presence of a murmur could be indicative of any of the conditions. The presence of a continuous machine-like murmur is indicative of a patent ductus arteriosus (PDA). The ventilator requirements are increased due to increasing pCO2 (as the lungs become “wet,” the pCO2 increases). The diastolic blood pressure usually drops and there is a widened pulse pressure (usually greater than 20). The PDA was always there, it is just that her pulmonary vascular resistance relaxed enough to allow more left-to-right shunting and more blood flow to the lungs (less to the body).

An atrial septal defect (ASD), such as a persistent foramen ovale, could be eliminated from the diagnosis because the murmur would be heard as an abnormal splitting of the second sound during expiration.

A patent foramen ovale is a common echo finding in premature babies and is usually not followed up unless it appears remarkable to the pediatric cardiologist or there is a persistent murmur. A patent foramen ovale might result in only minimal or intermittent cyanosis during crying or straining to pass stool.

A murmur caused by a ventricular septal defect (VSD, answer c), occurs between the first and second heart sounds (S1 and S2) and is described as holosystolic (pansystolic) because the amplitude is high throughout systole.

Pulmonary stenosis would be heard as a harsh systolic ejection murmur. Coarctation of the aorta would result in a systolic murmur.

PDA refers to the maintenance of the ductus arteriosus, a normal fetal structure. In the fetus, the ductus arteriosus allows blood to bypass the pulmonary circulation, since the lungs are not involved in CO2/O2 exchange until after birth. The placenta subserves the function of gas exchange during fetal development. The ductus arteriosus shunts flow from the left pulmonary artery to the aorta. High oxygen levels after birth and the absence of prostaglandins from the placenta cause the ductus arteriosus to close in most cases within 24 hours. A PDA most often corrects itself within several months of birth, but may require infusion of indomethacin (a prostaglandin inhibitor) as a treatment, insertion of surgical plugs during catheterization, or actual surgical ligation.



95. IgA deficiency, the most common immunoglobulin deficiency. IgA functions in several ways, one of which is to coat pathogens with a negative charge that repels the polyanionic charge on the cell surface. In IgA deficiency, pathogens can more easily attach to the cell surface leading to persistent infections. The carbohydrate of biological membranes is found in the form of glycoproteins and glycolipids rather than as free saccharide groups. The polyanionic charge of the membrane is produced by the sugar side chains on the glycoproteins and glycolipids. Glycoproteins often terminate in sialic acid side chains, which impart a negative (polyanionic) charge to the mem-
brane. Similarly, the glycolipids (also called glycosphingolipids), particularlythe gangliosides, terminate in sialic acid residues with a strong negative charge. Cholesterol alters membrane fluidity (see figure below and question 34) and is amphipathic (hydrophilic and hydrophobic properties). It
reduces the packing of lipid acyl groups through its steroid ring structure and hydrocarbon tail and cements hydrophilic regions of the membrane through interactions with its hydroxyl (OH) region. Peripheral membrane proteins are found primarily on the cytosolic leaflet of the membrane
bilayer. Integrins (answer e) are heterodimeric receptors that bind with extra-cellular matrix (ECM) molecules such as laminin and fibronectin.




96. In its anion exchanger role, band 3 protein exchanges bicarbonate ion for chloride ion. Bicarbonate is transported by band 3 out of the RBC in exchange for chloride, permitting the highly efficient transport of CO2 to the lungs as bicarbonate. In the absence of band 3 protein, the bicar-
bonate buffering of the blood is reduced, leading to acidosis or lowering of blood pH. The result is reduced capacity to carry CO2. In addition to its functional, bidirectional anion exchanger role, band 3 plays a key membrane structural role, since the cytoplasmic domain of the protein interacts with spectrin through an ankyrin bridge. Spectrin exists as dimers and trimers; the trimers are bound together by actin, thus providing a connection to the cytoskeleton maintaining the shape and stability of the RBC. The result of a null mutation in band 3 is the formation of erythrocytes that are small and round instead of biconcave (spherocytosis). Spherocytes are osmotically fragile because of their decreased surface area per unit volume. The defective RBCs do not readily pass through the small sinusoids of the spleen, resulting in destruction and further membrane conditioning, which leads to accelerated destruction and, eventually, enlargement of the spleen (splenomegaly). The
accelerated hemolysis leads to increased bile production and jaundice. Hemoglobin production is also increased, as exemplified by an increase in mean corpuscular hemoglobin concentration (MCHC) by about 35 to 40%. The bone marrow compensates for the increased destruction of RBCs with hyperplasia of erythroid precursors in the bone marrow and increase in the number of reticulocytes (polychromasia)





97. The patient in the scenario is suffering from cirrhosis in which there are alterations in plasma
lipoproteins. Binding of an antibody to a cell surface receptor results in lateral diffusion of protein in the lipid bilayer, resulting in increased membrane fluidity—patching and capping. Rotational and lateral movements of both proteins and lipids contribute to membrane fluidity. Restriction reduces
membrane fluidity. Phospholipids are capable of lateral diffusion, rapid rotation around their long axis, and flexion of their hydrocarbon (fatty acyl) tails. They undergo transbilayer movement, known as “flip-flop,” between bilayers in the endoplasmic reticulum; however, in general thisdoes not occur in the plasma membrane. Other factors reduce membrane fluidity. An increase in the amount of cholesterol relative to phospholipid has been shown by a variety of physicochemical techniques to decrease fluidity in both biological and artificial membranes by interacting with the hydrophobic regions near the polar head groups and stiffening this region of the membrane. Association or binding of integral membrane proteins with cytoskeletal elements on the interior of the cell and peripheral membrane proteins on the extracellular surface limit membrane mobility and fluidity.


Asymmetry of the lipid bilayer is established during membrane synthesis in the endoplasmic retic-
ulum before reaching the Golgi apparatus. Carbohydrates are associated with the N terminals of transmembrane proteins that extend from the extracellular surface, not the cytoplasmic surface. Cholesterol is different from proteins and phospholipids that are asymmetrically distributed within the bilayer. Cholesterol is found on both sides of the bilayer. The small polar head group structure
of cholesterol allows it to flip-flop from leaflet to leaflet and respond to changes in shape. In contrast to cholesterol, most proteins and phospholipids are capable of only rare flip-flop. For example, transbilayer movement of phospholipid is limited mostly to the endoplasmic reticulum.


98. Albuterol binds to β-receptors, which are multipass G-protein-linked receptors. Binding to G-protein-linked receptors activates or inactivates enzymes bound to the plasma membrane (adenylyl cyclase or phospholipase C) or opens or closes ion channels using G proteins. A table of G proteins and their functions appears below. The β-receptors, as well as muscarinic cholinergic receptors and rhodopsin, are multipass transmembrane proteins consisting specifically of seven hydrophobic
spanning segments of the single polypeptide chain. The peptide bonds of the spanning segments are polar. In the hydrophobic environment of the lipid bilayer, in the absence of water, they form hydrogen bonds with eachother. There is a remarkable homology between the cell-surface receptors
linked to the G proteins. Ligand binding occurs on the extracellular surface. Receptors with intrinsic enzyme activity belong to a separateclass of single-pass transmembrane proteins. All of these trans-
membrane proteins show a carboxyl terminus on the cytosolic side and N-linked glycosylation sites on the extracellular surface.







99. Anti-vimentin is specific for mesenchymal cells such as fibroblasts, macrophages, endothelial cells, and smooth muscle of the vasculature. In the salivary glands fibrous stromal tissue is derived from mesenchyme.
The acini and ducts are derived from epithelium.
The parasympathetic ganglia will stain with pan-neuronal markers such as peripherin.
The type of intermediate filament protein is relatively specific for cells derived from the three embryonic germ layers. Antibodies to intermediate filament proteins have been used by pathologists to determine the origin of tumors. Intermediate filament proteins have a structural role but also are involved in the anchorage of the proteins that form ion channels.
Cytokeratins (also known as keratins) are specific for epithelial cells.
Neurofilament proteins (NFL, NFM, and NFH) are found in neurons. In Alzheimer’s disease, extensive plaques of neurofilament proteins occur.
Desmin is found in striated and most smooth muscle, except vascular smooth muscle.
Glial fibrillary acidic protein, GFAP, is specific for astrocytes, not microglia or oligodendrocytes





100. The large subunit of the ribosome catalyzes peptide bond formation by activation of peptidyl transferase. The small ribosomal subunit contains the peptidyl-tRNA-binding (P) site that binds the tRNA molecule attached to the carboxyl end of the growing end of the polypeptide chain.
The small subunit also contains the aminoacyl-tRNA-binding (A) site that holds the incoming tRNA and amino acid. The initiation factors are loaded on the small ribosomal subunit that must locate the AUG (start) codon to initiate protein synthesis. This occurs before binding of the large subunit. In addition, the initiator tRNA containing methionine provides the amino acid necessary to start protein synthesis. The initiator tRNA is also located on the small subunit. It resides at the P site (the normal peptidyl site) even though it is an aminoacyl-tRNA. This occurs before binding to the mRNA. Therefore, the initiation phase of protein synthesis is regulated by the small subunit of the ribosome.
Ribosomes are composed of both protein and RNA (predominantly rRNA, but also mRNA and
tRNA). Single ribosomes are involved in synthesis of cytosolic proteins. Polyribosomes, linked by mRNA, synthesize proteins that are translocated into the cisternal space of the rough endoplasmic reticulum (RER) and destined for export or specific organelles.



101. Histochemical stains, such as acid phosphatase and nucleoside diphosphates, show that the Golgi apparatus is topologically compartmentalized. It presents two faces: a cis face, which is the point of entry of transport vesicles (COP-II-coated), in transit from the rough endoplasmic reticulum (RER) to the Golgi, and a trans face, which is the exit point associated with
granule formation and the maturation of proteins. Both proteins and lipids are transported from the transitional elements of the ER to the Golgi apparatus. Packaging is not the sole function of the
Golgi. This organelle is also involved in the processing of proteins (e.g.,addition and trimming of oligosaccharide chains) that was initiated in the RER as well as sulfation.


102. Oxidative metabolism by cytochrome p450 enzymes in hepatocytes is a primary mechanism for drug metabolism. Barbiturates are modified in the liver by oxidative demethylation through the P450 oxidase system found in the smooth endoplasmic reticulum (SER) (the structure shown in the electron micrograph). The SER in hepatocytes responds to Phenobarbital ingestion by increasing its volume. The proliferation (hypertrophy) of the SER facilitates metabolism of drugs. There is a concomitant increase in enzymatic activity, however, the synthesis of those enzymes occurs in the
rough endoplasmic reticulum (RER) not in the SER (answer d). The purpose of drug metabolism is to make drugs more water soluble so they can be more easily excreted from the liver through the bile. Increase in enzymatic activity following Phenobarbital ingestion catalyzes reactions that increase the solubility of various xenobiotics including toxins, alcohol, steroids, eicosanoids, carcinogens, insecticides, and other environmental pollutants. Lysosomes not the SER contain acid hydrolases. The P450 system and the SER are involved in drug interactions. Hepatocytes adapted to metabolize one drug may develop increased capability to metabolize other drugs. For example, if patients taking Phenobarbital for epilepsy increase their alcohol intake they may be ingesting subtherapeutic levels of the antiseizure medication because of induction of smooth ER in
response to the alcohol.



103. The woman in the sce nario suffers from retinitis pigmentosa. Vesicles and organelles move
unidirectionally along microtubules from the inner segment to the outer segment of the photoreceptor. Opsin, which is needed to sense light, is transported to sites of utilization in the disks of the outer segment. Transport occurs through the connecting, non-motile cilium, driven by the microtubule motor, kinesin, an ATPase. Microtubules are composed of tubulin and are involved in motility as the principal protein in the composition of the axoneme (the core of the cilium or flagellum). Micro-filaments (thin filaments) are composed of actin, the most abundant protein in cells of eukaryotes. They are involved in cell motility and changes in cell shape. Myosin is the main constituent of the thick filament that binds to actin and functions as an ATPase activated by actin. Intermediate filaments that are “intermediate” in diameter (8 to 10 nm) between thin and thick filaments are of five different types. Type I and type II are the acidic and basic keratins (cytokeratins) respectively and are found specifically in epithelial cells. Type III intermediate filaments are composed of vimentin, desmin, and glial fibrillary acidic protein (GFAP). Vimentin is found in cells of mesenchymal origin, desmin in muscle cells, and glial fibrillary acidic protein in astrocytes. Type IV intermediate filaments are neurofilament proteins found in neurons. Type V intermediate filaments include the nuclear lamins A, B, and C and are associated with nuclear lamina of all cells. Spectrin heterodimers stabilize the plasma membrane and connect the membrane to actin.





104.














105. The common fibular (peroneal) nerve bifurcates into superficial and deep branches. The deep fibular nerve innervates all muscles of the anterior compartment of the leg. The lateral sural cutaneous is a cutaneous branch of the common fibular nerve. The superficial fibular nerve
emerges from the deep fascia and descends in the lateral compartment, where it innervates the fibularis (peroneus) longus and brevis muscles before dividing into median dorsal cutaneous and intermediate dorsal cutaneous nerves, which supply the distal third of the leg, dorsum of the
foot, and all the toes. The saphenous nerve [ the terminal branch of the common femoral nerve] distributes cutaneous branches to the anterior and medial aspects of the leg as well as to the dorsomedial aspect of the foot. The sural nerve follows the course of the lesser saphenous vein and becomes the lateral sural cutaneous nerve to supply the anterolateral aspect of the foot.



106. All of the listed choices are branches of the internal iliac artery. The inferior vesical artery in the male supplies the seminal vesicle, prostate, fundus of the bladder, distal ureter, and the vas deferens. In the female, the vaginal artery supplies the vagina, urinary bladder, and pelvic portion of the urethra. The obturator artery (Br of post division) gives off muscular and nutrient branches within the pelvis and then leaves the pelvis via the obturator canal to supply the thigh. The internal pudendal artery crosses the piriformis muscle, exits the pelvic cavity via the greater sciatic foramen, and enters the ischiorectal fossa via the lesser sciatic foramen. It supplies the external genitalia (penis and clitoris). The middle rectal artery supplies the inferior rectum and forms important anastomoses with other rectal arteries. The umbilical artery (Br of Ant division of Internal iliac artery) gives off the superior vesical artery in both sexes. Its distal portion degenerates to form the medial umbilical ligament.





107. The Celiac Plexus (Plexus Cœliacus; Solar Plexus) —The celiac plexus, the largest of the three sympathetic plexuses, is situated at the level of the upper part of the first lumbar vertebra and is composed of two large ganglia, the celiac ganglia, and a dense net-work of nerve fibers uniting them together. It surrounds the celiac artery and the root of the superior mesenteric artery. It lies behind the stomach and the omental bursa, in front of the crura of the diaphragm and the commencement of the abdominal aorta, and between the suprarenal glands. The plexus and the ganglia receive the greater and lesser splanchnic nerves of both sides and some filaments from the right vagus, and give off numerous secondary plexuses along the neighboring arteries

The Celiac Ganglia (ganglia cæliaca; semilunar ganglia) are two large irregularlyshaped masses having the appearance of lymph glands and placed one on either side of the middle line in front of the crura of the diaphragm close to the suprarenal glands, that on the right side being placed behind the inferior vena cava. The upper part of each ganglion is joined by the greater splanchnic nerve, while the lower part, which is segmented off and named the aorticorenal ganglion, receives the lesser splanchnic nerve and gives off the greater part of the renal plexus.
The secondary plexuses springing from or connected with the celiac plexus are the
Phrenic.

Renal.
Hepatic.

Spermatic.
Lienal.

Superior mesenteric.
Superior gastric.

Abdominal aortic.
Suprarenal.

Inferior mesenteric.




The Hypogastric Plexus (Plexus Hypogastricus)—The hypogastric plexus is situated in front of the last lumbar vertebra and the promontory of the sacrum, between the two common iliac arteries, and is formed by the union of numerous filaments, which descend on either side from the aortic plexus, and from the lumbar ganglia; it divides, below, into two lateral portions which are named the pelvic plexuses.

The Pelvic Plexuses—The pelvic plexuses supply the viscera of the pelvic cavity, and are situated at the sides of the rectum in the male, and at the sides of the rectum and vagina in the female. They are formed on either side by a continuation of the hypogastric plexus, by the sacral sympathetic efferent fibers from the second, third, and fourth sacral nerves, and by a few filaments from the first two sacral ganglia. At the points of junction of these nerves small ganglia are found. From these plexuses numerous branches are distributed to the viscera of the pelvis. They accompany the branches of the hypogastric artery.

The superior mesenteric plexus (plexus mesentericus superior) is a continuation of the lower part of the celiac plexus, receiving a branch from the junction of the right vagus nerve with the plexus. It surrounds the superior mesenteric artery, accompanies it into the mesentery, and divides into a number of secondary plexuses, which are distributed to all the parts supplied by the artery, viz., pancreatic branches to the pancreas; intestinal branches to the small intestine; and ileocolic, right colic, and middle colic branches, which supply the corresponding parts of the great intestine. The nerves composing this plexus are white in color and firm in texture; in the upper part of the plexus close to the origin of the superior mesenteric artery is a ganglion (ganglion mesentericum superius).


The inferior mesenteric plexus (plexus mesentericus inferior) is derived chiefly from the aortic plexus. It surrounds the inferior mesenteric artery, and divides into a number of secondary plexuses, which are distributed to all the parts supplied by the artery, viz., the left colic and sigmoid plexuses, which supply the descending and sigmoid parts of the colon; and the superior hemorrhoidal plexus, which supplies the rectum and joins in the pelvis with branches from the pelvic plexuses.



The Hypogastric Plexus (Plexus Hypogastricus)—The hypogastric plexus is situated in front of the last lumbar vertebra and the promontory of the sacrum, between the two common iliac arteries, and is formed by the union of numerous filaments, which descend on either side from the aortic plexus, and from the lumbar ganglia; it divides, below, into two lateral portions which are named the pelvic plexuses.

The superior gastric plexus (plexus gastricus superior; gastric or coronary plexus) accompanies the left gastric artery along the lesser curvature of the stomach, and joins with branches from the left vagus.

The suprarenal plexus (plexus suprarenalis) is formed by branches from the celiac plexus, from the celiac ganglion, and from the phrenic and greater splanchnic nerves, a ganglion being formed at the point of junction with the latter nerve. The plexus supplies the suprarenal gland, being distributed chiefly to its medullary portion; its branches are remarkable for their large size in comparison with that of the organ they supply.

The renal plexus (plexus renalis) is formed by filaments from the celiac plexus, the aorticorenal ganglion, and the aortic plexus. It is joined also by the smallest splanchnic nerve. The nerves from these sources, fifteen or twenty in number, have a few ganglia developed upon them. They accompany the branches of the renal artery into the kidney; some filaments are distributed to the spermatic plexus and, on the right side, to the inferior vena cava.

The spermatic plexus (plexus spermaticus) is derived from the renal plexus, receiving branches from the aortic plexus. It accompanies the internal spermatic artery to the testis. In the female, the ovarian plexus (plexus arteriæ ovaricæ) arises from the renal plexus, and is distributed to the ovary, and fundus of the uterus.




108. Preganglionic parasympathetic neurons to the lower colon arise from the spinal cord at sacral levels two to four and reach the wall of the colon via pelvic splanchnic nerves. The nucleus ambiguus is the source of preganglionic parasympathetic neurons that innervate the heart via the vagus nerve and cardiac plexus. Neurons arising in the cervical intermediolateral cell column are sympathetic preganglionics. Preganglionic parasympathetic neurons arising from the motor nucleus of the vagus innervate the upper GI tract. Neurons arising from the ventral horn are primary somatic motor neurons to skeletal muscle.



109. The lower thoracic and upper lumbar portion of the spinal cord tend to receive a single major
radicular artery (of Adamkiewicz), which supplies blood to the anterior longitudinally running spinal artery. The anterior spinal artery mainly supplies the anterior two-thirds of the spinal cord in this region, which includes motor neurons that control the lower limbs. Because the metabolic needs of the spinal cord nerves are so great, the lack of blood during the surgery can lead to nerve cell death and thus paraplegia. Both muscle and peripheral nerves generally can survive the temporary disruption in blood flow. A process of cooling the spinal cord, by perfusing ice cold saline into the extradural space (called epidural cooling), is often performed to reduce the metabolic needs of the spinal nerves, thus often preventing central nervous system cell death during the surgical procedure. Muscles and nerves of the lower limb can survive reduced blood flow for an hour.





110. The lateral umbilical folds are produced by the underlying inferior epigastric arteries as they course from the external iliac artery in the inguinal region toward the rectus sheath. A direct inguinal hernia starts medial to the lateral ambilical fold and an indirect inguinal hernia starts lateral to the same fold. The medial umbilical folds are peritoneal elevations produced by the obliterated umbilical arteries. In the midline, the median umbilical ligament is formed by the underlying urachus, a remnant of the embryonic allantois. The Falx inguinalis represents infero-medial attachment of transversus abdominis with some fibers of internal abdominal oblique, also known as: conjoint tendon. The lateral border of the rectus sheath forms the medial edge of the inguinal triangle.

Notes

45. The fetus derives its oxygen from the maternal arterial blood supply by gas exchange across the placenta. The umbilical vein draining the placenta, therefore has the highest oxygenation in the fetus, with a PO2 of ~30 mmHg and 80% oxygen saturation. The ductus venosus has only a slightly lower PO2, and serves to direct much of the highly oxygenated blood from the umbilical vein to the inferior vena cava, bypassing the liver. From the right atrium, about two-thirds of the inferior venal caval flow (67% O2 saturation) is diverted across the foramen ovale to the left atrium. The PO2 in the left ventricular outflow tract going to the ascending aorta is ~25 mmHg. The PO2 in the ductus arteriosus is ~18 mmHg, and blood in the descending aorta and umbilical arteries, is ~20 mmHg with an oxygen saturation of ~60%.

46. Contractile activity in the small intestine is initiated in response to distention of the bowel

wall. Three types of smooth muscle contractions contribute to small intestinal motility—peristalsis, segmental contractions, and tonic contractions. A fourth type of contraction, peristaltic rushes, are very intense peristaltic waves that may occur in intestinal obstruction. The basal electrical

rhythm (BER) are the spontaneous rhythmic fluctuations in membrane potential in the smooth muscle along the GI tract. The BER itself rarely causes muscle contraction, but contractions only occur during the depolarizing phase of BERs, which function to coordinate the various types of

contractile activity. The BER is initiated by the interstitial cells of Cajal, which, in the small intestine, are located in the outer circular muscle layer near the myenteric plexus. There are an average of ~12 BER cycles/min in the duodenum and proximal jejunum and 8/min in the distal ileum. During fasting between periods of digestion, cycles of motor activity, called migrating motor complexes (MMC), migrate from the stomach to the distal ileum. The MMCs immediately stop with ingestion of food. After vagotomy, contractile activity becomes irregular and chaotic.

47. Increases in basal and maximal acid output are suggestive of inflammation or removal of the proximal small intestine. Intestinal receptors monitor the composition of chyme and elicit feedback mechanisms that regulate gastric acid secretion and gastric emptying. Absence of feedback leads to an increased presence of excitatory mediators of gastric function. Gastrin is the primary stimulus of meal-induced acid secretion by the parietal cells. Somatostatin (paracrine), secretin (endocrine), and enterogastrone (endocrine) inhibit gastric acid secretion by the parietal cells. Histamine is an excitatory paracrine mediator of parietal cell acid secretion.

48. Orad stomach accommodation depends exclusively on an intact vago-vagal reflex. Vagal innervation of the gastrointestinal tract extends from the esophagus to the level of the transverse colon. Preganglionic fibers from cell bodies in the medulla synapse with ganglion cells located in the enteric nervous system. Distention-induced contraction of gastrointestinal smooth muscle devel-

ops as the result of long (vago-vagal) and local (enteric nerves) reflexes. The importance of long versus local reflex pathways varies along the gut. Secondary esophageal peristalsis, intestinal segmentation, and migrating motor complexes are unaffected by vagotomy, whereas caudad stomach peristalsis is decreased but not abolished by vagotomy.

Increases in intragastric volume normally are not associated with large increases in intragastric

pressure because of distention-mediated activation of a vago-vagal inhibitory reflex, called receptive relaxation or the accommodation reflex. The reflex, which is abolished by vagotomy, is a property of the orad stomach only and counterbalances the stretch-induced myogenic contraction of the gastric smooth muscle. Peristalsis, trituration (grinding), and retropulsion (mixing) are terms referring to the contractile activity and functions of the caudad stomach. Segmental contractions are the primary contractile pattern of the small intestine during the digestive period.

49. Histamine (H2) receptor antagonists inhibit both gastrin-induced and vagal-mediated secretion of acid. Secretion of acid by gastric parietal (oxyntic) cells involves stimulation of adenyl cyclase and cyclic AMP-mediated stimulation of the active transport of chloride and potassium-hydrogen ion exchange. Neither gastrin nor vagal stimulation activates adenyl cyclase directly; both depend on concomitant release of histamine and histamine-induced activation of adenyl cyclase.

50. Inflammation or removal of the upper small intestine leads to a decrease in pancreatic and

hepatobiliary function. The proximal small intestine contains a number of “receptors” that monitor the physical (volume) and chemical (pH, fat content, caloric density, osmolality) composition of the chyme emptied from the stomach. Stimulation of these receptors releases secretin, which acts on

pancreatic ductal cells to increase HCO3–secretion, as well as cholecystokinin, which acts on pancreatic acinar cells to increase pancreatic enzyme secretion (lipases, amylases, and proteases). Stimulation of proximal small intestine receptors also activates neural reflexes, which initiate pancreatic enzyme and bicarbonate secretion, stimulate gallbladder emptying, and provide feedback for inhibitory regulation of gastric function (enterogastrone, enterogastric reflex). Removal of these reflexes decreases pancreatic secretion and gallbladder emptying and increases gastric emptying and acid output.

51. Inflammation of the duodenum may lead to increased acid output, hypocalcemia, and microcytic anemia. Increased basal and maximal acid outputs may result from excessive stimulation of the parietal cell (e.g., hypergastrinemia) or reduced inhibitory feedback (i.e., reduced effect of enterogastrone and the enterogastric reflex). The latter may occur when the proximal small intestine is inflamed. Although calcium is absorbed along the entire length of the small intestine, it is absorbed primarily in the duodenum. Similarly, iron is absorbed primarily in the duodenum. Micro-

cytic anemia is the result of reduced stores of iron, the most common anemia. Glucose-6-phosphatase deficiency is the most common metabolic disorder of red blood cells, and is also associated with a microcytic anemia, as is α-thalassemia.

52. Removal of the terminal ileum can lead to diarrhea and steatorrhea. The ter-

minal ileum contains specialized cells responsible for the absorption of pri-

mary and secondary bile salts by active transport. Bile salts are necessary for

adequate digestion and absorption of fat. In the absence of the terminal ileum

there will be an increase in the amounts of bile acids and fatty acids delivered

to the colon. Fats and bile salts in the colon increase the water content of the

feces by promoting the influx (secretion) of water into the lumen of the

colon. Amino acids are absorbed in the jejunum. Iron is primarily absorbed

in the duodenum.

Gastrointestinal neuroendocrine tumors are derived from

the diffuse neuroendocrine system of the GI tract, which is composed of

amine- and acid-producing cells with different hormonal profiles, depending

on the site of origin. The tumors they produce are generally divided into car-

cinoid tumors (ectodermal stem cells) and pancreatic endocrine tumors. One

third of all primary gut tumors are carcinoid. Carcinoid tumors are fre-

quently classified according to their anatomic area of origin (foregut, midgut,

hindgut). Small intestinal (midgut) carcinoid tumors arise from the argentaf-

fin cells of the crypts of Lieberkühn in the terminal ileum, and have a high

serotonin content. Small intestinal carcinoids are the most common cause of

the carcinoid syndrome (classic triad: cutaneous flushing, diarrhea, bron-

chospasm, right heart valvular lesions), which is manifest when they metas-

tasize, but only occurs in 5 to 10% of carcinoid tumors.

53. Both the absorption of Na+ and secretion of K+ from the colon are affected by changes in circulating levels of aldosterone. The major route of absorption of sodium in the colon is electrogenic transport. Because of the “tight” nature of the tight junctions that connect cells in the colon, a relatively large potential difference exists between the mucosal (negative) and serosal (positive) surfaces of the absorptive cells. This electrical difference favors the net secretion of K+

into the lumen. Secretion of HCO3– occurs in exchange for absorption of Cl–. No counterbalancing cation exchange pumps are present in the colon.

54. Although only small amounts of bile acids are lost in the stool each day, the loss represents the only route of elimination of cholesterol from the body. The predominant organic component of bile is the bile salts, which make up about 67% of the total solutes. Bile salts are amphiphilic molecules, that is, they exhibit both water and lipid solubility. Primary bile acids, cholic acid and chenodeoxycholic acid, are synthesized from cholesterol. Secondary bile acids, deoxycholic acid and lithocholic acid, are produced by biotransformation of primary bile acids by intestinal bacteria. Prior to secretion, the bile acids are conjugated with either glycine or taurine, which greatly enhances their water solubility. In general, taurine conjugates are more water-soluble than glycine conjugates.

55. Osmotic diarrhea occurs when ingested, poorly absorbable, osmotically active solutes draw fluid into the lumen of the small intestine or colon leading to osmotic water loss in the stool. In osmotic diarrhea, the stool osmotic gap (290 – 2[Na++ K+]) exceeds 50 mOsm, consistent with an unmeasured solute contributing to the fecal electrolyte content. Osmotic diarrhea generally ceases with fasting or discontinued ingestion of the solute. The most common causes of osmotic diarrhea are (1) lactase (and other disaccharide) deficiency with resultant lactose intolerance and carbohydrate malabsorption, (2) ingestion of magnesium-containing antacids or laxatives, and (3) ingestion of nonabsorbable sugars, such as sorbitol.

Secretory diarrhea, on the other hand, is caused by the overproduction of water by the small and large bowel. Crypt cell secretion of an isosmotic chloride solution increases combined with inhibition of electroneutral NaCl absorption from the small intestine. In contrast to osmotic diarrhea, secretory diarrhea has a normal stool osmotic gap and is not remedied with fasting. The other major patho-physiologic mechanisms of chronic diarrhea include steatorrheal, inflammatory, infectious, dysmotile, radiation injury, and factitial causes.

56. The transport protein responsible for the sodium-dependent glucose transport in the small

intestine is termed the SGLT1 (Na+-glucose transporter). The absorption of glucose occurs through the coordinated action of transport proteins located in the brush border and basolateral membranes of the enterocyte. Glucose uptake into the enterocyte from the lumen of the GI tract occurs primarily via the sodium-dependent SGLT1 secondary active transport mechanism. Glucose exit from the enterocyte into the extracellular fluid occurs by facilitated diffusion and is mediated by the membrane transporter, Glut-2. The Na+ glucose cotransporter also transports galactose. Thus, when the cotransporter is congenitally defective, the resulting glucose and galactose malabsorption causes severe diarrhea that can be fatal if glucose and galactose are not removed from the diet. A similar secondary active transport process (Na+-glucose cotransport) occurs in the renal tubules via SGLT1 and SGLT2. Glut-5 is the membrane transporter located on the apical portion of the enterocyte responsible for the facilitated entry of fructose into the cell.

57. The colon is the major site for the generation and absorption of short-chain fatty acids. They are products of bacterial metabolism of undigested complex carbohydrates derived from fruits and vegetables. In addition to exhibiting trophic effects on the colonic mucosa, they are believed to pro-

mote sodium absorption from the colon. The mechanism of action remains controversial.

58. Medium-chain triglycerides are hydrolyzed by lipases more rapidly than long-chain fatty acids and are much more water-soluble than long-chain triglycerides. Medium-chain triglycerides (MCTs) are fatty acids of 6 to 12 carbon chain lengths that are present in small amounts in the normal diet. MCTs are not utilized for resynthesis of triglycerides and therefore are not packaged into chylomicrons. Instead, they are released directly into the portal blood. Because they are readily absorbed, MCTs can be used in patients with a wide variety of GI diseases resulting in malabsorption.

Long-chain fatty acids are extruded from enterocytes in the form of chylomicrons into the lymphatic system. Triglycerides are hydrolyzed to monoglycerides and taken into mucosal cells. If the fatty acids are short chains (less than 10 to 12 carbon atoms), they are extruded in the form of free fatty acids into the portal blood. Chylomicrons represent triglycerides and esters of cholesterol that have been invested in the intestinal mucosa with a coating of phospholipid, protein, and cholesterol.

58. Iron is transported in the blood bound to the β-globulin, transferrin. Excess iron is stored in all cells, but especially in hepatocytes where it combines with apoferritin. The stored form is called ferritin. The rate of iron absorption is extremely slow, with a maximum of only a few milligrams per day. Iron is absorbed primarily in the ferrous form. Therefore, ferrous iron compounds, rather than ferric compounds, are effective in treating iron deficiency.

59. Somatostatin, located within the gastric antral mucosa, is the principal paracrine secretion involved in the inhibitory feedback of gastric acid secretion by parietal cells. Somatostatin has a short half-life of several minutes, which limits its clinical use, but the analog octreotide (Sandostatin) should be administered subcutaneously to inhibit the secretion of gastrin and gastric

acid and visceral blood flow in patients with bleeding esophageal varices secondary to portal hypertension, after stabilizing with IV fluids, as acute variceal bleeds have a 50% mortality.

Acid secretion is stimulated by acetylcholine (via M3 muscarinic receptors), histamine (via H2 receptors) and gastrin (directly via gastrin receptors and principally via stimulation of histamine secretion by enterochromaffin-like [ECL] cells). Gastrin secretion is stimulated by the amino acids and peptides produced by pepsin’s action in protein digestion.

60. Liberation of the enzyme enteropeptidase (enterokinase) from the duodenal mucosal cells

causes the inactive trypsinogen to be converted to the active form, trypsin. Enteropeptidase contains 41% polysaccharide. It is this high level of polysaccharide that protects enteropeptidase from digestion. Trypsin is responsible for the conversion of chymotrypsinogens and other proenzymes into their active forms.

61. One of the actions of colonic bacteria is to convert NH3 to NH4+. Thus, a total colectomy would increase blood ammonia levels, which would be exacerbated in a person with cirrhosis. NH3 is in equilibrium with NH4+. Most of the NH4+ formed by oxidative deamination of amino acids in the liver is converted to urea, and the urea is excreted in the urine. The NH4+ forms carbamoyl phosphate, and in the mitochondria it is transferred to ornithine by ornithine carbamoyl-transferase forming citrulline. Citrulline is converted to arginine, after which urea is split off and ornithine is regenerated (urea cycle). Most of the urea is formed in the liver, and in severe liver disease the blood urea nitrogen falls and blood NH3 rises.

Normally, about 5 to 10% of bile salts enter the colon. In the colon, bacteria convert the two primary bile acids, cholic acid and chenodeoxycholic acid to the secondary bile acids, deoxycholic acid and lithocholic acid, respectively. Lithocholate is relatively insoluble and is mostly excreted in the stool, but deoxycholate is reabsorbed from the colon, where it is transported back to the liver in the portal vein and reexcreted in the bile (enterohepatic circulation).

Humans can survive after total removal of the colon if fluid and electrolyte balance is maintained. When total colectomy is performed, the ileum is brought out through the abdominal wall

(ileostomy). Advances in surgical techniques make ileostomies relatively trouble-free and patients with them can lead essentially normal lives.

62. The bilirubin in serum represents a balance between input from production of bilirubin and hepatic/biliary removal of the pigment. Hyperbilirubinemia may result from (1) overproduction of bilirubin; (2) impaired uptake, conjugation, or removal of bilirubin; or (3) regurgitation of unconjugated or conjugated bilirubin from damaged hepatocytes or bile ducts.

Alkaline phosphatase, which is excreted in bile, increases in patients with jaundice due to bile duct obstruction, but generally not when the jaundice is due to hepatocellular disease. Bile acids are synthesized in the liver by a series of enzymatic steps that also involve cholesterol catabolism. Liver disease decreases bile acid synthesis.

63. Clearance is a measure of how much plasma is totally cleared of a substance. It is calculated using the formul

Clearance = Uuric acid × V/Puric acid = 36 mg/dL × 1 mL/min / 0.6 mg/dL

= 60 mL/min

Urine volume = 1 mL/min

Urine uric acid = 36 mg/dL

serum uric acid concentration (0.6 mg/dL)

Free Water Clearance (CH2O) = V ˙− Cosmolar

Cosmolar = Uosm × V ˙/Posm , where Uosm = 2 × (UNa+ + UK+)

CH2O = V ˙– [2 (UNa+ + UK+) × V ˙/Posm

CH2O = 1 L/day − [2 (125 mM + 25 mM) × 1 L/day] / 2 × 125 mM

CH2O = − 0.2 L/day

Some Notes

SPECIAL NOTES


1. In an acute respiratory alkalosis, the bicarbonate typically decreases by 2 mM for each 10 mmHg decrease in PCO2; in a chronic respiratory alkalosis, the bicarbonate typically decreases 4 mM for each 10 mmHg decrease in PCO2. In this case the PCO2 has decreased by 30 mmHg. Because bicarbonate has decreased by 12 mM, the diagnosis is consistent with a chronic respiratory alkalosis.



pH = 6.1 + log [HCO3–] / (PaCO2 × 0.03 mmol/L/mmHg)
pH = 6.1 + log 12 mmol/L / (10 mmHg × 0.03 mmol/L/mmHg)
pH = 6.1 + log 40 = 6.1 + 1.6 = 7.7




2. The anion gap is equal to the difference between the plasma concentration of sodium, the major cation in the plasma, and the sum of the concentrations of plasma chloride and bicarbonate, the major measured anions in the plasma.

Anion gap = [Na+]–([Cl–] + [HCO3–])



3. The normal plasma concentrations of Na+, Cl–, and HCO3–are 142, 105,and 24 mEq/L, respectively. The normal anion gap is about 12 mEq/L, and is comprised of minor ions, such as lactate, phosphate, and sulfate. The anion gap is useful in differentiating the causes the metabolic acidosis. In normal anion gap metabolic acidosis, the decline in plasma bicarbonate ion is replaced by an increase in plasma chloride concentration with the concentration of unmeasured minor anions remaining normal, such as occurs with renal or gastrointestinal (GI) losses (e.g., diarrhea). High anion gap metabolic acidosis results from an increase in unmeasured organic anions, such as occurs in the lactic acidosis accompanying tissue hypoxia, the accumulation of ketoacids in diabetes and its resultant coma, or by an increase in organic anions or their metabolic byproducts produced from
such ingested toxins as ethylene glycol, methanol, and salicylates. COPD and myasthenia gravis are causes of respiratory acidosis. Nasogastric suctioning causes metabolic alkalosis.




4. The alkaline pH resulting from the hyperventilation is keeping most of the aspirin in an ionized form in which it cannot easily cross the blood-brain barrier. If the patient is placed on a ventilator to prevent muscle fatigue, it is important to maintain hypocapnic alkalosis or the aspirin will cross the
blood-brain barrier and the situation may become far worse. Gastric lavage with isotonic saline followed by administration of activated charcoal is indicated. Excessive insensible water loss from vaporization of sweat may cause severe volume depletion, requiring fluid replacement. Glucose
should be administered to prevent hypoglycemia.


5. Absorption of cobalamin occurs exclusively from the ileum, where specific receptors on ileal enterocytes bind a complex of cobalamin and intrinsic factor. Although intrinsic factor is secreted by gastric parietal cells, binding of the vitamin to intrinsic factor occurs primarily in the proximal small intestine. The acidic environment of the gastric lumen favors the binding of cobalamin to R protein-type binding proteins that originate from salivary and gastric secretions. Pancreatic proteases in the small intestine degrade the R proteins, and the rise in pH favors rapid and complete transfer of the vitamin to intrinsic factor.




6. The patient’s condition is caused by a decrease in the serum concentration of ionized calcium
(Ca2+), which increases nerve and muscle excitability, leading to spontaneous axonal discharges and muscle contractions, calledhypocalcemic tetany. Decreased serum ionized calcium and thus the symptoms of tetany can appear at higher total calcium levels when respiratory alkalosis is present because the H+ that dissociates from plasma proteins in the presence of a high pH is replaced by Ca2+.





7. Hypothermia reduces hemoglobin’s affinity for oxygen, causing the oxyhemoglobin dissociation curve to shift to the left. With a leftward shift, the saturation of hemoglobin with oxygen is greater than normal at any PO2, as denoted by a lower P50 value than normal. Acidosis, hypercapnia (increased PCO2), and an increase in erythrocyte [2,3–BPG] all cause rightward shifts of the oxyhemoglobin dissociation curve.

8. Factors that shift the curve to the left, such as a decrease in PCO2, an increase in pH, or a decrease in temperature, would increase the percentage of hemoglobin saturated with oxygen as would an
increase in PO2, provided that the percentage of saturation was not already at 100%. At a given PO2, increasing the concentration of hemoglobin would not affect the percentage of saturation but would increase the oxygen content of the blood.



9. CO2 is transported in arterial blood in three forms: as physically dissolved CO2 (about 5%), in combination with the amino groups of hemoglobin as carbaminohemoglobin (about 10%), and as bicarbonate ion HCO3– (about 85%). The amount of CO2 actually carried as carbonic acid, H2CO3, is negligible. Carboxyhemoglobin refers to the combination of carbon monoxide (CO) and hemoglobin.




10. Vitamin K is a fat-soluble vitamin produced by intestinal bacteria that is essential for maintaining normal clotting of blood. The vitamin is essential for hepatic synthesis of prothrombin and factors VII, IX, and X. Common causes of vitamin K deficiency include cholestasis, and factors that limit fat absorption.





11. Warfarin is often prescribed for patients at risk for thromboembolic episodes. Vitamin K is necessary for the conversion of prothrombin to thrombin. Thrombin is an important intermediate in the coagulation cascade. It converts fibrinogen to fibrin and is a powerful activator of platelets. Warfarin interferes with the activity of vitamin K and therefore reduces the likelihood of clot formation. Administering vitamin K can restore coagulation if warfarin therapy leads to excessive bleeding.





12. Normal Hb is 50% saturated at a PO2 of approximately 27 mmHg (the P50), 75% saturated at a PO2 of 40 mmHg (the normal PO2 of mixed venous blood), and 97% saturated at a PO2 of 100 mmHg (the normal arterial PO2). Fetal blood has a higher-than-normal oxygen affinity and therefore is represented by the curve labeled a. Increasing the affinity of Hb for O2 shifts the HbO2 saturation curve to the left and decreases the P50.



13. Aphasias are caused by lesions to the language centers, which are located in the categorical hemisphere of the neocortex. There are a number of different classifications of aphasias, but one divides them into fluent, nonfluent, and anomic aphasias. In this case, the boy developed an anomic aphasia, in which there was no difficulty with his speech and he was able to understand and follow commands, but he had difficulty understanding written language and pictures. Anomic aphasia is the single most common language disturbance seen in head trauma, metabolic encephalopathy, and Alzheimer’s disease. Anomic aphasia can be caused by lesions anywhere within the language
network, but often is caused by damage to the angular gyrus without damage to Broca’s or Wernicke’s areas. A lesion in Broca’s area leads to nonfluent aphasia, such as seen in Pick’s disease. Fluent aphasias are due to lesions to Wernicke’s area or to lesions in and around the auditory cortex. Language disorders caused by memory loss, which could be the result of a hippocampal lesion, are not classified as aphasias, nor are language disorders caused by vision or hearing abnormalities or motor paralysis.





14. The precentral gyrus is the motor area of the cortex that contains the cell bodies of the neurons that form the corticospinal tract (also referred to as the pyramidal tract). The corticospinal tract contains axons that cross to the contralateral side of the brain within the pyramids and end within the motor areas of the spinal cord. These structures are essential for the generation of fine voluntary movements. Kinesthesia, the sense of movement and position of the limbs, is handled primarily by the Ia and Ib afferents that innervate the muscle spindles and Golgi tendon organs, respectively, and by the parietal lobe.



15. In a normal sleep cycle, a person passes through the four stages of slow-wave sleep before entering REM sleep. In narcolepsy, a person may pass directly from the waking state to REM sleep. REM sleep is characterized by irregular heart beats and respiration and by periods of atonia (loss of
muscle tone). Hypoventilation is characteristic of both REM and non-REM sleep because sleep depresses the central chemoreceptors. Brain activity during REM sleep is higher than during wakefulness so there is an increase in brain metabolism. It is also the state of sleep in which
dreaming occurs.


16. In a totally relaxed adult with eyes closed, the major component of the electroencephalogram (EEG) will be a regular pattern of 8 to 12 waves per second, called the α rhythm. The α rhythm disappears when the eyes are opened. It is most prominent in the parieto-occipital region. In deep sleep, the α rhythm is replaced by larger, slower waves called delta waves. In REM sleep, the EEG will show fast, irregular activity.



17. Those within the anterior cerebellum produce ataxia; those within the substantia nigra produce Parkinson’s disease; and those within the limbic system yield emotional disorders. Ataxia, dysmetria, and an intention tremor all are classic findings in a patient with a lesion involving the cerebellum. Affected persons also exhibit adiadochokinesia, which is a loss of ability to accomplish a swift succession of oscillatory movements, such as moving a finger rapidly up and down. High-amplitude EEG waves occur in the late stages of slow-wave sleep.

Parkinson’s disease ischaracterized by resting tremor rigidity and akinesia. It is caused by destruction of the dopamine secreting neurons within the substantia nigra of the basal ganglia. Levo (L)-dopa is a precursor for dopamine. L-dopa, rather than dopamine, is administered because it can cross the blood-brain barrier, but dopamine cannot. In contrast to the resting tremor of Parkinson’s disease, cerebellar disease is characterized by an intention tremor. In contrast to damage to the nigrostriatal dopaminergic system in Parkinson’s disease, Huntington’s disease results in a loss of the intrastriatal GABAergic and cholinergic neurons in the caudate nucleus and putamen of the basal ganglion.





18. Pathologic vertigo is generally classified as peripheral (labyrinthine) or central (brainstem or cerebellum). The clinical presentation in this case is most consistent with central vertigo. Positional (especially horizontal) nystagmus (to-and-fro oscillation of the eyes) is common in vertigo of central origin, but absent or uncommon in peripheral vertigo. The chronicity of the vertigo is characteristic of central vertigo, whereas the symptoms of peripheral vertigo generally have a finite duration and may be recurring. Tinnitus and/or deafness is often present in peripheral vertigo, but absent in central vertigo. The flocculonodular lobe, or vestibulocerebellum, is connected to the vestibular nuclei and participates in the control of balance and eye movements, particularly changes in the vestibuloocular reflex (VOR), which serves to maintain visual stability during head movement; a lesion of this area of the cerebellum may result in vertigo and nystagmus, whereas the spinocerebellum is involved in the coordination of limb movement. Labyrinthitis and Ménière’s syndrome are examples of vertigo of peripheral origin. In psychogenic versus organic vertigo, nystagmus is absent during a vertiginous episode.



19. The catecholamines, norepinephrine and epinephrine, will activate both α- and β-adrenergic receptors. When the α1-adrenergic receptors are stimulated, they activate a G protein, which in turn activates phospholipase C, which hydrolyzes PIP2 and produces IP3 and DAG. The IP3 causes the release of Ca2+ from the sarcoplasmic reticulum, which in turn increases muscle contraction. α1-Adrenergic receptors predominate on arteriolar smooth muscle, so these muscles contract when stimulated with norepinephrine. The bronchiolar, pupillary, and ciliary smooth muscles all contain β- receptors, which cause smooth muscle relaxation. The intestinal smooth muscle relaxation is initiated by an α2-adrenergic receptor.




20. These variations in activity are called circadian rhythms and are controlled by the suprachiasmatic nucleus of the hypothalamus. The paraventricular nucleus secretes oxytocin and vasopressin, the ventromedial and lateral nuclei control food intake, and the arcuate nucleus secretes gonadotropin-releasing hormone.



21. Activating nociceptors on the free nerve endings of C fibers produces ischemic pain. The C fibers synapse on interneurons located within the substantia gelatinosa (laminas II and III) of the dorsal horn of the spinal cord. The pathway conveying ischemic pain to the brain is called the paleospinothalamic system. In contrast, well-localized pain sensations are carried within the neospinothalamic tract. Ischemic pain does not adapt to prolonged stimulation. Pain is produced by specific nociceptors and not by intense stimulation of other mechanical, thermal, or chemical receptors.



22. The hypothalamus regulates body temperature. Core body temperature, the temperature of the
deep tissues of the body, is detected by thermoreceptors located within the anterior hypothalamus. The anterior hypothalamus also contains neurons responsible for initiating reflexes, such as vasodilation and sweating, which are designed to reduce body temperature. Heat-producing reflexes, such as shivering, and heat-maintenance reflexes, such as vasoconstriction, are initiated by neurons located within the posterior hypothalamus.


23. The visual receptor cells, the rods and cones, are depolarized when the eyes are in the dark. When exposed to light, they hyperpolarize. Light causes the rods and cones to hyperpolarize by activating a G protein called transducin, which leads to the closing of Na+ channels. Auditory receptors are depolarized by the flow of K+ into the hair cells. Touch receptors are activated by opening channels through which both Na+ and K+ can flow. Depolarization is caused by the inward flow of Na+. Smell and taste receptors are activated by G protein-mediated mechanisms, some of which cause the receptor cell to depolarize; other G proteins cause the release of synaptic transmitter without any change in membrane potential.

Transducin is the G protein activated by rhodopsin when light strikes the eye. Transducin activates a phosphodiesterase that hydrolyzes cGMP. When cGMP concentrations within the rods or cones decrease, sodium channels close, sodium conductance decreases, and the cell membrane potential becomes more negative (hyperpolarizes). Hyperpolarization of the cell causes a decrease in the
release of neurotransmitter. Eventually the all-trans retinal dissociates from opsin and reduces the concentration of rhodopsin in the cell



24. g-Aminobutyric acid (GABA) is the major inhibitory mediator in the brain. GABA-A receptors are pentameric Cl–ion channels that are widely distributed in the CNS. The increase in Cl–
conductance produced by GABA-A receptors is potentiated by the anxiolytic drug, diazepam, and other benzodiazepines. Glutamate is the major excitatory transmitter in the brain. Neuropeptide Y is an excitatory neurotransmitter that has a stimulatory effect on food intake. Central nervous system actions of histamine have been implicated in arousal, sexual behavior, drinking, pain thresholds, and the sensation of itch. Antagonism of central NK-1 receptors has antidepressant activity in humans.




25. Among the causes of acute vision loss, detachment of the retina is painless, and accompanied by floaters, flashing lights, and a scotoma in the peripheral visual field corresponding to the detachment. Another cause of sudden painless vision loss is a transient ischemic attack of the retina, also called amourosis fugax. Amourosis fugax usually results from an embolus that lodges in a retinal arteriole. Complete occlusion of the central retinal artery produces arrest of blood flow and a milky retina with a cherry red spot on the fovea. Optic neuritis is a common inflammatory disease of the optic nerve that is accompanied by eye pain, especially with eye movements. It is caused by demyelination, and often progresses to multiple sclerosis. Glaucoma and macular degeneration cause chronic vision loss. Glaucoma is the leading cause of blindness in African-Americans; it is a slowly progressive, insidious optic neuropathy. Macular degeneration is the major cause of gradual, painless, bilateral central blindness in the elderly.



26. Mammalian nerve fibers are classified into A, B, and C groups, and A fibers are further subdivided into α, β, γ, and δ fibers, each of which has different histologic characteristics and functions. Aβ fibers have touch, pressure, and motor functions. The dorsal root C fibers conduct some impulses generated by touch and other cutaneous receptors, as well as impulses generated by pain and temperature receptors. Aβ fibers are most susceptible to pressure and C fibers are least susceptible to pressure, which explains why a limb with a transiently compressed nerve loses motor function, but not pain sensation. B fibers are preganglionic autonomic nerves (autonomic postganglionic fibers, vagal fibers); they are most susceptible to hypoxia, whereas C fibers are least susceptible to hypoxia. Local anesthetics depress transmission in the group C fibers before they affect the touch fibers in the A group. C fibers are unmyelinated, whereas A and B fibers are myelinated. In addition, C fibers generally have smaller diameters than A or B fibers. For both reasons, C fibers have lower conduction velocities than A fibers.

The upstroke of the action potential is caused by an inward flow of sodium ions, and therefore its magnitude depends on the extracellular sodium concentration. Decreasing the external Na+
concentration decreases the size of the action potential, but has little effect on the resting membrane potential because the permeability of the membrane to Na+ at rest is low. Conversely, increasing the external K+ concentration decreases the resting membrane potential. Changes in external Ca2+ concentration affect the excitability of nerve and muscle cells, but not the magnitude of the resting potential or the action potential

When the permeability of a particular ion is increased, the membrane potential moves toward the equilibrium potential for that ion. The equilibrium potentials for chloride (–80 mV) and potassium (–92 mV) are close to the resting membrane potential, so increases in their permeability have little effect on the resting membrane potential. The equilibrium potential for sodium (+60 mV) is very far from the resting membrane potential. Thus, increasing the permeability for sodium causes a large depolarization.


Peripheral nerves consist of primary sensory afferent axons, motor neurons, and sympathetic
postganglionic neurons. Primary sensory afferent nerves include those with large-diameter A-beta (Aβ), which normally are not involved in pain, as well as two populations of primary afferent nociceptors, the small-diameter myelinated A-delta (Aδ) and unmyelinated (C fiber) axons, which are both present in nerves to the skin and to deep somatic and visceral structures. Many Aδ and C fibers innervating viscera are completely insensitive in normal, uninjured, noninflamed tissue, but become sensitive to mechanical stimuli in the presence of inflammatory mediators. An important concept to emerge in recent years is that afferent nociceptors also have a neuroeffector function, in that they contain polypeptide mediators that are released from their nerve terminals when activated. Most notably, Substance P, an 11-amino acid polypeptide found in neurons within the hypothalamus and spinal cord, is released from small Aδ and C fibers that relay information from nociceptors to neurons within the substantia gelatinosa of the spinal cord. The biologic actions of substance P include vasodilation, neurogenic edema and the accumulation of bradykinin, the release of histamine from mast cells and the release of seratonin from platelets. Endorphins and other opioid peptides such as the enkephalins may partially inhibit the perception of pain by presynaptically inhibiting the release of substance P from nociceptor afferent fibers.





27. Guillain-Barré Syndrome (GBS) is an acute, rapidly evolving demyelinating polyradiculopathy, that generally manifests as an areflexic ascending motor paralysis and is autoimmune in nature. The basis for the flaccid paralysis and sensory disturbance is conduction block in the Aβ fibers; axonal conduction remains intact unless there is secondary axonal degeneration. Most cases are preceded by a viral upper respiratory infection or a GI infection.The
postulated immunopathogenesis of GBS associated with C. jejuni infection involves production of autoantibodies against gangliosides present on the surface of Schwann cells, causing widespread myelin damage. The wide spread administration of the swine influenza vaccine in the United States in 1976 was associated with an increased occurrence of GBS, but influenza vaccines in use from 1992 to 1994 resulted in only one additional case of GBS per million persons vaccinated. Older type rabbies vaccines prepared in nervous system tissue are still used in developing countries and are thought to be a trigger for GBS, presumably via immunization of neural antigens. Nerve growth factor is necessary for the growth and maintenance of sympathetic neurons and some sensory neurons, not motoneurons. Experimental injection of antiserum against nerve growth factor in new born animals produces an immunosympathectomy. Oligodendrogliocytes are involved in myelin formation in the CNS, whereas Schwann cells are involved in myelin fomation in peripheral nerves.




28. Muscarine binds to acetyl- choline muscarinic receptors on cardiac and smooth muscle. These are the same receptors activated by the release of acetylcholine by the vagus nerve. Cardiac muscarinic receptors decrease the rate of phase 4 depolarization and therefore, decrease the heart rate. A heart rate less than 60 beats per minute is called bradycardia. Acetylcholine receptors on the skeletal muscle end plate are nicotinic receptors and do not respond to muscarine. Dilation of the pupils and hypertension are signs of sympathetic, not parasympathetic activity.



29. Epinephrine (adrenalin) acts on both α- and β-adrenergic receptors, but has a greater affinity for β-adrenergic receptors. Activation of β2-adrenergic receptors leads to relaxation of smooth muscle in the bronchi, vasculature, intestine, uterus, and bladder, to increased pancreatic insulin and glucagon secretion, and an increase in liver glycogenolysis. The bronchodilator effects of epinephrine are key in the treatment of the life-threatening effects of anaphylactic shock. Activation of β1- and β2-adrenergic receptors in the heart leads to an increase in the rate of SA nodal phase 4 depolarization and thus heart rate (positive chronotropic response), an increase in contractility (positive inotropic response), an increase in conduction velocity (positive dromotropic response), and an increase in cardiac excitability/irritability. The transport of Ca2+ into skeletal muscle fibers is not affected by β-receptors. The effects of epinephrine-induced β-adrenergic receptor activation are due to G-protein mediated activation of adenylate cyclase, which catalyzes the formation of cyclic adenosine monophosphate (cAMP) and activation of protein kinase A.




30. The Ruffini ending is a tonic receptor that produces a train of action potentials proportional to the intensity of pressure applied to the skin. The Pacinian corpuscle is a very rapidly adapting receptor that fires once or twice in response to skin deformation, but can produce a continuous train of action potentials if the stimulus is repetitively applied and withdrawn. Therefore, the Pacinian corpuscle is used to encode vibration.



31. Narcolepsy is associated with low CSF levels of the orexins and a defect in one of the receptors for orexins (hypocretins) in the hypothalamus. Adenosine induces sleep and serotonin agonists suppress sleep. Fatal familial insomnia is a progressive prion disease, characterized by worsening insomnia, impaired autonomic and motor functions, dementia, and death.



32. In both smooth and striated muscle, contraction is produced by the cross-bridge cycle in which the cross-bridge on the thick filament binds to the actin molecule on the thin filament. In excitation-contraction coupling in striated muscle, calcium initiates contraction by binding to troponin. The calcium-activated troponin then acts to remove the tropomyosin-mediated inhibition of the actin-myosin interaction. In excitation-contraction coupling in smooth muscle, calcium initiates contraction by binding to calmodulin. The calcium-activated calmodulin then activates the myosin light chain protein kinase enzyme, which phosphorylates the myosin light chains. Actin-myosin interaction follows light-chain phosphorylation.



33. Strenuous exercise and a high protein diet can cause overproduction of uric acid. Allopurinol, which inhibits xanthine oxidase, decreases the primary cause of gout by decreasing uric acid production. Colchicine is given in acute gout to inhibit phagocytosis of uric acid crystals by leukocytes, a process that in some way produces the joint symptoms. Nonsteroidal anti-inflammatory agents, particularly indomethacin, are also used to relieve the acute arthritic symptoms of gout. Aspirin is contraindicated in acute gout because it decreases urate excretion. Uricosurics are effective in increasing the excretion of uric acid in patients whose gout is caused by decreased urate excretion, such as chronic renal disease, diabetes ketoacidosis, use of thiazide diuretics, and ethanol ingestion.



34. Decreasing extracellular Ca2+ will increase the excitability of skeletal muscle fibers but does not have a direct effect on contractile force. Increasing the Mg2+ concentration will decrease skeletal muscle excitability. Increasing the preload beyond 2.2 mm decreases the overlap between thick and thin filaments and therefore decreases the force of contraction. Increasing the activity of
acetylcholine esterase enhances the hydrolysis of ACh and therefore decreases the likelihood that muscle contraction will be initiated.


36. The end-plate potential in skeletal muscle is produced by an influx of sodium into the cell, which results from the increase in sodium permeability that occurs with acetylcholine binding to the nicotinic receptors on the membrane of the motor end plate. Acetylcholine binding at the motor end plate also increases the potassium conductance of the membrane. The plateau phase of ventricular muscle action potentials and the upstroke of smooth muscle action potentials are produced by an increase in calcium conductance. An increase in potassium conductance is responsible for the down stroke of the action potential. The refractory period is caused by an increase in potassium conductance and a decrease in the number of sodium channels available to produce an action potential (i.e., sodium channel inactivation).



38. The alveolar oxygen tension is calculated using the modified alveolar gas equation:
PAO2 = PIO2 – PaCO2/R.
PAO2 = [0.5 × (747 – 47 mmHg)] – 40 mmHg/0.8
PAO2 = 350 mmHg – 50 mmHg = 300 mmHg.



37. Both the central chemoreceptors, located on or near the ventral surface of the medulla, and the peripheral chemoreceptors, in the carotid and aortic bodies, cause an increase in ventilation in
response to an increase in PaCO2. The peripheral chemoreceptors also cause an increase in ventilation in response to a decrease in arterial pH and a decrease in PaO2, but the central chemoreceptors are unresponsive to hypoxemia and do not cause an increase in ventilation in response to a decrease in arterial pH because the blood-brain barrier is relatively impermeable to
hydrogen ions. Neither the central chemoreceptors nor the carotid bodies are stimulated by a decrease in arterial blood pressure or O2 content.




38. The oxygen consumption can be calculated if the cardiac output (CO) and the difference between the arterial and venous oxygen content are known using the Fick equation:
V ˙O2 = CO × (CaO2 – CVO2)
V ˙O2 = 6 L/min × (18 mL/dL – 14 mL/dL)
V ˙O2 = 240 mL/min


The fraction of the pulmonary blood flowing bypassing the lung (the shunt, Q ˙S) compared to the total pulmonary blood flow (Q ˙T) is calculated using the equation
Q ˙S/Q ˙T = C´ cO2 – CaO2 / C´ cO2 – CVO2
= 19 mL/dL – 18 mL/dL
19 mL/dL – 14 mL/dL
= 0.2
where C´ c is the end pulmonary capillary blood oxygen content, CaO2 is thearterial oxygen content, and CVO2 is the mixed venous oxygen content. At a resting cardiac output, the normal amount of shunting is 3–5% of the cardiac output. In this case, there is a 20% shunt.




39. The decrease in arterial oxygen saturation caused by carbon monoxide poisoning reduces the oxyhemoglobin and thus total arterial oxygen contents but does not reduce the amount of oxygen dissolved in the plasma, which determines the arterial oxygen tension. Carbon monoxide is odorless and tasteless and dyspnea and resiratory distress are late signs, which is the reason that it is so important to install carbon monoxide detectors in homes and businesses. Respiratory distress becomes manifest with severe tissue hypoxia and anaerobic glycolysis, which leads to lactic acidosis. The decrease in arterial pH stimulates ventilation via the peripheral chemoreceptors. The resultant hyperventilation decreases arterial (and CSF) PCO2, causing CSF pH to rise. Carboxyhemoglobin has a cherry-red color.




40. Lung compliance is an index of lung distensibility or the ease with which the lungs are expanded; thus, compliance is the inverse of elastic recoil. Compliance is defined as the ratio of change of lung volume to the change in pressure required to inflate the lung (∆V/∆P). Compliance decreases in patients with pulmonary edema or surfactant deficiency and increases when there is a loss of elastic fibers in the lungs, such as occurs in patients with emphysema and with aging.




41. Early systolic murmurs begin with the first heart sound and end in mid-systole. The higher-than-normal height of the jugular blood column reflects an increased right atrial pressure. The combination of an early systolic murmur and high right atrial pressure is indicative of tricuspid regurgitation. This lesion is common in narcotic abusers with infective endocarditis. Mitral stenosis and aortic regurgitation produce diastolic murmurs.



42. Phase-4 depolarization is caused by the activation of a Na+ channel. The channel is activated
when the membrane hyperpolarizes in contrast to the Na channel responsible for the action potential, which is activated when the cell depolarizes. Potassium conductance decreases during phase-4 depolarization and thus the flow of potassium out of the cell is diminished. However, this change in potassium current is not responsible for phase-4 depolarization. Chloride conductance does not change during phase 4. The Na/Ca exchanger maintains low intracellular calcium at rest and may reverse its direction and pump calcium into the cell during phase 2 of the cardiac action potential. However, neither the Na/Ca exchanger nor the Na-K pump is involved in phase-4 depolarization.


43. The increase in radius of the dilated ventricle increases wall tension (stress) according to the Laplace relation-ship,
T = Pr/w,
(where T = tension, P = systolic pressure, r = ventricularradius, and w = ventricular wall thickness.) The increase in wall tension requires an increase in energy consumption. The increase in preload
increases the left ventricular end-diastolic pressure. Because the pulmonarycapillaries are supplying the blood to the left ventricle, an increase in left ventricular end-diastolic pressure must be accompanied by an increase in pulmonary capillary hydrostatic pressure. The decrease in left ventricular contractility associated with heart failure causes the ejection fraction to decrease. Heart rate will be increased by the increased sympathetic nerve activity that accompanies heart failure.



At which point on the ventricular action potential is membrane potential most dependent on calcium
permeability?
The plateau phase (phase 2) is the result of the influx of calcium. Although calcium channels
begin to open during the upstroke (phase 0), the greatest number of calcium channels is open during the plateau. The upstroke is primarily dependent on the opening of Na+ channels. The initial repolarization (phase 1) is dependent on the inactivation of Na+ channels and the opening of a tran-
sient K+ channel. Repolarization (phase 3) is produced by the inactivation of Ca2+ channels and the activation of the delayed rectifier K+ channels.


44. he left ventricular pressure-volume loop represents the changes in pressure and volume that
occur during a cardiac cycle. Point E represents the end of the filling phase and the beginning of the isovolumic contraction phase. At this point, the pressure in the left ventricle increases above the pressure in the left atrium, causing the mitral valve to close. The retrograde flow of blood against the closed mitral valve produces the first heart sound. Systole is defined as the period between the first and second heart sounds and includes the isovo lumic contraction and ejection phases. Aortic pressure continues to fall during the isovolumic contraction phase so that the rise in aortic blood
pressure (which begins at point D) lags behind the beginning of systole. Point B represents the end of the ejection phase. At this point, the pressure in the left ventricle falls below the pressure in the aorta, and the aortic valve closes. The retrograde flow of blood against the closed aortic valve pro-
duces the second heart sound. Point A represents the end of the isovolumic relaxation phase and the beginning of the filling phase. At the point the pressure in the left ventricle falls below that in the left atrium, the mitral valve opens and blood begins to flow into the left ventricle.

Sorry folks I was too busy maintaining the balancing the act between my job & preparation. We have conducted a medical camp recently.
Well, the preparations are a bit hampered. I will try to cover up as much as possible.
I came across a new site with lot of books & preparation material, I am giving the URL below--

http://www.medishared.com/forumdisplay.php?f=125

Bye for now will be posting more.