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Angiotensin-Converting Enzyme (ACE) is an peptidase that catalyses the conversion of

Angiotensin I to Angiotensin II, a potent vasoconstrictor.

ACE can also inactivate bradykinin, a potent vasodilator.

Angiotensin II is a more potent vasoconstrictor than Angiotensin I. Inhibiting ACE to preventing

the formation of Angiotensin II (and to some extent, to also prevent the breakdown of bradykinin)
is a common strategy to treat high blood pressure.

The ACE gene encodes 2 isozymes. The somatic ACE isozyme is expressed in many tissues,
including vascular endothelial cells, renal epithelial cells, and testicular Leydig cells, whereas the
germinal ACE isozyme is expressed only in sperms.

ACE is also known as:

peptidyl dipeptidase A
carboxycathepsin
kininase II
CD 143
ACE 1 (A second ACE gene, ACE 2 (http://content.nejm.org/cgi/content/extract/347/22/1795),
has recently been identified. ACE 2 has direct effects on cardiac function, and is expressed
predominantly in vascular endothelial cells of the heart and the kidneys. Whereas ACE 1 converts
Angiotensin I to Angiotensin II, which has 8 amino acids, ACE 2 converts Angiotensin I to
Angiotensin[1-9], which has 9 amino acids. Whereas Angiotensin II is a potent vasoconstrictor,
Angiotensin[1-9] has no effect on blood vessels but can be converted by ACE 1 to a shorter
peptide, Angiotensin[1-7], which is a mild vasodilator.)

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Common Laboratory Tests;;;;;;;;;;

This chapter discusses the normal and pathologic values for commonly ordered tests of the blood
(cells and chemistries), urine, cerebrospinal fluid, and other serous fluids. The tests discussed
here are those in common use for helping to formulate physiologic and diagnostic hypotheses.
There are many more tests used in the diagnosis of a specific disease. These tests are highly
specific, but may not be sensitive. They are a useful means for confirming an hypothesis, but
should not be used until a narrow differential diagnosis has been established. These more
specific tests are not discussed here.

Laboratory tests are ordered by the clinician for one of four reasons:

1. Screening: A small number of tests have been demonstrated to find "silent" disease in the
patient who has no symptoms or signs or specific risk factors for the disease. Common examples
include testing for hemochromatosis with iron studies and for hypercholesterolemia.

2. Case finding: Some tests are used to find disease in specific clinical populations at risk, even if
signs or symptoms are not present. They differ from screening tests because they are not used in
the general population. An example is testing the bone density of elderly women for osteoporosis.

3. Diagnosis: This is the use of tests to assist in making (or excluding) a diagnosis suggested by
the symptoms and signs in patients.

4. Monitoring: Tests are often used to monitor the progress of disease, response to therapy, or
concentration of medication.

Blood Chemistries

ALKALINE PHOSPHATASE, SERUM. Pathophysiology: This includes a number of cellular

enzymes that hydrolyze phosphate esters. They are named from their optimum activity in alkaline
media. High concentrations of the enzymes occur in the blood during periods of rapid growth,
either physiologic or pathologic, and from cellular injury. The enzymes are normally plentiful in
hepatic parenchyma, osteoblasts, intestinal mucosa, placental cells, and renal epithelium.
Abnormally rapid growth or cell destruction will augment the blood concentration of these
enzymes.

Normal Alkaline Phosphatase: 30-120 U/L (SI Units: 0.5-2.0 nkat/L). It is high in newborns,
declining until puberty and then rising every decade after 60 years of age.

Increased Alkaline Phosphatase. This is usually associated with disorders of bone, liver or the
biliary tract. CLINICAL OCCURRENCE: Technical Error dehydration of blood specimen;
Endocrine hyperparathyroidism (osteitis fibrosa cystica), acromegaly, hyperthyroidism (effect on
bone), subacute thyroiditis, last half of pregnancy; Idiopathic Paget disease, benign transient
hyperphosphatasemia; Infectious liver infections (hepatitis, abscesses, parasitic infestations and
infectious mononucleosis), chronic osteomyelitis; Inflammatory/Immune primary biliary cirrhosis,
sarcoidosis; Mechanical/Trauma healing fractures, common bile duct obstruction from stone or
carcinoma, intrahepatic cholestasis, passive congestion of the liver; Metabolic/Toxic
osteomalacia, rickets, drug reactions (intrahepatic cholestasis), chlorpropamide, ergosterol,
sometimes intravenous injection of albumin, pernicious anemia, hyperphosphatasia, dehydration,
rapid loss of weight; Neoplastic osteoblastic bone tumors, metastatic carcinoma in bone,
myeloma, liver metastases, cholangiocarcinoma; Neurologic cerebral damage; Psychosocial
abuse with skeletal trauma; Vascular myocardial, renal, and sometimes pulmonary infarction.

Decreased Alkaline Phosphatase. CLINICAL OCCURRENCE: Technical Errors use of oxalate in

blood collection; Endocrine hypothyroidism; Idiopathic osteoporosis; Inflammatory/Immune celiac
disease; Metabolic/Toxic vitamin D toxicity, scurvy (vitamin C deficiency), milk-alkali syndrome,
pernicious anemia/B12 deficiency.

ANION GAP, SERUM. Pathophysiology: The anion gap is the difference between the
concentrations of measured cations and the measured anions in the blood, measured in
milliequivalents per liter, mEq/L: AG = [Na+] - ([Cl-] + [HCO3-]). The anion gap accounts for
phosphates, sulfates, amino acids, and albumin.

Normal Anion Gap: 12 ± 2.

Increased Anion Gap. An increased anion gap indicates the accumulation of organic acids and
the presence of an anion gap metabolic acidosis. CLINICAL OCCURRENCE: Ketoacidosis
(diabetes, alcoholism, starvation), intoxication with salicylates, methanol or ethylene glycol, lactic
acidosis, or renal failure.

Decreased Anion Gap. This occurs uncommonly and suggests the accumulation of positively
charged proteins in the blood. CLINICAL OCCURRENCE: Multiple myeloma.

ALANINE AMINOTRANSFERASE, SERUM: ALT. Pathophysiology: This enzyme occurs mostly

in hepatocytes with smaller quantities in skeletal and heart muscle. It is released into the
circulation when cells are damaged or necrotic.

Normal Concentration: 0-35 U/L (SI units: 0-0.58 mkat/L).

Increased ALT. Increased ALT usually indicates damage to the liver, although severe damage to
skeletal muscle can produce significant elevations. CLINICAL OCCURRENCE: Infectious viral
hepatitis, infectious mononucleosis, liver abscess; Mechanical/Trauma passive liver congestion,
extrahepatic biliary obstruction; Metabolic/Toxic drug-induced liver disease, alcohol; Neoplastic
hepatocellular carcinoma, liver metastases.

ASPARTATE AMINOTRANSFERASE, SERUM: AST. Pathophysiology: This enzyme is

concentrated mostly in the cells of the heart, liver, muscle, and kidney; lesser amounts are in
pancreas, spleen, lung, brain, and erythrocytes. Tissue injury releases the enzyme into the
extracellular fluids, but not necessarily in amounts proportionate to the injury.

Normal AST: 9-40 U/L.

Increased AST. This usually reflects damage to the liver, the muscles, including the heart, and,
less commonly, to other organs. It usually rises in concert with the ALT. When the AST is ≥2.0
times the ALT, alcohol abuse with cirrhosis or alcoholic hepatitis should be suspected. CLINICAL
OCCURRENCE: Technical Error false-positive from opiates and erythromycin, dehydration of
blood specimen; Congenital muscular dystrophy; Endocrine diabetes mellitus; Idiopathic Paget
disease, cholecystitis; Infectious viral hepatitis, pulmonary infections; Inflammatory/Immune
hemolytic diseases, polymyositis, pancreatitis, regional ileitis, ulcerative colitis;
Mechanical/Trauma severe exercise, clonic and tonic seizures, crushing or burning or necrosis of
muscle, inflammation from intramuscular injections, rhabdomyolysis, peptic ulcer, extrahepatic
biliary obstruction; Metabolic/Toxic hepatic necrosis and drug-induced hepatitis, uremia,
myoglobinemia, pernicious anemia, drugs (salicylates, alcohol), dehydration; Neoplastic bone
metastasis, myeloma; Neurologic; Psychosocial; Vascular myocardial, renal and cerebral
infarction.

Decreased AST. CLINICAL OCCURRENCE: Endocrine pregnancy; Metabolic/Toxic chronic

dialysis, uremia, pyridoxine deficiency, ketoacidosis, beriberi, severe liver disease.

BICARBONATE, TOTAL SERUM (HCO3-, CO2 CONTENT). Pathophysiology: Bicarbonate

(HCO3-) is formed in the kidney by carbonic anhydrase and diffused through the body fluids as
ionized bicarbonate in association with sodium. Bicarbonate is the major buffer consumed when
protons (H+) are produced by the metabolism of amino acids or the increased production or
ingestion of organic acids. It accumulates to buffer the acidosis of hypoventilation (increased
PaCO2). In respiratory alkalosis with a low PaCO2, the kidney excretes bicarbonate to maintain
the blood pH and the bicarbonate concentration falls.

Normal Serum Bicarbonate: 22-26 mEq/L (SI: 22-26 mmol/L).

Increased Bicarbonate. This indicates a metabolic alkalosis, either primary or secondary to a

respiratory acidosis. CLINICAL OCCURRENCE: Endocrine hyperaldosteronism, Cushing
disease, severe hypothyroidism; Metabolic/Toxic primary metabolic alkalosis (diarrhea, gastric
suction, nausea, and vomiting), diuretics (especially loop diuretics), hypercapnia; Psychosocial
bulimia, purging.

Decreased Bicarbonate. A decreased bicarbonate concentration indicates the presence of a

metabolic acidosis. These are further classified by the anion gap, see page 935. CLINICAL
OCCURRENCE: Endocrine Addison disease; Metabolic/Toxic hypocapnia from hyperventilation,
metabolic acidosis, for example, renal failure, ketoacidosis (diabetic, alcoholic, starvation), lactic
acidosis, salicylate intoxication, methanol or ethylene glycol intoxication, renal tubular acidosis.

BILIRUBIN, TOTAL SERUM. Pathophysiology: See Jaundice, page 539. Unconjugated bilirubin
is insoluble in water until conjugated in the liver with glucuronic acid. Four-fifths or more is derived
from the catabolism of the heme from aging erythrocytes. The water-soluble conjugated bilirubin
is normally excreted in the bile. It is bound to the plasma proteins; when the level exceeds 0.4
mg/dL, the water-soluble form appears in the urine.

Normal Serum Bilirubin: 0.3-1.0 mg/dL (SI Units: 5.1-17 mmol/L).

Increased Bilirubin: Hyperbilirubinemia. Increased bilirubin indicates an increased breakdown of

red blood cells or failure of hepatic excretion. CLINICAL OCCURRENCE: Congenital Dubin-
Johnson disease, Gilbert syndrome; Idiopathic acute cholecystitis; Infectious viral hepatitis,
infectious mononucleosis; Inflammatory/ Immune hemolysis; Mechanical/Trauma common bile
duct obstruction, hemolysis; Metabolic/Toxic drug-induced hepatitis, alcoholic hepatitis, cirrhosis,
or any cause; Vascular pulmonary infarction, gastrointestinal bleeding, hematoma.

Unconjugated Hyperbilirubinemia. This is caused by hemolysis, ineffective erythropoiesis,

decreased hepatic uptake of unconjugated bilirubin (Gilbert syndrome), or impaired hepatic
conjugation (neonatal jaundice, drugs or Crigler-Najjar syndrome).

Conjugated Hyperbilirubinemia. Because the liver is able to conjugate bilirubin, the problem is
either hepatocyte excretion (Dubin-Johnson syndrome, Rotor syndrome), intrahepatic cholestasis
(hepatitis, drugs, granulomatous disease), or bile duct obstruction.

Decreased Bilirubin: Hypobilirubinemia. Nonhemolytic anemias and hypoalbuminemia.

BLOOD UREA NITROGEN, SERUM: BUN. Pathophysiology: Molecular weight 60. Urea is
synthesized in the liver from ammonia derived from the metabolism of protein in the body and gut.
It is filtered and reabsorbed by the kidney; reabsorption is inversely related to the rate of urine
flow.

Normal Serum Blood Urea Nitrogen (BUN): 10-20mg/dL (SI Units: 3.6-7.1 mmol/L).

Increased BUN. An increase indicates decreased glomerular filtration and/or increased tubular
reabsorption, or increased production in the gut from ingested protein or blood. CLINICAL
OCCURRENCE: Prerenal hypotension, hemorrhage, dehydration (vomiting, diarrhea, excessive
sweating), Addison disease, hyperthyroidism, heart failure, sepsis, upper gastrointestinal
hemorrhage, increased protein ingestion; Renal any cause of acute or chronic renal insufficiency;
Postrenal obstruction of the ureters, bladder, or urethra.

Decreased BUN. CLINICAL OCCURRENCE: Low-protein diets, muscle wasting, starvation,

cirrhosis, cachexia, high urine flow.

BUN:Creatinine Ratio Greater than 10:1. This indicates relatively preserved glomerular filtration
with either increased urea production or decreased urine flow. CLINICAL OCCURRENCE:
Excessive protein intake, blood in the gut, excessive tissue destruction (cachexia, burns, fever,
corticosteroid therapy); postrenal obstruction, inadequate renal circulation (heart failure,
dehydration, shock).

BUN:Creatinine Ratio Less than 10:1. This indicates decreased urea production. CLINICAL
OCCURRENCE: Low protein intake, multiple dialyses, severe diarrhea or vomiting, hepatic
insufficiency.

B-TYPE NATRURETIC PEPTIDE. Pathophysiology: Heart failure is accompanied by increased

wall tension in the ventricles and atria because of dilation. Natruretic peptides types A and B are
released into the circulation in congestive heart failure.

Normal Concentration: 400 ng/dL, often >1000 ng/dL), inflammation, infection, or cancer.

Decreased Serum Ferritin. CLINICAL OCCURRENCE: Iron deficiency.

GLUCOSE, SERUM. Pathophysiology: This is a six-carbon monosaccharide, a primary energy

source for metabolism. The serum level remains fairly constant during fasting; there is a
moderate rise after the ingestion of food. Hepatocytes convert other carbohydrates to glucose.
Surpluses of glucose are converted to glycogen in the liver and muscle, or form fat that is
deposited throughout the body, predominately in adipocytes. Glucose uptake by the liver, muscle,
and adipocytes is insulin dependent. After an average meal, the normal person has a blood sugar
rise to approximately 180 mg/dL serum; this returns to normal fasting levels within 2 hours.
Higher blood glucose levels result from excessively rapid absorption or impaired peripheral
disposition, usually related to insulin insufficiency or resistance. When the blood concentration of
glucose becomes high, the tubular reabsorption threshold is exceeded and glucose is excreted in
the urine (glycosuria). The normal renal threshold occurs at a serum glucose of 160-190 mg/dL.
This may be higher in a damaged kidney.

Normal Serum Glucose: 75-110 mg/dL (SI Units: 4.2-6.4 mmol/L).

Diagnostic Criteria for Diabetes.

1. A fasting glucose of ≥126 mg/dL (SI Units: ≥7.0 mmol/L); or

2. Symptoms of diabetes plus a random glucose of ≥200 mg/dL (SI Units: ≥11.1 mmol/dL); or

3. A plasma glucose ≥200 mg/dL (SI Units: ≥11.1 mmol/L) 2 hours following a 75-g oral glucose
load.

The abnormal test must be confirmed on another day.

Diagnostic of Impaired Fasting Glucose (IFG). A fasting glucose of 110-126 mg/dL (SI Units: 6.1-
7.0 mmol/L).

Diagnostic of Impaired Glucose Tolerance (GT). A blood glucose of 140-199 mg/dL (SI Units: 7.8-
11.0 mmol/L) 2 hours after a 75-g oral glucose load.

Increased Glucose: Hyperglycemia. Hyperglycemia indicates insulin resistance from the

metabolic syndrome, diabetes or release of stress-associated hormones (epinephrine, cortisol,
growth hormone). CLINICAL OCCURRENCE: Endocrine diabetes mellitus, impaired glucose
tolerance, acromegaly, hyperthyroidism, Cushing disease, increased adrenalin,
adrenocorticotropic hormone (ACTH), pheochromocytoma, pregnancy, toxemia of pregnancy;
Infectious any acute severe infection, for example, pneumonia; Inflammatory/Immune systemic
inflammatory response syndrome (SIRS), regional enteritis, ulcerative colitis; Metabolic/Toxic
drugs (corticosteroids, diazoxide, epinephrine), poisoning (streptozotocin); Neurologic Wernicke
syndrome, subarachnoid hemorrhage, hypothalamic lesions, convulsions; Vascular myocardial
infarction, pulmonary embolism, hemorrhage.

Decreased Glucose: Hypoglycemia. Inability to maintain a normal blood glucose indicates

excessive insulin secretion or administration, or severely impaired hepatic gluconeogenesis.
CLINICAL OCCURRENCE: Congenital galactosuria, maple syrup urine disease, hepatic
glycogenoses; Endocrine hypopituitarism, hypothalamic lesions, hypothyroidism, Addison
disease; Infectious sepsis; Inflammatory/Immune pancreatitis; Mechanical/Trauma
postgastrectomy dumping syndrome, gastroenterostomy; Metabolic/Toxic insulin administration,
oral hypoglycemics, glycogen deficiency, hepatitis, cirrhosis, malnutrition; Neoplastic insulinoma,
some sarcomas.

HEMOGLOBIN A1C: GLYCOHEMOGLOBIN. Pathophysiology: Glycosylation of cellular and

extracellular proteins occurs at a rate dependent upon the ambient plasma glucose concentration.
Hemoglobin is glycosylated in this manner and the amount of glycosylated hemoglobin is an
accurate measure of the average blood sugar over the average life of the circulating erythrocytes,
approximately 6 weeks. Measurement of one glycosylated form of hemoglobin, hemoglobin A1c,
is used to estimate the average blood sugar as a determinate of diabetes control.

Normal Hemoglobin A1c: 3.8-6.4% (SI Units: 0.038-0.064).

IRON, SERUM (FE2+). Pathophysiology: The body contains about 3-4 g of iron. It is a component
of hemoglobin, the cytochromes, and other cellular metalloproteins. Approximately 1 mg of iron is
absorbed and excreted each day. Most of the iron circulates in erythrocyte hemoglobin (1.0
mg/1.0 mL packed erythrocytes), with the rest bound to ferritin in stores (approximately 1.0 g), in
myoglobin, and with a small fraction incorporated into respiratory enzymes and other sites. Iron is
absorbed in the duodenum by a complex pathway regulated at the level of the enterocyte; most
ingested iron is not absorbed, or is sloughed in the enterocytes, never entering the plasma.
Absorbed iron is bound to transferrin. Iron is cleared from the plasma with a half-time of 60-120
minutes, and 80-90% is incorporated into new circulating erythrocytes over the subsequent 2
weeks. The serum concentration of iron decreases by 50-100 ug/dL with the diurnal acceleration
of erythropoiesis in the afternoon, so the time of day the specimen is drawn and its relationship to
meals should be known. Iron deficiency is a very common disorder.

Normal Serum Iron: 50-100 mg/dL (SI Units: 9-27 mmol/L).

Increased Serum Iron: Hyperferremia. An increase in serum iron may be seen following a high-
iron meal, or with hemochromatosis and liver disease. CLINICAL OCCURRENCE: Congenital
hemochromatosis, thalassemia; Inflammatory/Immune acute hepatic necrosis, aplastic anemia,
hemolytic anemia; Metabolic/Toxic excessive absorption (iron therapy, dietary excess), cirrhosis,
pernicious anemia.

Decreased Serum Iron: Hypoferremia. Low serum iron results from inadequate dietary intake,
excessive blood loss (both with increased iron-binding capacity), or chronic inflammation
(decreased iron-binding capacity). CLINICAL OCCURRENCE: Endocrine iron loss to the fetus
during gestation; Infectious tuberculosis, osteomyelitis, hookworm; Inflammatory/Immune celiac
disease, rheumatoid arthritis, systemic lupus erythematosus (SLE); Mechanical/ Trauma
intravascular hemolysis with hemoglobinuria (paroxysmal nocturnal hemoglobinuria, march
hemoglobinuria, prosthetic heart valves); Metabolic/Toxic iron deficiency, repeated phlebotomy,
diminished absorption (decreased ingestion, celiac disease, pica, postgastrectomy); Neoplastic
gastrointestinal cancers, loss of transferrin in nephrotic syndrome; Psychosocial poverty;
Vascular intrapulmonary hemorrhage (e.g., idiopathic pulmonary hemosiderosis), chronic
bleeding (e.g., menorrhagia, hematuria, peptic ulcer disease, gastritis, polyps, ulcerative colitis,
colon carcinoma).

IRON-BINDING CAPACITY (TIBC), SERUM TOTAL. The TIBC mainly reflects transferrin and,
with the serum iron, helps to distinguish iron deficiency anemias from the anemia of chronic
inflammation.

Normal Iron-Binding Capacity: 250-370 mg/dL (SI Units: 45-66 mmol/L).

Increased Iron-Binding Capacity. This generally reflects a response to iron deficiency. CLINICAL
OCCURRENCE: Iron deficiency, acute or chronic blood loss, hepatitis, late pregnancy.

Decreased Iron-Binding Capacity. Transferrin falls with chronic inflammation. CLINICAL

OCCURRENCE: Anemias of chronic disorders (infections, inflammations, and cancer),
thalassemia, cirrhosis, nephrotic syndrome.

LACTIC DEHYDROGENASE (LDH), SERUM. Pathophysiology: This enzyme catalyzes the

oxidation of lactate to pyruvate reversibly. It is found in all tissues, so an elevation of the blood
level is a nonspecific indicator of tissue damage.

Normal LDH: 100-190 U/L (SI Units: 1.7-3.2 mkat/L).

Increased LDH. Elevations of LDH suggest injury to the muscles, liver, hemolysis, or rapid cell
division as in lymphomas. CLINICAL OCCURRENCE: Congenital muscular dystrophy in 10% of
cases, progressive muscular dystrophy, myotonic dystrophy (but creatine phosphokinase [CPK] is
more specific for muscle than LDH); Endocrine hypothyroidism; Infectious hepatitis with jaundice,
infectious mononucleosis; Inflammatory/Immune polymyositis in 25% of cases, dermatomyositis,
hemolytic anemias; Mechanical/Trauma cardiovascular surgery, common bile duct obstruction,
intestinal obstruction; Metabolic/Toxic muscle necrosis, celiac disease, untreated pernicious
anemia, alcohol; Neoplastic 50% of cases of lymphoma and leukemia; Vascular acute myocardial
infarction, pulmonary embolism or infarction.

Decreased LDH. CLINICAL OCCURRENCE: Irradiation, ingestion of clofibrate.

PHOSPHATE, SERUM INORGANIC. Pathophysiology: This term includes the inorganic

phosphorus of ionized HPO42- and H2PO4 in equilibrium in the serum; only 10-20% is protein
bound. Phosphorus is necessary for synthesizing nucleotides, phospholipids, and the high-energy
adenosine triphosphate (ATP). Phosphates are excreted by the kidney; parathormone (PTH)
increases phosphate excretion. When the energy demands are great for glycolysis, the serum
inorganic P is decreased.

Normal Phosphate: 3.0-4.5 mg/dL (SI Units: 1.0-1.4 mmol/L).

Increased Phosphate: Hyperphosphatemia. CLINICAL OCCURRENCE: Congenital Fanconi

disease; Endocrine acromegaly, hyperparathyroidism; Idiopathic Paget disease; Infectious
sepsis; Inflammatory/Immune sarcoidosis; Mechanical/Trauma healing fractures, crush injury,
high intestinal obstruction; Metabolic/Toxic acute and chronic renal failure, vitamin D deficiency
(rickets, osteomalacia), muscle necrosis, milk-alkali syndrome, respiratory alkalosis, excess of
vitamin D; Neoplastic multiple myelomas, osteolytic metastases, myelocytic leukemia.

Decreased Phosphate: Hypophosphatemia. CLINICAL OCCURRENCE: Congenital primary

hypophosphatemia; Endocrine hyperparathyroidism, diabetes mellitus; Metabolic/Toxic renal
tubular defects (Fanconi syndrome), anorexia, vomiting, diarrhea, lack of vitamin D, in refeeding
after starvation, malnutrition, gout, ketoacidosis, respiratory alkalosis, hypokalemia,
hypomagnesemia, primary hypophosphatemia, drugs (intravenous glucose, anabolic steroids,
androgens, epinephrine, glucagon, insulin, salicylates, phosphorus-binding antacids, diuretic
drugs, alcohol).

POTASSIUM, SERUM (K+). Pathophysiology: This is the predominant cation in the intracellular
fluid, while sodium predominates in the extracellular fluids. Approximately 90% of the
exchangeable K+ is within the cells; less than 1% is in the normal serum. Small shifts of K+ from
the cells causes relatively large changes in the smaller serum [K+]. Intracellular acidosis causes
an extracellular shift of K+. Plasma [K+] is tightly regulated by the kidney; hyperkalemia leads to
aldosterone secretion and potassium excretion. Changes in serum concentration of K+ produce
profound effects on nerve excitation, muscle contraction, and in cardiac conduction. Because the
concentration of K+ in the erythrocytes is about 18 times as great as that in the serum, hemolysis
occurring during sample collection falsely elevates the serum K+.

Normal Potassium: 3.5-5.0 mEq/L (SI Units: 3.5-5.0 mmol/L).

Increased Potassium: Hyperkalemia. (Note: high levels of serum K+ pose great danger of
producing cardiac arrest.) CLINICAL OCCURRENCE: Technical Error hemolysis in performing
venipuncture or intentional clotting in collecting blood specimens, especially with thrombocytosis;
Congenital hyperkalemic periodic paralysis; Endocrine primary and secondary
hypoaldosteronism, adrenal insufficiency (Addison disease, adrenal hemorrhage);
Mechanical/Trauma rhabdomyolysis, crush injury, hemolyzed transfused blood, urinary
obstruction; Metabolic/Toxic acute and chronic renal failure, acidosis (metabolic or respiratory),
muscle necrosis, drugs (amiloride, spironolactone, triamterene, angiotensin-converting enzyme
inhibitors), foods (fruit juices, soft drinks, oranges, peaches, bananas, tomatoes, high-protein
diet), dehydration; Neurologic status epilepticus; Vascular gastrointestinal hemorrhage,
hemorrhage into tissues.

Decreased Potassium: Hypokalemia. This is almost always associated with depletion of in total
body K+. CLINICAL OCCURRENCE: Endocrine diabetes mellitus, Cushing syndrome,
hyperaldosteronism; Mechanical/Trauma ureterosigmoidostomy with urinary reabsorption,
adynamic ileus; Metabolic/Toxic vomiting, gastric suction, postgastrectomy dumping syndrome,
gastric atony, laxative abuse, polyuria, renal injury, salt-losing nephritis, metabolic alkalosis (from
diuresis, primary aldosteronism, pseudoaldosteronism), metabolic acidosis (from renal tubular
acidosis, diuresis phase of tubular necrosis, chronic pyelonephritis, diuresis after release of
urinary obstruction), malabsorption and malnutrition, drugs (diuretics, estrogens, salicylates,
corticosteroids) Neoplastic aldosteronoma, villous adenoma, colonic cancer, Zollinger-Ellison
syndrome.

PROTEIN, TOTAL SERUM. Pathophysiology: Most serum proteins are synthesized in the liver
(albumin and others) or by mature plasma cells (immunoglobulins). Increases or decreases in
serum proteins represent a balance between synthesis and protein catabolism or loss into third
spaces or in the urine. This is the total of the serum albumin and the serum globulins; the
fibrinogen was discarded in the clot that separated from the plasma to form the serum specimen.
The quantity of the total serum protein, minus the albumin fraction, gives an estimate of the
serum globulins.

Normal Total Protein: 5.5-8.0 g/dL (SI Units: 55-80 g/L).

Increased Total Protein: Hyperproteinemia. This represents increased concentration of normal

proteins, or excessive production of immunoglobulins. CLINICAL OCCURRENCE: Water
depletion, multiple myeloma, macroglobulinemia, and sarcoidosis.

Decreased Total Protein: Hypoproteinemia. This is caused by decreased synthesis, increased

catabolism because of malnutrition, or loss into third spaces or into the urine in nephrotic
syndrome. CLINICAL OCCURRENCE: Congestive cardiac failure, ulcerative colitis, nephrotic
syndrome, chronic glomerulonephritis, cirrhosis, viral hepatitis, burns, malnutrition.

PROTEIN: ALBUMIN, SERUM. Pathophysiology: Molecular weight about 65,000. Normally,

albumin comprises more than half the total serum protein. Because its molecular weight is low
compared to that of the globulins (between 44,000 and 435,000), its smaller molecules exert 80%
of osmotic pressure of the plasma. In addition, (a) serum albumin serves as a protein store for the
body that can be used when a deficit develops; (b) it serves as a solvent for fatty acids and bile
salts; and (c) it serves as a transport vehicle by loosely binding hormones, amino acids, drugs,
and metals.

Normal Albumin: 3.5-5.5 g/dL (SI Units: 35-55 g/L).

Increased Albumin: Hyperalbuminemia. No significant correlation with diseases.

Decreased Albumin: Hypoalbuminemia. CLINICAL OCCURRENCE: Congenital analbuminemia;

Endocrine diabetes mellitus; Infectious viral hepatitis; Inflammatory/Immune ulcerative colitis,
protein-losing enteropathies, chronic glomerulonephritis, lupus erythematosus, polyarteritis,
rheumatoid arthritis, rheumatic fever; Mechanical/Trauma peptic ulcer; Metabolic/Toxic
congestive cardiac failure, cirrhosis, nephrotic syndrome, malnutrition, drugs (estrogens);
Neoplastic multiple myeloma, Hodgkin disease, lymphocytic leukemia, macroglobulinemia.

PROTEIN: GLOBULINS, SERUM. The difference between the values for total serum protein and
for serum albumin is referred to as the serum globulin fraction of the serum protein. When the
globulin level is increased, fractionation of the globulins is indicated to identify each component.
This is accomplished by serum protein electrophoresis.

SERUM PROTEIN ELECTROPHORESIS (SPEP). The proteins are separated by

electrophoresis; the proteins migrate, each at its own rate, dependent on its charge and
molecular weight. A serum specimen contains proteins that separate into several zones
according to their mobility. The proteins are named for the zone in which they are found (named
with Greek lowercase letters): alpha 0 (for albumin), alpha 1 (α1), alpha 2 (α2), beta (β),
gamma (γ), and phi (φ) (for fibrinogen).

PROTEIN: ALPHA-1 (α1)-GLOBULINS. Alpha-1-globulins include α1-antitrypsin,

oromucil, and some cortisol-binding globulin.

Increased a1-Globulins. Hodgkin disease, peptic ulcer, ulcerative colitis, cirrhosis,

metastatic carcinoma, protein-losing enteropathy.

Decreased a1-Globulins. Viral hepatitis.

PROTEIN: ALPHA-2 (α2)-GLOBULINS. Alpha-2- globulins include macroglobulins,

haptoglobin, HS glycoprotein, ceruloplasmin, and some immunoglobulins.

Increased a2-Globulins. Hodgkin disease, peptic ulcer, ulcerative colitis, cirrhosis,

nephrotic syndrome, chronic glomerulonephritis, systemic lupus erythematosus,
polyarteritis nodosa, rheumatoid arthritis, metastatic carcinoma, protein-losing
enteropathies.

Decreased a2-Globulins. Cirrhosis, viral hepatitis.

PROTEIN: BETA (β)-GLOBULINS. Beta-globulins include transferrin, hemopexin, and

some immunoglobulins.

Increased b-Globulins. Rheumatoid arthritis, rheumatic fever, analbuminemia.

Decreased b-Globulins. Nephrotic syndrome, lymphocytic leukemia, metastatic

carcinoma.

PROTEIN: GAMMA (γ)-GLOBULINS. Gamma globulins are predominately

immunoglobulins of the IgG class. Increases in gamma globulins can be (a)
monoclonal, arising from a clonal proliferation of plasma cells or lymphocytes, or (b)
polyclonal, as part of an inflammatory response. Polyclonal gamma globulins produce
a broad-based pattern in the gamma zone, indicating the presence of proteins from
many cell lines.

Increased Polyclonal g-Globulins. Cirrhosis, myelocytic leukemia, lupus

erythematosus, rheumatoid arthritis, analbuminemia.

Decreased Polyclonal γ-Globulins. Nephrotic syndrome, lymphocytic leukemia,

common variable immunodeficiency, hypogammaglobulinemia, protein-losing
enteropathies.

PROTEIN: IMMUNOGLOBULIN IgG. Pathophysiology: Molecular weight 160,000. This is

the smallest molecule of the immunoglobulins and the only one that can pass the
placental membrane; consequently, it serves as a protection for the newborn until
the child's own immunoglobulins can be generated. IgG is synthesized after IgM in
response to a new antigen. IgG producing plasma cells are the major humoral
effector of chronic inflammation.

Normal IgG: 800-1500 mg/dL (SI Units: 8.0-15.00 g/L).

Increased IgG. CLINICAL OCCURRENCE: Infectious pulmonary tuberculosis, hepatitis,

osteomyelitis; Inflammatory/Immune systemic lupus erythematosus, rheumatoid
arthritis, vasculitis; Metabolic/Toxic cirrhosis; Neoplastic myeloma, monoclonal
gammopathy of undetermined significance (MGUS).

Decreased IgG. CLINICAL OCCURRENCE: Congenital lymphoid aplasia,

agammaglobulinemia; Inflammatory/Immune common variable immunodeficiency,
nephrotic syndrome; Neoplastic heavy- chain disease, IgA myeloma,
macroglobulinemia, chronic lymphocytic leukemia.

PROTEIN: IMMUNOGLOBULIN IgA. Pathophysiology: Molecular weight 170,000. This

globulin is especially involved in the protection against viral infections. It has an
excretory form with a molecular weight of 400,000, found in colostrum, saliva, tears,
bronchial secretions, gastrointestinal secretions, and nasal discharges. It has a
special action against viruses of influenza, poliomyelitis, adenoviral diseases, and
rhinoviruses.

Normal IgA: 90-325 mg/dL (SI Units: 0.90-3.2 g/L).

Increased IgA. CLINICAL OCCURRENCE: Congenital Wiskott-Aldrich syndrome;

Inflammatory/Immune systemic lupus erythematosus, rheumatoid arthritis,
sarcoidosis; Metabolic/Toxic cirrhosis; Neoplastic IgA myeloma.

Decreased IgA. CLINICAL OCCURRENCE: Congenital absent in some people,

hereditary telangiectasia, lymphoid aplasia; Inflammatory/Immune nephrotic
syndrome, Still disease, systemic lupus erythematosus, common variable
immunodeficiency, agammaglobulinemia; Metabolic/Toxic cirrhosis; Neoplastic
heavy-chain disease, acute lymphocytic leukemia, chronic lymphocytic leukemia,
chronic myelocytic leukemia.

PROTEIN: IMMUNOGLOBULIN IgM. Pathophysiology: Molecular weight 900,000. This is

the largest of the immunoglobulins. It is formed during a primary antibody response.
The rheumatoid factor and the isoantibodies anti-A and anti-B belong mostly to this
class.
Normal IgM: 45-150 mg/dL (SI Units: 0.45-1.5 g/L).

Increased IgM. CLINICAL OCCURRENCE: Infectious hepatitis, trypanosomiasis;

Inflammatory/Immune biliary cirrhosis, rheumatoid arthritis, systemic lupus
erythematosus; Neoplastic macroglobulinemia.

PROTEIN: IMMUNOGLOBULIN IgD. Pathophysiology: Molecular weight 185,000. There

is no known specific activity for this protein.

Normal IgD: 0-8 mg/dL (SI Units: 0-0.08 g/L).

Increased IgD. Chronic infections, IgD myeloma.

PROTEIN: IMMUNOGLOBULIN IgE. Pathophysiology: Molecular weight 200,000. IgE

binds to mast cells in body tissue. Specific antigen (allergen) binding to mast cell IgE
causes degranulation of the mast cell and an allergic response. This protein is
involved in allergic and atopic reactions.

Normal IgE: 3.5 g/d of proteinuria. Glomerulonephritis, diabetes mellitus, systemic

lupus erythematosus, renal vein thrombosis, amyloidosis, and other causes of
nephrotic syndrome.

GLUCOSE. Pathophysiology: Glucose is normally filtered in the glomerulus and

completely reabsorbed, mostly in the proximal tubule. Glucose in randomly collected
fresh urine specimens is normally undetectable. When the serum glucose rises above
200 mg/dL, the filtered load will exceed the capacity for tubular reabsorption and
glucose will appear in the urine. Dipsticks, impregnated with glucose oxidase and an
indicator color, provide a convenient, rapid and semiquantitative estimate for the
patient and physician.

Normal Glucose Excretion: 3-25 mg/dL; 50-300 mg/d.

Increased Urine Glucose: Glucosuria. CLINICAL OCCURRENCE: Hyperglycemia in

diabetes mellitus; infrequently with renal abnormalities, including acute tubular
damage, hereditary renal glycosuria, and proximal tubular dysfunction as in the
Fanconi syndrome.

KETONES. Pathophysiology: Ketones are the products of fatty acid metabolism.

Increased ketones in the urine indicate that cellular metabolism is dependent upon
fatty acids rather than glucose for energy. Progressively diminished glucose
utilization in uncontrolled diabetes mellitus leads to lipolysis with increasing plasma
and urinary concentrations of acetoacetic acid, beta-hydroxybutyric acid, and
ketones.

Increased Urinary Ketones: Ketonuria. CLINICAL OCCURRENCE: Diabetic acidosis,

fasting, starvation, alcoholic ketoacidosis, isopropyl alcohol intoxication (the clue is
an obtunded patient with normal glucose and acid-base status and urine tests
positive for ketones).

URINARY SEDIMENT. Pathophysiology: Normally erythrocytes, leukocytes, hyaline

casts, and crystals (urate, phosphate, oxalate) are found in the sediment of a fresh
specimen collected after a night's fast.

PROCEDURE FOR EXAMINING THE URINARY SEDIMENT. Centrifuge 10 mL of urine in a

conical tube for 5 minutes, decant the supernatant, flick the tube to disperse formed
elements in the remaining drop, and place it on a slide under a cover slip to be
examined with the high-power objective of a microscope (hpf). Abnormal numbers of
cells and casts or any bacteria reveal the presence of disease.

Erythrocytes: Hematuria. Normal: 0-5 red blood cells (RBCs)/hpf. CLINICAL

OCCURRENCE: Microscopic hematuria may occur with fever and exercise and many
lesions of the urinary tract from the glomerulus to the urethral meatus [Cohen RA,
Brown RS. Microscopic Hematuria. NEJM 2003;348:2330-2338]. Causes of gross
hematuria include coagulation defects, renal papillary necrosis, renal infarction,
sickle cell disease, glomerulonephritis, Goodpasture syndrome, stone or carcinoma of
the kidney, hemorrhagic cystitis, stone or carcinoma of the bladder, and prostatitis.

Leukocytes: Pyuria. Normal: 0-10 white blood cells (WBCs)/hpf. CLINICAL

OCCURRENCE: In addition to neutrophils excreted into the urine from the same
anatomic sites as erythrocytes, leukocytes from vaginal exudates frequently
contaminate routine specimens collected from women. When pyuria exceeding 10
WBCs/hpf is present in an uncontaminated specimen, a site of infection or
inflammation in the urinary tract or kidney should be sought.

Casts. Occasional hyalin casts, arising from the normal renal tubular secretion of
mucoproteins, are seen in fresh concentrated specimens. Finding many broad, fine,
or coarse granular casts (composed of serum proteins like albumin, IgG, transferrin,
haptoglobin) in urine containing excessive protein indicates renal parenchymal
disease. Red cell casts generally indicate glomerular disease with RBCs passing the
damaged glomeruli in large quantities. The urine of patients with the nephrotic
syndrome, who exhibit glomerular proteinuria and hyperlipoproteinuria, contains
fatty casts, casts with doubly refractile fat bodies, and Maltese crosses when
examined in polarized light. Red cell casts, containing 10 to 50 distinct erythrocytes
and doubly refractile fat bodies, indicate glomerular disease (glomerulonephritis).
White cell and/or renal tubular epithelial cell casts are found in the urinary sediment
of patients with pyelonephritis, polyarteritis, exudative glomerulonephritis, and renal
infarction. Bacteria accompanying white cell casts indicate urinary tract infection.
Broad orange or brown hematin casts occur in acute tubular injury and chronic renal
failure.

Cerebrospinal Fluid (CSF)

The brain and spinal cord are surrounded by, and suspended in, a clear, colorless
fluid. Patients with acute CNS symptoms often require testing of the fluid. Below are
found the most commonly ordered tests, their reference ranges, and the more
frequent causes of abnormality.

PROTEIN. Normal CSF Protein: 20-50 mg/dL (SI Units: 0.5-2.0 g/L).

Increased CSF Protein. Traumatic tap, infection, hemorrhage, metabolic and

demyelinating disorders.

Decreased CSF Protein. Young children, CSF leakage, water intoxication, CSF
removal, hyperthyroidism.

GLUCOSE. Normal CSF Glucose: 40-70 mg/dL (SI Units: 2.2-3/9 mmol/L).

Elevated CSF Glucose. Hyperglycemia.

Decreased CSF Glucose. Hypoglycemia, infection (especially bacterial or

mycobacterial), meningeal malignancy.

CELL COUNT AND DIFFERENTIAL. Normal CSF Cell Count: Adult, 0-5 mononuclear
cells per microliter; neonates, 0-30 mononuclear cells per microliter.

Increased CSF Leukocytes. Mononuclear cells increase in infection of the CNS (viral
and early bacterial meningitis, meningoencephalitis, or abscess), neurologic
disorders, and hematologic malignancies. Neutrophils increase in bacterial infection,
hemorrhage, and meningeal malignancy. Eosinophils increase in shunt, parasitic
infection, and allergic reactions.

Serous Body Fluids

Normally, a very small amount of fluid resides in the pleural, pericardial and
peritoneal spaces. Any clinically detectable accumulation of fluid (effusion or ascites)
in the cavity is caused by a pathologic condition. Effusions should be examined
microscopically to determine the distribution (differential count) of cells and to detect
malignant cells. Cell counts are useful in peritoneal fluid (below), but are somewhat
less helpful in pleural fluid. Increased inflammatory cells have indications similar to
those in other locations: Neutrophils (infection, neoplasm, leukemia); lymphocytes
(infection, infarction, lymphoma, leukemia, neoplasm, rheumatologic serositis);
eosinophils (air in cavity, infection, infarction, neoplasm, rheumatologic disease,
congestive heart failure). Microbiologic examination, stains, and culture are indicated
in exudates; cytologic examination will identify abnormal/malignant cells. Effusions
are generally classified as transudate (low protein) or exudate (high protein).

Transudates. Transudates, commonly bilateral in the pleural cavities, are secondary

to heart failure or medical conditions that cause a low serum albumin, for example,
cirrhosis or nephrotic syndrome. Clear and pale, straw-colored fluids are usually
transudates, and additional information is rarely provided by testing beyond that
required to confirm that the fluid is a transudate. The few cells found in transudates
are mesothelial cells and mononuclear cells (lymphocytes and monocytes) with very
few neutrophils.

Exudates. Exudates are more frequently unilateral in the pleural cavities and
secondary to localized disorders such as infection or neoplasm. Exudates can be
cloudy from cellular increases (leukocytes), red or pink from hemorrhage (or trauma),
green white from purulence, or milky from increased lipid.

PLEURAL EFFUSION. See page 397. Tests frequently useful in pleural effusions
include gross appearance, fluid/serum protein ratios (0.5 = exudate), fluid/serum
lactate dehydrogenase (LDH) ratios (0.6 = exudate), fluid/serum cholesterol ratio (0.3
= exudate), morphologic exam (hematology and cytology), and pH (1000/mm3 and
low glucose suggests empyema). Note: If the protein and LDH ratios are equivocal,
the cholesterol ratios may help identify transudate/exudate. Transudates rarely
benefit from further testing. Cell counts are rarely useful.

PERITONEAL EFFUSION: ASCITES. See page 542. Tests frequently useful in peritoneal
effusion include gross appearance, serum/ascites albumin concentration gradient,
cell count and differential, cytology and cultures for bacteria and mycobacteria.

Serum/Ascites Albumin Gradient. Subtracting peritoneal albumin from simultaneously

determined serum albumin determines the serum/ascites albumin gradient. Values
1.1 indicate a transudate (portal hypertension caused by cirrhosis, hepatic vein
thrombosis, portal vein thrombosis, congestive heart failure). Note: Protein and
lactate dehydrogenase (LDH) ratios described above for pleural fluid are not reliable
in peritoneal fluid to separate transudates from exudates.

White Blood Cell Counts. Detection of spontaneous bacterial peritonitis in patients

with transudative ascites is important. Neutrophil counts of >250/mm3 indicate
infection and the need for treatment and long-term prophylaxis. High leukocyte
counts (>500/mm3), mostly mononuclear cells, are also seen in malignancy.

/////////////

Metabolic alkalosis

Metabolic alkalosis may occur secondary to ingestion of exogenous alkali, HCl losses (renal, GI),
or ECF volume contraction around a fixed blood content of bicarbonate. The kidneys are normally
capable of excreting excess bicarbonate, but this ability may be impaired as a result of ECF
volume contraction, hypokalemia, chloride depletion, or excess mineralocorticoid or glucocorticoid
states. Measurement of the urine chloride concentration can help differentiate the causes of the
metabolic alkalosis. This, in turn, has therapeutic implications since it indicates whether or not the
alkalosis can be corrected by the administration of chloride (chloride-responsive vs. chloride-
resistant alkalosis).

Causes

1. Chloride-responsive alkalosis with a urine chloride less than 10 mEq/liter is the more common
form of metabolic alkalosis. It is usually, but not necessarily, accompanied by ECF volume
depletion ("contraction alkalosis"). It most commonly occurs with GI HCl losses (vomiting,
nasogastric suction, villous adenoma) or with diuretic use. Acutely, diuretic therapy may raise the
urine chloride. Measurement after the duration of the diuretic effect (12-24 hours) will then reveal
a low urine chloride. Hypokalemia often accompanies these disorders and helps perpetuate the
alkalosis. Other causes include the posthypercapnic state and cystic fibrosis. Treatment should
be directed at correction of the underlying disorder. Correction of the chloride depletion can be
achieved by administration of NaCl tablets or, if significant volume contraction is present, IV
saline. Hypokalemia should be treated with potassium chloride. In edematous states where there
is effective circulatory volume depletion (left-sided heart failure, cor pulmonale, liver cirrhosis),
NaCl administration will worsen the volume overload. Therefore, if adequate renal function is
present, a carbonic anhydrase inhibitor (acetazolamide) is often useful. This is also effective in
the post-hypercapnic state. The usual dosage of acetazolamide is 250-500 mg PO or IV q8h.
Gastric HCl losses may be attenuated with the use of either IV or PO H2-receptor antagonists or
omeprazole.

2. Chloride-resistant alkalosis with a urine chloride greater than 20 mEq/liter is much less
common. Causes include those associated with hypertension, such as primary
hyperaldosteronism, Cushing's syndrome, renal artery stenosis, licorice, and Liddle's syndrome;
and those without hypertension, such as Bartter's syndrome, severe hypokalemia (K+ <2
mEq/liter), and perhaps hypomagnesemia. Hypokalemia of a less severe degree often
accompanies many of the other disorders and helps perpetuate the alkalosis. Treatment is
directed at the underlying disorder. Potassium deficits should be corrected. In states of
mineralocorticoid excess, spironolactone or amiloride may be helpful.

3. Exogenous administration of alkali including massive blood transfusions containing citrate,

bicarbonate administration, milk-alkali syndrome, and ingestion of antacids along with cation
exchange resins in renal failure all may cause metabolic alkalosis.
4. Miscellaneous causes include hypercalcemia of nonparathyroid origin (malignancy,
sarcoidosis, hypervitaminosis D), refeeding alkalosis (prolonged fasts broken with high-
carbohydrate meals), and high-dose carbenicillin or penicillin.

So it is chloride in this case

_________________

causes of metabolic alkalosis:

1.Administering diuretics (except carbonic anhydrase)
increased flow of fluid along the tubules--->rapid reabsorption of Na+ ---->enhanced H+ secretion
because of Na-H exchange --->excessive loss of H
2.Excessive Ingestion of alkaline drugs - Eg. NaHCo3 for peptic ulcer
3.Loss of Chloride Ions
Excessive vomiting of gastric contents without vomiting of lower GI contents---> Excessive loss of
HCl secreted by stomach mucosa. --->Loss of acid from ECF---> alkalosis
4. Excess aldosterone
aldosterone --->reabsorption of Na from distal tubule--->H secretion coupled with Na reabsorption

////////

insulin decreases the surfactant production by downregulating the rna production for surfactant
protein synthesis

thyroid hormones increase the surfactant protein production... n they have got a therapeutic role
in ARDS in preterm infants..

//////////

Paneth cells are found in the small intestine but not in the large intestine.

It's recently been shown that the granules contain a form of bactericide, and lysozyme-like
agents.

This suggests they're responsible for protecting the gut against bacterial overgrowth

They can be seen in H&E preparations, but the PAS routine makes them really stand out.

The granules of Paneth cells are much coarser and more obvious than those of enteroendocrine
cells.

The cells are usually found clustered in groups of three to six or so, and in this image you see a
cluster of them, located (as they tend to be) at the very deepest part of an intestinal crypt.
They aren't endocrine cells, although they often are located in the same vicinity.

Unlike the endocrine cells' products, the secretions of the Paneth cells are relased into the lumen
of the intestine.

/////////

lysozymes

A number of lysozymes are found in nature; in human tears and egg white, for examples.

ThIS enzyme is antibacterial because it degrades the polysaccharide that is found in the cell walls
of many bacteria. It does this by catalyzing the insertion of a water molecule

Most of the bacteria affected by lysozyme are not pathogenic. It could be argued that lysozyme is
a primary reason these organisms did not develop pathogenic strains...

Lysozyme serves as an unspecific innate opsonin by binding to the bacterial surface to reduce
the negative charge and facilitate phagocytosis of this bacterium before opsonins from the
acquired immune systems enter the scene.

The enzyme functions by attacking peptidoglycans and hydrolyzing the bond that connects N-
acetylmuramic acid with the fourth carbon atom of N-acetylglucosamine.

THIS MEANS THEY SHUD BE CIDAL IN ACTION

////////

Pain Physiology
1. What is pain?
The "standard" definition of pain is that of the International Association for the Study of Pain:-

"An unpleasant sensory or emotional experience associated with actual or potential tissue
damage, or described in terms of such damage. Pain is always subjective. Each individual learns
the application of the word through experiences related to injury in early life. It is unquestionably a
sensation in a part of the body, but it is also unpleasant, and therefore also an emotional
experience. Many people report pain in the absence of tissue damage or any likely
pathophysiological cause; usually this happens for psychological reasons. There is no way to
distinguish their experience from that due to tissue damage, if we take this subjective report".
(IASP. Pain 1979(6)249-252, ex Shipton, 1993).

This definition is extremely unfortunate. Definitions tend to force people into particular ways of
thinking. By concentrating on the subjective nature of pain, this definition allows us to
conveniently ignore individuals whose physical findings are all consistent with a diagnosis of
"pain", but who cannot relate a subjective feeling of pain. Indeed, it tells us that (appearances to
the contrary) such people are not in pain!
Let us consider a few examples:
A patient is under anaesthesia, and has a tachycardia and hypertension. We administer
analgesia, and both settle. We wake her up and - voila - she reports no sensation or recollection
of pain. By the above definition, she was never in pain!

Even more tellingly, we now have a fairly good "molecular memory for pain stimulation". The
gene c-fos is rapidly expressed in the spinal cord in response to painful (but not to other)
peripheral stimuli.

This is further evidence that we should not rely only on pain being "always subjective". Pain is
also something that can now be documented in a fairly objective fashion, albeit only using fancy
tools in the laboratory. Clinically it is still, and always will be vitally important to listen to the patient
who reports pain. But pain does not stop there. As Cross [1994] has said:

"The affective-motivational aspects of pain originate in the periphery, and suffering is not merely a
matter for the neocortex; it is profoundly more ancient and primitive phylogenetically and is
reflected in fibre tracts and neural networks throughout the nervous system".

Note that c-fos is a proto-oncogene, and is therefore likely to be involved in regulation of major
structural and functional changes in the cells where it is induced. We know that volatiles and N2O
are not adequate to suppress c-fos expression, and that opiates are not as effective at this task
as local or neuraxial block. Some evidence suggests that the latter approaches are more effective
in preventing chronic pain states.

We must also remember that although acute pain may have survival value (causing e.g. removal
of the injured limb from a harmful stimulus), chronic pain is of no value whatsoever, and is indeed
a major scourge of humanity.

2. Pain pathways.
Previously, pain pathways were seen as having three components:-

A first order neurone (cell body in dorsal root ganglion) which transmits pain from a peripheral
receptor to ..
A second-order neurone in the dorsal horn of the spinal cord, which axon crosses the midline to
ascend in the spinothalamic tract to the thalamus where..
A third-order neurone projects to the postcentral gyrus (via the internal capsule).
This scenario, while partially correct, is now known to be horribly over-simplified. We will consider
the following components of pain pathways:-
Peripheral receptors;
Neural pathways;
Spinal Cord mechanisms & long tracts;
Brainstem, thalamus, cortex & other areas.
Descending pathways.

a. Peripheral receptors
We must even here make the important distinction between:

First pain
Second pain
It is important to realise that there are two distinct responses to a painful stimulus, a "first pain"
and a "second pain". The first pain is well-localised and brief, the second is more diffuse and
protracted.
First pain is described as sharp, and "pricking". It localises to a well-defined part of the body
surface.The receptors for this first pain are high threshold mechanoreceptors. There appear to be
specific "nociceptors" which mediate pain, and ONLY pain.

Second pain is due to stimulation of receptors that exist in many tissues (but not in, paradoxically,
the brain). It is often described as dull (i.e. not sharp) and aching. It is poorly localised. Receptors
for this second pain are termed polymodal nociceptors. This pain tends to last beyond the
termination of an acute painful stimulus. Sources, pathways, perception of and treatment of the
two types of pain are very different. Visceral pain is predominantly of the "second pain" type.

Visceral pain can however sometimes be referred to a region of the body surface (for example,
shoulder tip pain with sub-diaphragmatic irritation). See [Cervero, F. Physiological Rev
1994(74.1) 95-129pp] for a review of the sensory innervation of the viscera.
There is some evidence that neurotransmitters such as substance P (=sP), vasoactive intestinal
polypeptide (VIP) and calcitonin gene-related peptide are important mediators, either as
neurotransmitters, or sensitisers of visceral pain receptors. Prostaglandins, histamine, serotonin,
bradykinin, ATP, potassium, and H+ ions also appear important in this regard, especially
serotonin, which appears to act mainly on 5HT3 receptors.

In terms of pain perception, thresholds for feeling pain are remarkably constant from individual to
individual. i.e. Peripheral receptor stimulation of sufficient intensity will reproducibly cause pain at
the same level in most people. The response of the individual, and his tolerance of the pain, will
however differ markedly between individuals.

Of great interest is "Neurogenic Inflammation". Here, stimulation of C fibres causes a local

reaction consisting of vasodilatation and increased capillary permeability. This is due to
retrograde transport and local release of sP and calcitonin gene-related peptide. As a
consequence, K+, H+, acetylcholine, histamine and bradykinin may be released, and these in
turn cause prostaglandin and leukotriene production (which may end up sensitizing high-
threshold mechanoreceptors)! Neurogenic inflammation may spread to surrounding tissues
antidromically!!

Analgesic drugs that act peripherally include non-steroidal anti-inflammatory agents,

corticosteroids, local anaesthetic agents (which may theoretically inhibit neurogenic inflammation
if given early enough, an area of great controversy), and even novel drugs such as substance P
antagonists (One such antagonist that does NOT appear to work very well is capsaicin, but
opioids, serotonin antagonists, baclofen and clonidine may also inhibit sP release). Of note is the
recent identification of two different types of cyclo-oxygenase, with the potential for developing
more specific non-steroidal anti-inflammatories, with (perhaps) fewer side-effects.

b. Neural pathways.
"First pain" responses are conveyed from the periphery to the dorsal horn of the spinal cord in
small myelinated fibres (A delta) while "second" pain is conveyed in non-myelinated C fibres. This
is important, especially when considering the "gate control theory" detailed below. Also of
importance to this theory are afferent stimuli coming in in large myelinated fibres (A beta fibres),
from peripheral vibration / pressure / touch receptors.

Neurogenic pain, originating in damaged or abnormal C fibers, may respond to membrane-

stabilizing drugs such as anticonvulsants (e.g. carbamazepine).

c. Spinal cord pathways.

These are complex. We will consider:

initial connections : laminae in the spinal grey matter close to where the fibres enter the spinal
cord.
Local interconnections.
Ascending pathways and descending (control) pathways are considered much later.
1. Spinal pathways: initial connections.
About 70% of pain fibres enter in the dorsal root, but the rest double back and enter the ventral
(so called "motor" root). The grey matter of the spinal cord has ten "laminae" or layers. The
important ones that we must consider are:

Lamina I - marginal zone

Lamina II - substantia gelatinosa
Lamina V - part of "nucleus proprius of dorsal horn" (with IV,VI)
Laminae VII and VIII - intermediate spinal grey matter (with X)
Unmyelinated C fibres synapse in laminae I to V, while A delta fibres synapse in laminae I, V and
X. These different routes are only the start of dramatically different pathways! The two main
pathways are:-

The primitive, spino-reticulo-diencephalic tract (otherwise known to its friends as the

"palaeospinothalamic tract"). Impulses pass from type C fibres to several different "second order"
neurons.
The more modern neospinothalamic tract (which also answers to the name "anterolateral white
funiculus"). This takes most of its fibres from Laminae I and V, and appears to mediate "first"
pain;
Important second order neurons are
nerve cells that are not committed to responding only to pain, responding also to gentle stimuli
and increasing their response as the stimulus becomes more marked. This is the Wide Dynamic
Range cell (WDR cell). WDR cells are found in lamina V (and also laminae IV and VI)
Nociceptive specific neurones found in lamina I, responding only to noxious stimuli;
Complex neurons which receive numerous inputs and have been poorly studied. They are seen
mainly in laminae VII and VIII;
An important property of WDR neurons is "wind up". This occurs with repetitive stimulation at
about once per second via C fibres - each added stimulus increases the response of the WDR
cell. Wind-up is seen as a good justification for treating pain early and well! Wind up may be
related to stimulation of glutamate receptors (especially the N-methyl D Aspartate or "NMDA"
receptor, a receptor which is very topical at present)! Many NMDA antagonists exist, but most
have significant side effects (e.g. ketamine).

Clinically, evidence for wind-up has been hard to come by, although some recent studies attest to
the value of pre-emptive analgesia. See, for example, Mansfield(1996). Some evidence suggests
that mechanisms other than wind-up may be important in the development of visceral pain,
although the NMDA receptor appears to still be a major player [J Physiol(Lond) Dec 1995 489(2)
545-55pp].

The spino-reticulo-diencephalic system is rich in opiate receptors, while the spinothalamic tract
has very few. This explains why opiates (eg. morphine) have good analgesic properties for
visceral pain without affecting e.g. pinprick sensation.

2. Spinal pathways: local interconnections. There are several. Of great importance are
connections mediating so-called "gating". The basic idea here is that "painful stimuli" coming into
the cord on C fibres can be modified by other inputs, which "close the gate on the incoming pain".
These inputs come from:

A delta fibres;
A beta fibres;
others.
This arrangement has several practical consequences:
Transcutaneous Electrical Nerve Stimulation (TENS) works
Dorsal column stimulation (DCS) works
Acupuncture works!
Rubbing the skin locally helps decrease pain!
TENS works by high-frequency, low amplitude stimulation of larger peripheral fibres, and this
inhibits transmission of pain through the "gates". DCS is similar, but works by antidromically
stimulating the same A beta fibres. Acupuncture works in a different way: it causes low-frequency
high amplitude stimulation of small A delta fibres (amongst other fibres), and this also causes
inhibition of pain through gating mechanisms. Another difference between acupuncture and
TENS is that the effect of acupuncture can be blocked by giving opioid antagonists, which don't
inhibit the effect of TENS.
Mechanisms of inhibition in the dorsal horn may be very complex - incoming nociceptive fibres
express opioid receptors, opioids here blocking sP release, and they probably also act post-
synaptically. The presence of these opioid receptors at least partially explains the potent effect of
small doses of intrathecal opiates. In addition, GABA, somatostatin, neurotensin, CCK and
neuropeptide Y may play a role in pain transmission.

A wide variety of drugs has been used for "antinociception" at the spinal level, including opioids,
alpha-2 agonists, and local anaesthetics. Agents such as ketamine and somatostatin may
however be neurotoxic. Of interest is the potent analgesia induced by spinal octreotide! [Rawal N,
Ann Med Apr 1995 27(2) 263-8pp].

d. Higher ascending pathways.

1. The old spino-reticulo-diencephalic pathway does just that - it mainly ends in the reticular
system of the brainstem, but also sends fibres to the thalamus (the medial nuclei of the
thalamus). Probably important are connections between the reticular system and the
hypothalamus (and thalamus) - these may explain autonomic components of the pain response.
`Emotional'/affective responses to pain may be explained by projections that go from the medial
nuclei of the thalamus to most of the cortex, especially the frontal areas, and notably to the
anterior cingulate gyrus! (In the bad old days people sometimes did prefrontal lobotomies for
intractable pain)! The basal ganglia may also be involved in pain discrimination, the affective
component of pain, and even in pain modulation [Chudler E & Dong W, Pain 1995 60(1) 3-38pp].

2. The fresh, new "spinothalamic tract" nips up to the ventrobasal part of the lateral thalamus.
Connections go from here to the sensory cortex (postcentral gyrus), which explains the precise
localisation of somatic pain. It is obvious that this tract is NOT the main pain pathway, because
lesions along this pathway do not cancel out the sensation of pain, and, in fact, may cause severe
pain (the "thalamic syndrome" - possibly due to damage to inhibitory pathways).

Positron emission tomography (PET) has been used to study the response to pain. Acute
traumatic nociceptive pain appears to activate the hypothalamus and PAG, but a whole array of
other areas also become involved (including the prefrontal cortex, insula, anterior cingulate
cortex, posterior parietal cortex, primary motor and somatosensory areas, supplemental motor
area and even the cerebellum. Further demonstration of the complex nature of pain. [Pain Feb
1996 64(2) 303-14pp].

e. Descending pathways.
Descending modulation of pain sensation originates from three main areas:

Cortex;
Thalamus;
Brainstem, where the Periaqueductal grey matter (PAG) is particularly important.
Fibres pass from PAG to the reticular formation of the medulla (the nucleus raphe magnus or
"NRM", and the closely associated nucleus reticularis gigantocellularis pars alpha, and nucleus
reticularis paragigantocellularis, all together called the ventromedian medulla or "VMM") where
connections are serotoninergic, and from there axons descend in the "dorsolateral funiculus" of
the spinal cord, to end up (surprise, surprise) on interneurones right next to the substantia
gelatinosa (lamina II) in the cord. The synapses here are enkephalinergic. Stimulation of this
system causes inhibition of incoming pain impulses. Thus, although serotonin applied peripherally
augments pain, its action centrally is important in descending inhibition of incoming painful
impulses! New evidence suggests that GABA is also important in inhibition of pain pathways by
the VMM [Neuroscience Jul 1996 73(2) 509-18pp].

To make matters more complex, quite apart from the above inhibitory pathway that works mainly
on opiates, there is a separate, noradrenaline-based pathway that inhibits pain. Noradrenaline-
based projections appear to come from the NRM, and also from the locus coeruleus in the pons.
This is one explanation why antidepressants (which inhibit noradrenaline uptake) may be
effective in controlling pain, but remember that antidepressants also inhibit serotonin uptake, so
they may also increase activity in the fibres that pass from PAG to medulla!

"On" and "Off" cells:

There are probably two main classes of neurones in the PAG and VMM:
"On" cells increase pain transmission;
"Off" cells decrease it.
Opioids inhibit "on" neurones and increase transmission in "off" neurones, and noradrenaline also
inhibits "on" neurons.
3. The response to pain.
Responses to visceral pain are very different from those evoked by somatic pain. Visceral pain
generally results in tonic muscular spasm (teleologically, to decrease movement of the affected
area) while somatic pain usually causes withdrawal of the affected part of the body ("to protect
this region from further damage"). As already mentioned, the sensations reported for the two
pains are also quite different.

We are all also aware that pain (be it somatic or visceral) can have profound autonomic effects.
Some of the reasons for this have been alluded to: there is a good degree of cross-over between
the somatic and visceral systems, notably at the level of the WDR cell and "complex neurone" in
the spinal cord, but also extensively at higher centres, with projections to, for example, the
hypothalamus. Also of note is the close relationship between sensory afferents and sympathetic
outflow (See Cross, 1994). Recent studies suggest that epidural fentanyl alone blocks the
neurohormonal response to surgery (See Harukuni, I et al. anesth Analg. 1995(81)1169)!

4. A brief note on opiates and their receptors

There are three main types of opioid receptor: delta, kappa and mu. All of these are widely
distributed in the brain, and are not only concerned with modulation of pain perception, but also
with a variety of other functions. This explains why in trying to control pain, we encounter many
unwanted side-effects. For example, mu receptors are widespread in the brainstem parabrachial
nuclei (where stimulation of them causes respiratory depression), and dependence may be
related to receptors in the locus coeruleus and ventral tegmentum. Some have asserted that µ1
and µ2 receptors are mainly concerned with pain and respiratory depression, respectively, but
this is probably too simplistic.

Opioids work in two main ways: they either block neurotransmitter release (by inhibiting calcium
influx into the presynaptic terminal), or hyperpolarise neurones by opening a potassium channel
(and therefore effectively temporarily knock the neurone out of action)!

Corresponding (more-or-less) to the three receptor classes, there are three main groups of
endogenous opioids: the enkephalins, endorphins and dynorphins. Enkephalins act mainly on
delta receptors, dynorphins on kappa receptors, while beta endorphin acts on both mu and delta
receptors. Morphine is almost exclusively a mu agonist. Mu and delta receptors appear to be
expressed on the same cells, and stimulation of one receptor increases the affinity of the other!
Beta endorphin is also a "neurohormone" in that it may have distant effects on neurones with mu
receptors, after being released in the hypothalamus.
The effect of opioids on the "on" and "off" cells in the medulla is most interesting: ONLY the "on"
cell is affected by opioids - it is inhibited, probably by hyperpolarization due to opening of
potassium channels. The "off" cell certainly becomes more active in the presence of opioids, but
this is only secondary to the lessened activity of the "on" cell. The "on" cell is also inhibited by the
alpha-2 agonist clonidine. In fact, in some cells the mu receptor and the alpha-2 receptor are
linked to the same G protein and the same potassium channel! Of even more interest is evidence
that by giving morphine we can activate endogenous circuitry that turns on enkephalin release!
See [Fields, Ann Neurology, 1994 35 S42-45pp].

The roles of the various types of opiate receptor have recently been clarified by studies in opiate
receptor knockout mice. Mu-receptor knockout mice had shorter latencies on tail-flick and hot
plate tests, than did wild-type mice, and morphine did not reduce responses to pain. These
studies support the contention that the mu receptor is the main player in morphine-induced
analgesia. [Proc Natl Acad Sci U S A Feb 1997 94(4) 1544-9pp]

/////////////

New Drug of the day : Romiplostim

New Pharmacological Drug Classes Introduced in 2008

Romiplostim is an fusion protein (peptibody) that contains two identical single-chain subunits,
each consisting of a human immunoglobulin IgG1 Fc domain covalently linked to a peptide
containing two TPO receptor-binding domains.

The drug is licensed for the treatment of thrombocytopenia in patients with refractory chronic
immune thrombocytopenic purpura and acts as a thrombopoietin (TPO) receptor agonist to
activate intracellular transcriptional pathways leading to increased platelet production.

As a class, TPO receptor agonists are thought to increase the risk for development of bone
marrow fibrosis and may increase the risk for hematologic malignancies.

Romiplostim is administered as a subcutaneous injection with the dose adjusted to the lowest
dose necessary to reduce the risk of bleeding and achieve a platelet count ≥50 x 109/L. A
maximum weekly dose of 10 mcg/kg is recommended with therapy discontinued if the platelet
count does not increase sufficiently within 4 weeks of therapy. Hyporesponsiveness or failure to
maintain a platelet response may signal the development of neutralizing antibodies.

Discontinuation of therapy poses a risk for worsening of thrombocytopenia below baseline, with
subsequent hemorrhage. Patients receiving romiplostim must be monitored prior to initiation of
therapy, frequently during treatment, and for 2 weeks following cessation of therapy.

....................

New Drug of the day : PLERIXA

New Pharmacological Drug Classes Introduced in 2008

Plerixa started out as an investigational anti-retroviral drug for the treatment of AIDS. An
unexpected finding of increased CD34+ hematopoietic stem cell counts in the peripheral blood of
subjects exposed to the drug eventually lead to its licensing for use in combination with
granulocyte-colony stimulating factor (G-CSF) to mobilize hematopoietic stem cells to the
peripheral blood for collection prior to autologous transplantation in patients with non-Hodgkin’s
lymphoma and multiple myeloma.
Plerixa is an inhibitor of the CXCR4 chemokine receptor.

CXCR4, is normally responsible for ‘‘homing’’ (anchoring) stem cells in the bone marrow.16
Plerixa antagonizes the interaction between CXCR4 and its cognate ligand, stromal cell-derived
factor-1α. Plerixa works synergistically with G-CSF and is given after "priming" with 4
daily doses of G-CSF. Plerixa is administered subcutaneously, in a dose of 0.24 mg/kg
(up to 40 mg), approximately 11 hours prior to an apheresis session, in conjuction
with additional daily G-CSF, for up to 4 consecutive days.

Approximately 1/2 of non-Hodgkins lymphoma patients receiving plerixa will achieve

a yield >5 x 106 CD34+ cell harvests after 2 apheresis sessions.

Data for patients with multiple myeloma suggests that approximately 75% will
achieve a yield >6 x 106 CD34+ cell harvests after 2 apheresis sessions. Plerixa is
primarily eliminated by the kidneys. Drug-drug interactions may result from
coadministration with drugs that reduce renal function or compete for active tubular
secretion. (See Figure 4.) (CID: 16727404)

The most common adverse reactions reported in patients who received plerixa in
conjunction with G-CSF and aphresis were diarrhea, nausea, fatigue, injection site
reactions, headache, arthralgia, dizziness, vomiting, abdominal pain, hyperhidrosis,
abdominal distention, dry mouth, erythema, stomach discomfort, malaise,
hypoesthesia, constipation, dyspepsia, and musculoskeletal pain.

///////////////////

New Drug of the day : Methylnaltrexone

New Pharmacological Drug Classes Introduced in 2008

Methylnaltrexone is a peripherally acting μ-opioid receptor antagonist FDA approved for

the treatment of refractory opioid-induced constipation in patients with advanced
illness (e.g., cancer, AIDS) who are receiving palliative care.

Administered subcutaneously no more frequently than once per day,

methylnaltrexone stimulates laxation within 4 hours in approximately 60% of
patients.

Clinical experience confirms a much more rapid onset of action in patients who are
opioid tolerant. Methylnaltrexone is a quaternary amine derivative of naltrexone with
a limited ability to penetrate into the central nervous system. Side effects are largely
extensions of normal gastrointestinal functions: abdominal pain, flatulence, nausea,
and diarrhea. The drug is a weak CYP2D6 inhibitor with no known drug-drug
interactions. Methylnaltrexone undergoes hepatic metabolism; however, N-
demethylation to naltrexone is not thought to be a significant pathway.

Renal excretion of unchanged drug is the dominant route of elimination. The usual
dose of methylnaltrexone is 8-12 mg, depending on body weight. Therapy for longer
than 4 weeks in the target population of patients with terminal illness is unstudied.
Methylnaltrexone was investigated as a treatment for postoperative ileus, but with
disappointing results.

/////////

New Drug of the day : C1 inhibitor

New Pharmacological Drug Classes Introduced in 2008

C1 inhibitor : is licensed for the routine prophylaxis against angioedema attacks in patiets with
hereditary angioedema (HAE). Application for licensure as a treatment for acute angioedema
attacks is pending.

////////

New Drug of the day : Eltrombopag

New Pharmacological Drug Classes Introduced in 2008

Eltrombopag is an orally available non-peptide thrombopoietin (TPO) receptor agonist licensed

for the treatment of thrombocytopenia in patients with refractory chronic immune
thrombocytopenic purpura.

Eltrombopag is considered a second-generation thrombopoietin agent that does not lead to the
development of TPO-neutralizing antibodies. Administration of eltrombopag produces a dose-
dependent rise in platelet counts via JAK2 and STAT5 signaling pathways.

The drug is a hydrazone compound and carries a black box warning regarding hepatotoxicity. As
a class, TPO receptor agonists are thought to increase the risk for development of bone marrow
fibrosis and may increase the risk for hematologic malignancies. Eltrombopaq may also promote
the development of cataracts.

////////

New Drug of the day : Alvimopan

New Pharmacological Drug Classes Introduced in 2008

Alvimopan : is a peripherally acting μ-opioid receptor antagonist indicated to accelerate

gastrointestinal tract recovery following bowel surgery. Use of the drug beyond 7
days is not recommended because of adverse findings related to cardiovascular
events and cancer rates .

Alvimopan is a zwitterion with a relatively high molecular weight (461 Da) and low
lipophilicity; these physical characteristics hinder penetration of the drug into the
central nervous system and account for the predominantly peripheral action.
On average, post-operative patients receiving alvimopan recover GI function 17
hours earlier than patients given placebo. While a faster recovery logically translates
to a reduction in the length of hospitalization due to postoperative ileus, the clinical
and economic significance of the improved outcome remains unproven.
During pre-marketing clinical trials, the most common adverse reactions among
bowel resection patients receiving alvimopan were anemia, dyspepsia, hypokalemia,
back pain, and urinary retention. Vigorous gastrointestinal side effects (including
abdominal pain, nausea, vomiting, and diarrhea) can be expected when opioid-
tolerant patients are given alvimopan, so patients who have taken opioids for the 7
consecutive days immediately prior to surgery should not be considered candidates
for the drug.

The oral bioavailability of alvimopan is low (~6%).

An active metabolite is formed in the gut by intestinal microflora. Since both the
parent and metabolite are p-glycoprotein substrates, clinically significant drug
interactions may surface with strong p-glycoprotein inhibitors (e.g., verapamil,
cyclosporine, amiodorone, itraconazole, quinine, spironolactone, quinidine, diltiazem,
and bepridil).

Biliary secretion is the primary pathway of elimination for unabsorbed alvimopan and
the metabolite formed in the gut is eliminated in the feces and urine as unchanged
metabolite, the glucuronide conjugate, and other minor metabolites.

The half-life of alvimopan and the gut metabolite ranges from 10 to 18 hours. The
drug accumulates approximately 10-fold in patients with severe hepatic impairment

////////////

New Drug of the day : Lacosamide

Lacosamide, a "functionalized" amino acid, was licensed for adjunctive therapy of partial-onset
seizures. Lacsamide modulates sodium channels and also binds to collapsin response mediator
protein 2 (CRMP2). CRCMP2 is involved in neuronal differentiation, axonal outgrowth and
possibly epileptogenesis3

/////////

New Drug of the day : Sancuso®

A transdermal formulation of Granisetron - 5-HT3 blocker, was licensed for the prevention of
nausea and vomiting in patients receiving emetogenic chemotherapy

///////////

New Drug of the Day :Iobenguane I-123

Iobenguane I123 is a radiolabeled norepinephrine (NE) mimetic with a chemical structure similar
to guanethedine. Iobenguane is taken up by the NE transporter in adrenergic nerve terminals and
accumulates in adrenergically innervated tissues such as the adrenal medulla, salivary glands,
heart, liver, spleen, lungs, and tumors derived from the neural crest. Radiolabeled iobenguane
was licensed for use as an adjunct to other tests for the diagnosis of pheochromocytoma and
neuroblastoma.

//////////////

FDA Approves Febuxostat for Chronic Management of Hyperuricemia in Patients With Gout
February 17, 2009 — The US Food and Drug Administration (FDA) last week approved
febuxostat (Uloric), 40 mg and 80 mg, administered orally once daily, for chronic management of
hyperuricemia in patients with gout, according to an announcement by Takeda Pharmaceuticals
North American. This is the first new treatment option available for gout in more than 40 years.
In multiple clinical trials enrolling more than 4000 participants for up to 5 years in some studies,
the xanthine oxidase inhibitor safely and effectively reduced serum uric acid levels in patients with
hyperuricemia associated with gout.

CONFIRMS, the largest, pivotal, phase 3 clinical trial, showed that febuxostat 80 mg was superior
to febuxostat 40 mg and allopurinol 300/200 mg at achieving the main study outcome of serum
uric acid less than 6.0 mg/dL at the final visit (67%, 45%, and 42%, respectively; P < .001 for both
comparisons).

The safety profile of febuxostat is well established, with liver function abnormalities, nausea, joint
pain, and rash being the most frequently reported adverse reactions, occurring in at least 1% of
febuxostat-treated patients, and at a rate at least 0.5% greater than placebo. Mild to moderate
renal or hepatic impairment does not necessitate dose adjustments.

The mechanism of action of febuxostat is to inhibit xanthine oxidase, an enzyme that breaks
down hypoxanthine (a purine base) to xanthine and then to uric acid, thereby reducing elevated
levels of serum uric acid. Febuxostat is indicated for the chronic management of hyperuricemia in
patients with gout, but not for the treatment of asymptomatic hyperuricemia.

////////////

Few points regarding CARBAMAZEPINE

* Not an analgesic, but DOC for one of the most painful conditions.

* Acts by interrupting temporal summation of afferent impulses by a selective action on high

frequency nerve impulses.

* Carbamazepine has become the drug of choice for Trigeminal Neuralgia and Partial Seizures.

* Induces it's own metabolism

* MC dose related side effect of Carbamazepine : Diplopia and Ataxia.

* Can cause idiosyncratic Aplastic Anemia and Agranulocytosis.

//////
Drugs causing SIADH

SIADH - Syndrome of Inappropiate ADH Secretion

Drugs causing SIADH

1. Vasopressin /ADh / Desmopressin

2. Oxytocin High Dose
3. Chlorpropamide
4. Vincristine / Vinblastine
5. Cyclophosphamide
6. SSRIs
7.MAOIs
8. Phenothiazines
9. TCADs
10. Nicotine

//////

Most Commons : Cardiology.. Continued

Cardiac Tumor :Metastatic disease
Cause of a calcified mitral valve : Rheumatic heart disease
Primary cardiac tumor :Myxoma
Cause of a calcified mitral annulus : Degenerative process
Cardiac malignancy : Metastatic disease
Cause of a calcified aortic valve :Bicuspid aortic valve
Primary benign heart tumor : Myxoma
Site of true left ventricular aneurysm: Anterolateral and apical walls
Tumor of the heart in a child : Rhabdomyoma
Site of false left ventricular aneurysm: Post-MI rupture of LV into pericardium
Right Arch Associated with CHD: Mirror-image right arch
Type of Coarctation of Aorta : Adult (juxtaductal) type
Type of Truncus Arteriosus: Type 1-Supracardiac-Snowman Heart
CHD in Down Syndrome : Atrioventricular canal defects
Cause of a Pericardial Effusion :MI with left ventricular failure
CHD with highest association of pericardial abnormalities : ASD
Site of pulmonic stenosis :Valvular

/////////

6 Numbered Diseases : Childhood Viral Exanthems

FIRST DISEASE : ---> Measles.

SECOND DISEASE : ---> Scarlet Fever.

THIRD DISEASE :---> Rubella or German Measles.

FOURTH DISEASE :---> Duke's Disease

FIFTH DISEASE :---> Erythema Infectiosum caused by Parvovirus B19

SIXTH DISEASE :---> Exanthem Subitum / Roseola Infantum (HHV-6)(HHV-7 also mentioned)

Please Note : The terms "fourth disease" and "Dukes' disease" are rarely used today.

.////////////////

Re: OVERDOSE OF LOCAL ANAESTHETIC

Treatment of CNS complications and toxicity is still very controversial because no single remedy
exists. CNS manifestations, such as seizures, have been treated successfully
withbenzodiazepines and barbiturates (eg,phenobarbital). Recent reports indicate that 1 mg/kg of
intravenous propofol (Diprivan) and 2 mg/kg of intravenous thiopental (Pentothal) are successful
in stopping local anesthetic-induced seizures and muscle twitching. Clinicians should be aware
that propofol can by itself cause significant bradycardia that can further compromise the
cardiovascular status of the patient. Avoid use of phenytoin (Dilantin) because it shares
pharmacologic properties (ie, sodium channel blockade) with lidocaine and may potentiate toxicity

/////

brain wave;;;;

The neuropeptide nociceptin, also known as orphanin FQ, is an endogenous ligand for the
orphan opioid-like receptor which induces both hyperalgesia and allodynia when administered by
injection

Nocistatinblocks nociceptin-induced allodynia and hyperalgesia, and attenuates pain evoked by

prostaglandin E2. It is the carboxy-terminal hexapeptide of nocistatin (Glu-Gln-Lys-Gln-Leu-Gln),
which is conserved in bovine, human and murine species, that possesses allodynia-blocking
activity.

Nocistatin- pain relieving properties

nociceptin-pain giving properties

///////

brain wave;;;;

Alpha waves (8-11 Hz) are slower and larger. They are associated with a state of relaxation and
basically represent thebrain shifting into idling gear, relaxed and disengaged, waiting to respond
when needed. If one merely closes his or her eyes and begins picturing something peaceful, in
less than half a minute there will be an increase in alpha brainwaves. Alpha is present typically
when one feels at ease and calm or in a position to change one's mind efficiently and effectively
in order to accomplish a task.
Sensory Motor Rhythm (12-15 Hz) measured over the sensorimotor cortex are brain waves
associated with mental alertness and readiness for action, combined with behavioural stillness.
Beta waves (16 Hz and above) are small, faster brainwaves associated with a state of mental or
intellectual activity and outwardly focused concentration. Beta waves are present when one is
thinking, problem solving, processing information, or anxious.

Delta brain waves (1-3 Hz) are the slowest, highest amplitude brainwaves, and are present
primarily during sleep or when in an empathetic state. Excess delta activity in the awake state is
usually indicative of dysfunction.
Theta waves (4-8 Hz) are present when daydreaming or fantasising. At the same time, creativity
and intuition are also associated with theta waves. This contrast occurs because theta waves
occur at two levels: The lower range of theta (4-5 Hz) basically represents the twilight zone
between waking and sleep. It is a profoundly calm, serene, floaty, drifty state. In this range,
conscious intellectual activity is not occurring. It is also the range of frequencies produced in
excess by children and adults with ADHD.

////////

brain wave;;;;;;

imp concept

Decorticate posturing

Decorticate posturing, with elbows, wrists and fingers flexed, and legs extended and rotated
inward
Decorticate posturing is also called decorticate response, decorticate rigidity, flexor posturing, or,
colloquially, mummy baby. Patients with decorticate posturing present with the arms flexed, or
bent inward on the chest, the hands are clenched into fists, and the legs extended and feet turned
inward. A person displaying decorticate posturing in response to pain gets a score of three in the
motor section of the Glasgow Coma Scale.
There are two parts to decorticate posturing.
The first is the disinhibition of the red nucleus with facilitation of the rubrospinal tract. The
rubrospinal tract facilitates motor neurons in the cervical spinal cord supplying the flexor muscles
of the upper extremities. The rubrospinal tract and medullary reticulospinal tract biased flexion
outweighs the medial and lateral vestibulospinal and pontine reticulospinal tract biased extension
in the upper extremities.
The second component of decorticate posturing is the disruption of the lateral corticospinal tract
which facilitates motor neurons in the lower spinal cord supplying flexor muscles of the lower
extremities. Since the corticospinal tract is interrupted the pontine reticulospinal and the medial
and lateral vestibulospinal biased extension tracts greatly overwhelm the medullary reticulospinal
biased flexion tract.
The effects on these two tracts (corticospinal and rubrospinal) by lesions above the red nucleus is
what leads to the characteristic flexion posturing of the upper extremities and extensor posturing
of the lower extremities.
Decorticate posturing indicates that there may be damage to areas including the cerebral
hemispheres, the internal capsule, and the thalamus.[11] It may also indicate damage to the
midbrain. While decorticate posturing is still an ominous sign of severe brain damage,
decerebrate posturing is usually indicative of more severe damage as the rubrospinal tract and
hence, the red nucleus, is also involved indicating lesion lower in the brainstem.
[edit]Decerebrate posturing
Decerebrate posturing is also called decerebrate response, decerebrate rigidity, or extensor
posturing. It describes the involuntary extension of the upper extremities in response to external
stimuli. In decerebrate posturing, the head is arched back, the arms are extended by the sides,
and the legs are extended.[6] A hallmark of decerebrate posturing is extended elbows.[11] A
person displaying decerebrate posturing in response to pain gets a score of two in the motor
section of the Glasgow Coma Scale (for adults) and the Pediatric Glasgow Coma Scale (for
infants).
Decerebrate posturing indicates brain stem damage, specifically damage below the level of the
red nucleus (e.g. mid-collicular lesion). It is exhibited by people with lesions or compression in the
midbrain and lesions in the cerebellum.[11]
A patient with decorticate posturing may begin to show decerebrate posturing, or may go from
one form of posturing to the other;[1] progression from decorticate posturing to decerebrate
posturing is often indicative of uncal (transtentorial) or tonsilar brain herniation.Posturing may
occur on one or the other side of the body, or it may occur on both sides.[1] Activation of gamma
motor neurons is thought to be important in decerebrate rigidity due to studies in animals showing
that dorsal root transection eliminates decerebrate rigidity symptoms.

//////////

here r some topics based on previous mcqs....

1.BODY COMPOSITION:-
in an average young adult male,
18% of body weight is protein & related substances,
7% is mineral
15%is fat..
remaining 60% is water
2/3rd is intracellular & 1/3rd is extracellular...
among 1/3rd extracellular:-1/4th is in vascular system..
& 3/4th as interstitial fluid.

cholinergic receptors distribution:-

Cholinergic receptors can be divided into two types, muscarinic and nicotinic, based on the
pharmacological action of various agonists and antagonists.

1. Nicotinic :-found in N-M junction

Autonomic ganglia
& CNS.
2.Muscarinic:-
M1:-Cortex,Hippocampus
M2:-heart
M3:-Exocrine glands,GI tract
M4:-Neostriatum
M5:-substantia nigra.

***In smooth muscles M2,M3,& M4 type muscarinic receptors are found.

_________________

/////////
Sensory receptors for pain:-
When sensory nerve fibers are exposed to extremes, they signal pain. Pain receptors are also
called nociceptors.
Two types of sensory nerve fibers transmit signals that the brain interprets as pain.

* Aδ ("A-delta") fibers
o These are thinly-myelinated.
o They transmit signals rapidly that are associated with acute pain. This is "good
pain" because it warns you to do something to take care of the problems, e.g., a hot
saucepan.
* C fibers
o These are unmyelinated and thus conduct impulses slowly.
Their activation is associated with diffuse, dull, chronic pain. This is "bad pain"
because it cannot be alleviated simply by removing the stimulus. It is pain generated
by such things as damaged tissue or pain that remains after the stimulus that caused
acute pain has been removed
_________________

/////////

retina:-some facts..
**** Cones are more in centre & decreases towards periphery cones respond to bright light & role
in color vision.
Fovea centralis:-only cones (max. visual acuity)
macula lutea:- cones > rods (photopic vision)
blind spot:-no rods no cones.
in periphery:-rods> cones (scotopic vision)
Thinnest part of retina:-fovea centralis.
_________________

The human cerebral cortex is 2-4 mm (0.08-0.16 inches) thick and plays a central role in many
complex brain functions including memory, attention, perceptual awareness, "thinking", language
and consciousness.
The surface of the cerebral cortex is folded in large mammals where more than two thirds of the
cortical surface is buried in the grooves, called "sulci". The phylogenetically more ancient part of
the cerebral cortex, the hippocampus, is differentiated in five layers of neurons, while the more
recent neo-cortex is differentiated in six basic layers.

sections:
Occipital lobe - processes vision;
Temporal lobe - processes hearing, speech, language development
Parietal Lobe - processes sensory stimuli
Prefrontal lobe - allows us to plan and rehearse future actions; connected to the limbic area to
help regulate emotions
Frontal lobe - area where critical thinking and problem solving occur
Limbic system - controls emotions and long-term memory
Cerebellum - controls automatic movements and balance
_________________

ESR:-erythrocytes sedimentation rate:-some facts:-

Erythrocyte sedimentation rate (ESR) is a nonspecific screening test for various diseases. It is a
simple and inexpensive test that measures the distance that red blood cells have fallen after one
hour in a vertical column of anti coagulated blood under the influence of gravity.
The amount of fibrinogen (a blood protein) in the blood directly correlates with the ESR.. The use
of the ESR as a screening test in asymptomatic persons is limited by its low sensitivity and
specificity as it is affected by many variables.
Women tend to have higher ESR values, as do the elderly. Obese people too tend to have raised
ESR for some unknown reason though this is not thought to have any clinical significance.

Any condition that increases fibrinogen levels (e.g., pregnancy, diabetes mellitus, end-stage renal
failure, heart disease, collagen vascular diseases, malignancy, and chronic infection) may elevate
the ESR. In anaemia the ESR rises as the speed of the upward flow of plasma is altered so that
red blood cell aggregates fall faster. Macrocytic (larger) red cells with a smaller surface-to-volume
ratio also settle more rapidly.

ESR in healthy adults:-

Age<50
Men:- 0-15mm/hr
women:-0-20mm/hr

Age>50
Men:-0-20mm/hr
Women:-0-30mm/hr

*******The ESR remains an important diagnostic criterion only for polymyalgia rhuematica and
temporal arteritis.

# The ESR is an inexpensive, simple test of chronic inflammatory activity.

# Indications for the ESR have decreased as the sophistication of laboratory testing has
increased.
# The ESR rises with age, but this increase may simply reflect a higher disease prevalence in the
elderly.
# The use of the ESR as a screening test in asymptomatic persons is limited by its low sensitivity
and
specificity.
# When there is a moderate suspicion of disease, the ESR may have some value as a "sickness
index."
# An extremely elevated ESR (>100 mm/hr) will usually have an apparent cause--most commonly
infection, malignancy or temporal arteritis.
# A mild to moderately elevated ESR without obvious etiology should prompt repeat testing after
several months rather than an expensive search for occult disease

///////

*** Stages of iron deficiency & their detectable lab. abnormalities:-

Stage1:-Depleted iron stores:- Low ferritin & absent B.M iron.

Stage2:-Latent iron deficiency:-Low transferrin saturation,Low serum iron,

raised serum transferrin,normal Hb.

Stage3:-Low Hb.
////

Vit.B12 metabolism:-Vitamin B12 is synthesized only by microorganisms, and in our diets it is

supplied nearly exclusively by animal foods. Meat contains adenosyl-, and hydroxycobalamin;
dairy products contain methyl-, and hydroxycobalamin. These protein-bound forms of Vit B12 are
digested by gastric acid and pepsin so that the Vit B12 is released into gastric juice where it
becomes bound to a salivary B12 binding protein (haptocorrin) rather than to gastric intrinsic
factor (IF). Secretion of IF from parietal cells is stimulated by the same agents that stimulate acid
secretion, but drugs such as omeprazole which inhibit the H+/K+ pump do not block IF secretion.
Haptocorrin and IF are not digested by acid-pepsin, but pancreatic proteases can digest
haptocorrin, but not IF. Therefore, in the duodenojejunal lumen, Vit B12 is transferred from
haptocorrin to IF. The Vit B12-IF complex binds to a specific receptor in the brush border of ileal
absorptive cells. The Vit B12-IF complex enters the ileal absorptive cells by endocytosis and Vit
B12 is transferred to transcobalamin which exits through the basolateral membrane into portal
venous blood.

Hepatocytes secrete Vit B12 into bile and biliary B12 can be reabsorbed by ileal mucosa. This
enterohepatic circulation of Vit B12 helps to maintain normal body stores of the vitamin. Patients
who have had an ileal resection may become B12-deficient in 2-3 years. Subjects ingesting a Vit
B12-deficient diet may require 10-20 years to manifest B12-deficiency because they are able to
conserve biliary Vit B12.

Vit B12 is a cofactor for two enzymatic reactions which maintain the supply of methionine and
tetrahydrofolate, and which promote the synthesis of succinyl co-enzyme A. Vit B12 deficiency
leads to macrocytic anemia, and to neuropsychiatric abnormalities.

Absorption of Vit B12 can be assessed by a Schilling test.

****major site 4 vit.B12 absorption is ileum & that of folic acid is jejunum.
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ZOLLINGER-ELLISON SYNDROME:-
The cardinal features include:

* pancreatic non-beta islet cell tumor

* severe and recalcitrant upper gastrointestinal ulcerative disease (90-95% of the patients)
* excessive gastric acid secretion
* diarrhea in about 40% of the cases .
Seventy-five percent of the patients have ulcers localized in the first portion of the duodenum or in
the stomach. The ulcer symptoms are fulminant, progressive and persistent and respond poorly
to medical and surgical peptic ulcers treatment. Prompt recurrence of ulcer after usual peptic
surgery is characteristic of gastrinoma.

The diagnosis of Zollinger-Ellison syndrome is made on the demonstration of high serum gastrin
levels. Fasting gastrin levels in normals and in patients with ordinary duodenal ulcer average
approximately 60 pg/ml. Patients with gastrinoma almost always have levels greater than 150
pg/ml and not uncommonly greater than 1,000 pg/ml.

//
V/Qratio:- In respiratory physiology, the ventilation/perfusion ratio (or V/Q ratio) is a measurement
used to the efficiency and adequacy of the matching of two variables:

* "V" - ventilation - the air which reaches the lungs

* "Q" - perfusion - the blood which reaches the lungs

A normal value is approximately 0.8.

Because the lung is centered vertically around the heart, part of the lung is superior to the heart,
and part is inferior. This has a major impact on the V/Q ratio:

* apex of lung - higher

* base of lung - lower

The V/Q ratio can be measured with a ventilation/perfusion scan.

An area with no ventilation (and thus a V/Q of zero) is termed a shunt.

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cyanosis:-

Cyanosis is the characteristic blue color of the skin observed when the amount of unoxygenated
hemoglobin in the blood exceeds 5 grams per 100 milliters of blood (out of anywhere from 10 to
15 grams of hemoglobin per 100 milliliters). Cyanosis may be harmless - as in acrocyanosis of
newborn babies - but is usually a bad sign.

Cyanosis may be caused by lung problems when not enough oxygen is getting into the
bloodstream, or by circulatory problems. Circulatory problems include abnormal mixing of
unoxygenated blood with oxygen carrying blood. Cyanosis is usually noted first around the lips
and mouth, and perhaps in the nailbeds.
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Erythropoietin:-

*. Primary hormone regulator of RBC production

**. Erythropoietin sources
1. Fetus: Monocyte and Macrophage system in liver
2. Postnatal: Peritubular cells in kidney
Any condition that causes a reduction in tissue oxygenation will stimulate the kidney cells to
produce the hormone. These conditions include anaemia, chronic lung diseases and chronic
heart failure. Erythropoietin then exerts its effect on bone marrow cells to cause an increase in
number and rate of development and maturation of erythrocytes. When tissue oxygenation
reverts back to normal, the stimulus for erythropoietin production is removed and thus its
secretion is ceased.

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***GIT glandular cells:-

The stomach
The wall of the stomach is lined with millions of gastric glands, which together secrete 400–800
ml of gastric juice at each meal. Several kinds of cells are found in the gastric glands

* parietal cells
* chief cells
* mucus-secreting cells
* hormone-secreting (endocrine) cells

Parietal cells:-
Parietal cells secrete

* hydrochloric acid
* intrinsic factor.

Chief Cells:-

The chief cells synthesize and secrete pepsinogen, the precursor to the proteolytic enzyme
pepsin.

Hormones of the Gut:-

Over two dozen hormones have been identified in various parts of the gastrointestinal system.

* All of them are peptides.

* Many of them are also found in other tissues, especially the brain.
* Many act in a paracrine manner as well as being carried in the blood as true hormones.
* Their importance to health is uncertain as no known deficiency disorders have been found for
any of them.

* gastrin
* somatostatin
* secretin
* cholecystokinin (CCK)
* ghrelin
* neuropeptide Y (NPY)
* peptide YY3-36 (PYY3-36)

**G-cells :-pylorus/antrum:-secretes Gastrin.

**Brunner's gland:-duodenum:-mucus.
**paneth cells:- small intestine:-antimicrobial peptides that sterilized the contents of intestine.
**Enterochromaffin cells:-mucosa of small intestine:-Serotonin.
///////////

Basal ganglia:-

Basal Ganglia:

* Location: The basal ganglia is surrounds the thalamus, is enclosed by the cerebral cortex and
cerebral white matter.
* Function: The basal ganglia forms the major part of the extrapyramidal motor system.

Neurotransmitters

The different types of neuron of the basal ganglia biosynthesize a different neurotransmitter. The
most widely produced is the inhibitory transmitter GABA which is biosynthesized in the Purkinje
neurons .
Dopamine is biosynthesized in the dopaminergic neurons, primarily in the substantia nigra.
Disruption in the biosynthesis or transmission of dopamine can lead to serious motor and
cognitive deficits, such as occurs in Parkinson's disease.

**acetylcholine is an excitatory neurotransmitter in the basal ganglia ,whereas dopamine is

inhibitory.
**GABA:-the most prevalent neurotransmitter in CNS(20%)

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***Conduction speeds in cardiac tissue:-

SA node:-0.05 m/s
Atrial pathway:-1m/s
AV node:-0.02-0.05 m/s(slowest)
Bundle of his:- 1 m/s
Purkinje system:- 4m/s (fastest)
Ventricular muscles:-1m/s.
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Milk Ejection Reflex:-

The milk ejection reflex is a neuroendocrine reflex. The reflex has an afferent pathway (conducted
from the teats to the brain via neurons) and an efferent pathway (conducted from the pituitary to
the mammary gland via blood-borne hormones).

Afferent Pathway:

The greatest amount of innervation in the mammary gland is in the teats, where there are
pressure sensitive receptors in the dermis. Mechanical stimulation of the teats activates pressure
sensitive receptors in the dermis where the pressure is transformed into nerve impulses that
travel via the spinothalamic nerve tract to the brain. These nerves synapse in the paraventricular
nucleus and in the supraoptic nucleus in the hypothalamus. When the cell bodies of the oxytocin-
containing neurons are stimulated by these impulses originating in the teat, an action potential
moves down the oxytocin-containing neurons from the cell body in the hypothalamus down the
axon to the neuron ending in the posterior pituitary. This causes release of oxytocin and
neurophysin into the blood. The efferent pathway starts at this point.

Efferent Pathway:

The efferent pathway begins with the release of oxytocin into the blood. The oxytocin then travels
to the mammary gland via the blood, binds to oxytocin receptors on the myoepithelial cells,
causing the myoepithelial cells to contract, and resulting in increased intra-lumenal
(intramammary) pressure and ejection of milk from the alveolar lumen.

Oxytocin receptors are associated with the myoepithelial cells, not the smooth muscle of the
mammary gland.

**There is no parasympathetic innervation in the mammary gland.

Hormonal influences:-

From the third month of pregnancy (the second and third trimesters), a woman's body produces
hormones that stimulate the growth of the milk duct system in the breasts:

* Progesterone — influences the growth in size of alveoli and lobes. Progesterone and estrogen
levels drop after birth. This triggers the onset of copious milk production.
* Estrogen — stimulates the milk duct system to grow and become specific. Estrogen levels drop
at delivery and remain low for the first several months of breastfeeding. It is recommended that
breastfeeding mothers avoid estrogen-based birth control methods, as a spike in estrogen levels
may reduce a mother's milk supply.
* Follicle stimulating hormone (FSH)
* Luteinizing hormone (LH)
* Prolactin — contributes to the increased growth of the alveoli during pregnancy.
* Oxytocin — contracts the smooth muscle of the uterus during and after birth, and during
orgasm. After birth, oxytocin contracts the smooth muscle layer of band-like cells surrounding the
alveoli to squeeze the newly-produced milk into the duct system. Oxytocin is necessary for the
milk ejection reflex, or let-down to occur.
* Human placental lactogen (HPL) — From the second month of pregnancy, the placenta
releases large amounts of HPL. This hormone appears to be instrumental in breast, nipple, and
areola growth before birth.

By the fifth or sixth month of pregnancy, the breasts are ready to produce milk. It is also possible
to induce lactation.

****Suckling reflex (which is a neonatal reflex) sets the stimulus for both
milk ejection & maintenance of galactopoiesis.
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RBC's :-
Howell-Jolly bodies: associated with megaloblastic anemia, hemolytic anemia, post-splenectomy
state

b. Pappenheimer bodies: associated with iron loading anemias, post-splenectomy state, some
hemolytic anemias

a. Basophilic stippling:

· coarse stipples are associated with lead poisoning, megaloblastic anemia, other severe anemias

· fine stipples are a marker of reticulocytosis (polychromasia)

d. Heinz bodies: associated with hereditary hemoglobinopathies and hemolytic anemias due to G-
6-PD or drug induce hemolysis

e. Siderocytes: associated with post-splenectomy state, iron loading anemias, some hemolytic
anemias

f. Ringed sideroblasts: associated with iron loading anemias, lead poisoning, thalassemias,
megaloblastic anemia, leukemia, ethanolism, sideroblastic anemias.

***Maurer's dots:-falciparum malaria.

***Schuffner's dots:-P.vivax.
***James dots:-P.ovale.
***Zeimann's dots:-P.malariae.
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DIFFUSION:-
There are three main types of diffusion: simple, channel, and facilitated diffusion.

1.Simple diffusion is when a small,

non-polar molecule passes through a lipid bilayer.
It is classified as a means of passive transport.

In simple diffusion, a hydrophobic molecule

can move into the hydrophobic region of
the membrane without getting rejected.

Simple diffusion does not involve a proteIin.

***Hydrophilic molecules cannot participate in simple diffusion because they

would move into the hydrophobic region of the membrane and be rejected.

***Saturation does not occur with simple diffusion or with channel diffusion.
The bigger the gradient, the greater the transport of materials.

2.Channel diffusion is another type of passive transport.

Channel diffusion involves channel proteins where

material moves through an open, aqueous pore.
Channel diffusion can be regulated.
Ions and charged particles can
pass through the open pore.

3.Facilitated diffusion is a type of passive transport that is dependent on single transport protein
carriers.
These protein carriers operate on a bind, flip, release mechanism.
Facilitated diffusion is non-diffusional because the molecule moves along with the carrier.

****Saturation occurs in facilitated diffusion because not enough

carriers may be available to handle all the free solute molecules.
The rate of movement may reach a maximum.
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Anatomy review:-
* The thoracic cage:-the thoracic cage is formed by the sternum & costal cartilages in front,the
vertebral column behind & the ribs & intercostal spaces laterally.
it is separated from abdominal cavity by the diaphragm & communicates superiorly with the root
of the neck through thoracic inlet.
The ribs:-Of the 12 pairs of ribs the first seven articulates with the vertebrae posteriorly & with the
sternum anteriorly by way of the costal cartilages.
**first seven ribs= true ribs.
cartilages of 8th,9th & 10th ribs articulates with the cartilages of the above ribs.
11 & 12 ribs does not articulates anteriorly with sternum therefore called as "floating ribs".
**8-12th ribs=false ribs.

Typical ribs(3rd-9th ribs):-

characteristic of a true rib:-

1.Head consist of 2-demifacets for articulation with the numerically corresponding & the above
vertebra.
2.Tubercle:-lateral + medial facet (medial facet articulates with transverse process of the
corresponding vertebrae while lateral facet is non-articulating).
3.Subcostal groove:-accomodates intercostal neurovascular structures.

Atypical ribs (1st,2nd,10th,11th & 12th):-

*1st rib:-head bears a single facet for articulation.
A prominent scalene tubercle represents the insertion site for Scalenus anterior.(the subclavian
vein passes anterior to the tubercle while subclavian artery & lowest trunk of the brachial plexus
pass posteriorly).

**A cervical rib is a rare extra rib which articulates with C-7 posteriorly & 1st rib anteriorly.
a neurological deficit & vascular-insufficiency arise as a result of pressure pressure on lowest
trunk of Brachial-plexus (T1) & Sub-clavian artery respectively.

The Sternum:-A sternum comprises of the manubrium , body & xiphoid process.

The manubrium has facets for articulation with clavicle, 1st costal cartilage & the upper part of
2nd costal cartilage.
The body consists of 4-parts of sternebrae which fuse between 15-25 years of age.
The xiphoid usually remains cartilaginous well into adult life.

Costal cartilages:-these are bars of hyaline cartilage which connects 1-7 ribs directly to the
sternum & 8th,9th & 10th ribs to the cartilage immediately above.
**The manubriosternal joint & xiphisternal joint are symphysis....manubriosternal joint ossifies
after the age of 30.
**The 1st sternocostal joint is primary cartilaginous joint rest are synovial joints with single
synovial joint (exception:-2nd which is double).
**The costochondral joints (between ribs and costal cartilages) are primarily cartilaginous.
**The interchondral joints (between costal cartilages of 8th,9th & 10th ribs ) are synovial.
**The costovertebral joints are synovial.
**The costotransverse joints between facets of the rib tubercle & corresponding transverse
process are synovial joints.
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1.External intercostal:-fills the intercostal space from vertebra posteriorly to costochondral

junction anteriorly where it becomes the thin anterior intercostal membrane.
2.Inernal intercostal:-it fills the space from sternum to the angle of rib where it becomes the
posterior intercostal membrane.
3.Innermost intercostals:-this group comprises :-
1.subcostal muscles....posteriorly.
2.intercostales intimi .....laterally.
& transversus thoracis anteriorly.
(the fibers of innermost intercostals traverse more than 1 intercostal spaces).

*neurovarcular space is the plane between internal intercostal & innermost intercostal muscle
layers.
**pleural aspiration should be performed close to the upper border of a rib to minimize the risk of
injury.

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vascular supply & venous drainage of the chest wall:-

intercostal spaces receives their arterial blood supply from anterior & posterior intercostal
arteries.
1.The anterior intercostal arteries are branches of internal thoracic atrery & its terminal branch
musculophrenic artery.
The lowest 2 spaces have no anterior intercostal supply.
2.The first 2-3 posterior intercostal arteries are branch of costocervical trunk,a branch of the 2nd
part of the subclavian artery.
The lower 9 posterior intercostal arteries are branches of the thoracic aorta.
*Anterior intercostal veins drain into internal thoracic & musculophrenic veins whereas posterior
intercostal veins drain into azygous & hemi-azygous system.

lymphatic drainage of the chest wall:-

1.anterior chest wall:-anterior axillary nodes.
2.posterior chest wall:-posterior axillary nodes.
3.anterior intercostal spaces:-internal thoracic nodes.
4.posterior intercostal spaces :-para-aortic nodes.

Nerve supply of the chest-wall:-

The intercostal nerves are anterior primary rami of thoracic segmental nerves.
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