AETIOLOGY - rare isolated; usually associated with pulmonary hipertension caused by left heart valvular disease (e.g. aortic regurgitation - Graham Steel murmur), pulmonary disease, or Eisenmenger's syndrome

The murmur of PR - high pitched, early diastolic, decrescendo in character, and heard best at the second left intercostal space

Renal papillary necrosis refers to ischemic necrosis of the papilla in the medulla of the kidneys.

Renal papillary necrosis occurs in association with the following conditions:

• Use of analgesics

• Diabetes mellitus (DM) with infection (no increase occurs with uncomplicated DM)

• Urinary tract infection

• Urinary tract obstruction

• Haemoglobinopathies, such as sickle cell disease

• Prolonged hypotension

• Renal vein thrombosis

• Congestive heart failure

• Cirrhosis

• Haemophilia

• Christmas disease

• Paediatric gastroenteritis (infants)

• Severe neonatal jaundice

• Severe dehydration

• Acidosis and respiratory distress

Definition

• Diabetes insipidus (DI) is caused by decreased secretion or action of arginine vasopressin (AVP), resulting in the production of abnormally large volumes of dilute urine.
  • 24-hour urine volume is > 50 mL/kg body weight.
  • Urine osmolarity is <>
• Neurohypophyseal DI is caused by deficient AVP secretion from the neurohypophysis (posterior pituitary).
• Nephrogenic DI is caused by defective AVP action to reabsorb water via the renal collecting tubules.

Causes of Diabetes Insipidus

Pituitary diabetes insipidus

• Acquired

Head trauma (closed and penetrating)

Neoplasms

• Primary

Craniopharyngioma

Pituitary adenoma (suprasellar)

Dysgerminoma

Meningioma

• Metastatic (lung, breast)

• Hematologic (lymphoma, leukemia)

Granulomas

Neurosarcoid

Histiocytosis

Xanthoma disseminatum

• Infectious

Chronic meningitis

Viral encephalitis

Toxoplasmosis

• Inflammatory

Lymphocytic infundibuloneurohypophysitis

Wegener's granulomatosis

Lupus erythematosus

Scleroderma

• Chemical toxins

Tetrodotoxin

Snake venom

Vascular

Sheehan's syndrome

Aneurysm (internal carotid)

Aortocoronary bypass

Hypoxic encephalopathy

Pregnancy (vasopressinase)

• Idiopathic

Congenital malformations

Septooptic dysplasia

Midline craniofacial defects

Holoprosencephaly

Hypogenesis, ectopia of pituitary

• Genetic

Autosomal dominant (AVP-neurophysin gene)

Autosomal recessive (AVP-neurophysin gene)

Autosomal recessive-Wolfram-(4p - WFS 1 gene)

X-linked recessive (Xq28)

Deletion chromosome 7q

Nephrogenic diabetes insipidus

Acquired

Drugs

Lithium

Demeclocycline

Methoxyflurane

Amphotericin B

Aminoglycosides

Cisplatin

Rifampin

Foscarnet

Metabolic

Hypercalcemia, hypercalciuria

Hypokalemia

Obstruction (ureter or urethra)

Vascular

Sickle cell disease and trait

Ischemia (acute tubular necrosis)

Granulomas

Neurosarcoid

Neoplasms

Sarcoma

Infiltration

Amyloidosis

Pregnancy

Idiopathic

Genetic

X-linked recessive (AVP receptor-2 gene)

Autosomal recessive (aquaporin-2 gene)

Autosomal dominant (aquaporin-2 gene)

Primary polydipsia

Acquired

Psychogenic

Schizophrenia

Obsessive-compulsive disorder

Dipsogenic (abnormal thirst)

Granulomas

Neurosarcoid

Infectious

Tuberculous meningitis

Head trauma (closed and penetrating)

Demyelination

Multiple sclerosis

Drugs

Lithium

Carbamazepine

Idiopathic

Iatrogenic

Definition

Nephrotic syndrome Is a clinical syndrome associated with proteinuria in the nephrotic range (3.5mg/m2/24hrs), edema and hyperlipidemia.

Nephrotic syndrome is not due to inflammatory processes but due to direct action of the membrane attack unit of complement on the glomerulus.

Clinical suspicion

It should be suspected when a patient presents with generalized oedema, protein detected in urine, hypoalbuminemia.

Diagnosis
The diagnosis maybe established with proteinuria in the nephrotic range alone without the other criteria.

1. Proteinuria > 3.5 g/m2/day:
On detection of protein in urine a 24 hour urinary protein test is in order. There are two cut off values for this test: 1. increased urinary protein <1.5g/day;>3.5g/day; this establishes nephrotic syndrome.

2. Hypoalbuminaemia

3. Hyperlipidaemia:
As albumen in serum is lost through the kidneys, the liver increases its production of albumen and concomitantly increases the production of cholesterol.

4. Oedema: resulting from loss of intravascular fluid to the extravascular space due decreased intravascular oncotic pressure (decreased albumen).

However, the presence of proteinuria in the nephrotic range (3.5g/day) establishes the diagnosis.

Differential diagnosis: proteinuria

Causes
Once the diagnosis of nephrotic syndrome is established the cause of the syndrome is sought in order to treat accordingly.

Nephrotic syndrome with active sediment (mixed nephrotic/ nephritic)
This denotes the presence of RBC casts (active sediment). Causes include:

1ry glomerular diseases as MPGN (main cause), and 2ry glomerular diseases as SLE (most common presentation of SLE), vasculitis such as Henoch Schonlein purpura, mixed essential cryoglobulinemia.

Nephrotic syndrome with bland sediment (Pure nephrotic)
1ry glomerular diseases such as MCNS, Membranous glomerulonephritis, Focal glomerulosclerosis. As well as 2ry glomerular diseases that result from Diabetes (Klemelsteli-Wilson syndrome) and amyloidosis.

Treatment

Treatment of nephrotic syndrome depends primarily on the cause, however, it frequently involves the use the glucorticoids given over long periods of time. Especially in cases of minimal change disease. Here the role of steroids is to suppress the autoimmune basis for this disease. The use of cytotoxic agents maybe required in some cases (e.g. cyclophosphamide).

Dietary salt control, treatment of hypertension and hypercholestrolemia is also recommended. ACE inhibitors, in addition to controlling blood pressure have also been found to decrease the protein loss. Diuretics may help control the edema and the hypertension.

Causes: Increased production or decreased excretion of uric acid.

Pathophysiology: Acid pH promotes precipitation of urate. Leukocytes are damaged by urate, bursting and emptying contents (PGIs, lysosomes, IL-1) into joint tissue. This results in inflammation and propagation of a vicious cycle.

Risk factors: Thiazide diuretics, aspirin, blood diseases, obesity, heavy alcohol intake.

Treatment of acute attack is different than treatment of hyperuricemia.

Colchicine – only effective in gouty arthritis; not analgesic; rapid relief of acute attacks; also effective for prophylaxis; reserved for those who cannot tolerate NSAIDs.

MOA: Binds to tubulin causing depolymerization and disappearance of microtubules in motile granulocytes. Breaks inflammatory cycle by inhibiting leukocyte migration.

Toxicity: Since inhibitory to mitosis, toxic in rapidly proliferating cells such as intestinal epithelium. Long-term therapy may cause marrow depression, myopathy, neuropathy.

NSAIDs (indomethacin, naproxen, sulindac, ibuprofen, fenoprofen) – Preferred treatment for acute attacks. Can also be used for prophylaxis.

Allopurinol – Used to treat hyperuricemia

MOA: Inhibits conversion of hypoxanthine and xanthine to uric acid, thereby reducing production of uric acid. Competitive inhibitor at low concentrations and non-competitive at high concentrations. Converted to alloxanthine, which also is a noncompetitive inhibitor of xanthine oxidase.

Therapeutic place: Stops formation of uric acid stones. The incidence of acute gouty attacks frequently increases during the first months of tx, probably due to mobilization of urate from stores.

Pharmacokinetics: Alkalinization of the urine and increased fluid intake can aid in excretion.

Toxicity: Hypersensitivity is most common. Caution in patients with poor kidney function.

Drug interactions: Enhances effect of probenecid and mercaptopurine toxicity. May interfere with metabolism of oral anticoagulants.

Urosuric agents: Probenecid & Sulfinpyrazone – Both inhibit reabsorption while not affecting excretion of urate. Levels must be high enough, otherwise opposite becomes true. Aspirin inhibits action of both drugs.

Other drugs: Glucocorticoids, strong analgesics

Therapeutic indications

• Acute attack: NSAID (indomethacin/ibuprofen), colchicine for refractory episodes, steroids, analgesics.

• Long-term treatment and prevention: Prophylaxis with low-dose colchicine or indomethacin; urosuric agent; allopurinol; adequate fluid intake; weight reduction, diet modification (no shellfish, sardines, liver), reduce alcohol.

Tuberculosis: (TB) is a chronic, communicable disease caused by Mycobacterium tuberculosis made distinctively a necrotizing (caseating) granulomatous tissue response to seeded organisms.

Transmission is usually by inhalation of infected droplets produced by the coughing or sneezing of infected individuals (open cases).

Predisposing factors are any debilitating or immunosuppressive condition (e.g. diabetes, alcoholism, malnutrition, chronic lung disease.)

Pathogenesis:

1. Macrophages phagocytose bacteria (multiplies in macrophages!)  transported to regional lymph nodes (via lymphatics)

The cell wall lipids and carbohydrates of M. tuberculosis appear to enhance virulence by interfering with phagolysosomal fusion. This interference allows the intracellular survival of mycobacteria (resists killing by macrophages).

2. Macrophages at site of infection transforms into epithelioid cells (ample eosinophilic cytoplasm) and multinucleate giant cells

3. Outer ring of fibroblasts and lymphocytes accumulates; forming the ‘hard’ tubercle

4. After 2-3 weeks central caseous necrosis occurs; forming the ‘soft’ tubercle (characteristic TB lesion)

5. Later still areas of caseation may coalesce to form larger granulomatous lesions ( smaller peripheral tubercles)

Tuberculosis bronchopneumonia: caused by the spread of the bacilli from primary focus in the lung or hilar lymph nodes, via the bronchi

Mantoux reaction:

Delayed hypersensitivity (type IV) to the tubercle bacillus develops in 2-4 weeks after initial infection. A sensitized individual shows increased induration (>5mm) at the site of intradermal injection of purified protein derivative of M. tuberculosis (PPD test). A positive test result indicates sensitivity, however, not active disease.

Once sensitization appears during infection, the non-specific inflammatory response becomes granulomatous (abundant epithelioid histiocytes [modified macrophages], occasional giant cells and peripheral mononuclear cells). There is often central, caseous necrosis of the granulomas. A concomitant increase in resistance – the ability to inhibit intracellular replication of bacilli – occurs.

Primary tuberculosis: first time infection…

• Usually settles in middle zone of lung, forms Ghon focus: small subpleural inflammation (1-1.5cm)

• After ~2 weeks (sensitization); lesions spread to regional lymph nodes forming the Ghon complex

• Majority of cases will heal by fibrosis with later calcification (therefore may pass unnoticed clinically)

• Even so, a few viable bacilli may persist in quiescent, apparently healed lesions or in other organs to which they may have spread

Secondary tuberculosis: reactivation of primary lesion or reinfection; when resistance is lowered as in immunocompromised or malnutrition (esp. AIDS, poverty)…

• Classically the lesions (~1-3cm) settles at the apices of the lungs

• Pre-existing hypersensitivity / immunity  organisms tend to be localised, with rapid granulomatous caseation and fibrous reaction

Explores the first 6 divisions of the tracheobronchial tree down to the subsegmental bronchi. Use a topical anesthetic only. Washings with isotonic saline can be sent to cytology or Microbiology .


Indications:
The indications for a bronchoscopy are many. The object in each setting is different.

Diagnostic:
For Endobronchial Symptoms or Signs

Symptoms and signs of endobronchial disease are the most common indications for a bronchoscopy.

• Chronic cough
• Hemoptysis
• Atelectasis
• Obstructive pneumonia
• Localized wheezing

Lung Cancer:
Lung cancer is one of the most common conditions where a bronchoscopy is indicated. It is necessary for:

• Tissue diagnosis
• Staging
• Early diagnosis

Burn:
Patients who sustained burns and suspected of having injuries to the respiratory passages are bronchoscoped.

Assessment of the Endotracheal Tube Position:

Therapeutic

Removal of Foreign Body:
In general, foreign body removal is best done with a rigid bronchoscopy under general anesthesia.

A fiberoptic bronchoscopy may be used as a screening procedure for suspected cases of aspiration. Patients with known or suspected foreign bodies should undergo a rigid bronchoscopy. If the evidence for aspiration is equivocal, patients should undergo a diagnostic flexible bronchoscopy, and then a rigid bronchoscopy if a foreign body is found.

There have been reports of foreign body extraction using flexible bronchoscopes, but this is poorly suited for such work.


Lung Abscess:
To Rule out Endobronchial Lesion and for Drainage

Tracheal Stenosis:
For Dilation

Refractory Atelectasis: With a Balloon Cuff

Respiratory Toilette:
Occasionally, a bronchoscopy will be indicated for respiratory toilette. As a general rule, postural drainage, tapotage, cough and suction of secretions are sufficient. If for some reason these cannot be done, then bronchoscopy can be done for respiratory toilette. Prospective studies have shown that a good intensive respiratory toilette can accomplish good results in the control of atelectasis.

However, there are many clinical circumstances when respiratory toilette cannot ideally be accomplished. They are as follows:

• Spine injury
• Balloon pump
• Left lower lobe atelectasis
• Weekends
• Blind passage of the catheter to the left lower lobe is difficult. Hence, the poor success rate with respiratory toilette with lower lobe atelectasis.

Preliminary to Other Procedures

Pneumonia, Diffuse lung disease
A bronchoscopy is a preliminary to many other procedures . A bronchoscopy has to be done at times to obtain respiratory secretions for establishing the diagnosis of an infection. The choice of brushing, triple lumen Microbiology brush or broncho-alveolar lavage is made appropriate to the clinical situation. After inspection of the tracheobronchial tree, depending on the clinical situation, you can:

• Brush
• Biopsy
• Transbronchial lung or mass biopsy
• BAL
• Triple lumen catheter
• Lase

A bronchoscope acts as a medium through which these accessories are introduced to the desired location to accomplish the task.

Difficult Intubation:
If you experience difficulty in intubation, a fiberoptic bronchoscope can be used to help you. The endotracheal tube is passed over the bronchoscope and, under direct vision, can be introduced into the trachea.


Contraindications:
severe asthma, uncooperative pt, bleeding diathesis, uncorrectable hypoxemia/
hypercapnia.

Complications:
PTX, hemorrhage, bronchospasm, laryngospasm, epistaxis, vasovagal syncope and hypoxemia.

Lobar pneumonia:

• Usually caused by Streptococcus pneumoniae, although other organisms can cause this disease (e.g. Klebsiella pneumoniae)

• Involves a large portion of or an entire lobe of lung

• Typically affects young healthy adults and is thus a primary pneumonia

The following sequence of stages is classic but infrequently seen because of antibiotic therapy. The various stages portray the natural history of uncomplicated lobar pneumonia:

1. Congestion: of alveolar vessels; fluid exudate moves into the alveolar spaces ( organisms)

2. Red hepatisation: (consolidation) describes lung tissue with confluent acute exudation, containing neutrophils and red cells, giving a red, firm, liver-like gross appearance.

3. Grey hepatisation: follows, as the red cells disintegrate and the remaining fibrinosuppurative exudate persists, giving a grey-brown appearance.

4. Resolution: is the favourable final stage in which consolidated exudate undergoes enzymatic and cellular degradation and clearance; normal structure is restored.

Clinically the patient may have:

• Severe fever with rigors or shivering attacks

• Cough with ‘rusty’ blood-stained sputum (red hepatisation)

• Difficulty breathing

• Pleurisy; characterized by sharp pain on coughing or on deep inspiration and pleural friction rub

Bronchopneumonia:

• Caused by a wider variety of organisms (most commonly Staphylococci, also Streptococci, H. influenzae, P. aeruginosa, coliforms and some fungi)

• Initially infection is centred on bronchi and surround alveoli (lobular), although if untreated it can spread to become lobar.

• Tends to occur at the extremes of life or in those suffering from other illnesses (e.g. cancer, heart failure, renal failure, stroke, airways diseases etc.) – thus generally a secondary type of pneumonia

Grossly the lungs show dispersed (often in basal areas of both lungs) focal (patchy) areas of consolidated acute inflammation.

Histologic features consist of an acute (neutrophilic) suppurative exudate filling airspaces and airways, usually about bronchi and bronchioles.

Resolution of the exudate usually restores normal lung structure, but organization may occur and result in fibrous scarring (healing by fibrosis).

Clinically the patient may have:

• Septicaemia with high temperature

• Crackles (crepitations) on auscultation of affected areas

1. Chronic Obstructive Pulmonary Disease (COPD)

• Common features of COPD
  
• almost all have smoking history
• dyspnea - chronic "gasping" for air
• frequent coughing and infections
• often leads to respiratory failure

• obstructive emphysema - usually results from smoking

• a. enlargement & deterioration of alveoli
• b. loss of elasticity of the lungs
• c. "barrel chest" from bronchiole opening during inhalation & constriction during exhalation
  

• chronic bronchitis - mucus/inflammation of mucosa
  

Lung Cancer

• squamous cell carcinoma (20-40%) - epithelium of the bronchi and bronchioles
• adenocarcinoma (25-25%) - cells of bronchiole glands and cells of the alveoli
• small cell carcinoma (10-20%) - special lymphocyte-like cells of the bronchi
• 90% of all lung cancers are in people who smoke or have smoked

VSD - isolated or part of complex congenital heart disease

VSD - most congenital defects are perimembranous (at junction of the membranous and muscular portions)

VSD - may be present as cardiac failure in infants (in the first 4-6 weeks of life), as a murmur with only minor hemodynamic disturbances in children or adults, as Eisenmenger's syndrome, sometimes may close spontaneously

PATHOPHYSIOLOGY:

- flow from the high-pressure left ventricle to the low pressure right ventricle (pansystolic murmur at the left sternal edge radiating all over the precordium)

- small defect - loud murmur (maladie de Roger), large defect - softer murmur (particulary if pressure in RV is elevated)

- Eisenmenger's syndrome -

• severe pulmonary hypertension (irreversible increased pulmonary resistance) due to an initial left-to-right shunt and reversal of the shunt - i.e. right-to-left shunting leads to central cyanosis, erythrocytosis and digital climbing,

• signs of pulmonary arterial hypertension (left parasternal-right ventricular lift, palpable pulmonary artery pulsation, loud P2, diastolic decrescendo murmur of pulmonic insufficiency (Graham Steell murmur), holosystolic murmur of tricuspid regurgitation

• CXR- enlarged central pulmonary arteries with peripheral pruning of the pulmonary vessels,

• ECG - right ventricular hypertrophy (more common in large VSD, persistent ductus arteriosus, ASD),

(cardiac abnormalities present at birth, occurs approximately 6-8 of every 1000 live births)

LESIONS PREVALANCE

1. Ventricular septal defect (VSD) 25-30%

2. Atrial septal defect (secundum) 10-15%

3. Persisten ofductus arteriosus 10%

4. Complete transposition 5%

5. Atrial septal defect (ostrium primum) 5%

6. Hypoplastic left heart 5%

AETIOLOGY-

unknown cause, maternal infections in the early weeks of pregnancy (rubella-persistent ductus arteriosus, pulmonary artery stenosis), maternal alcohol abuse (septal defects), intrauterine radiation, drug effects, genetic or chromosal abnormalities (e.g. Down syndrome)

• common especially in rheumatic heart disease

• in additions to organic leasions, development of mitral and tricuspid regurgitation or pulmonary regurgitation may occur secondary to the hemodynamic disturbance of the other valvular lesions

• the manifestations of the other valvular lesions

Imp Points:

• Rare
• Less genetic

Causes/Risk Factors

• Amyloidosis (most common), desmin mutation, hemochromatosis (Fe metabolism defect)
• Endomyocardial fibrosis and fibroelastosis in kids/infants
• Löffler syndrome = eosinophilic endomyocardial fibrosis in the tropics
• Radiation injury
• Glycogen storage diseases (type II Pompe’s), Fabry’s disease (lysosomal storage disease, defect of α galactosidase)

Clinico-Pathological Findings

• Stiffening of heart muscle interferes with pumping action
• R and L sided failure Thick, waxy, opaque endocardium with normal sized chambers
• Thickened valves, patchy fibrosis throughout from hyaline deposition
• Mural and valvular thrombi
• Sometimes Eosinophilic infiltrate
• Clinically similar to hypertrophic cardiomyopathy, but without hyperdynamic state
• Fatigue, dyspnea, CP, late stage → CHF
• Fibrosis encroaches on conduction system → arrythmia
• Löffler – dilated atria, mural thrombi

Amyloid is Congo Red positive and gives apple green bifringence

Imp Points:

• Young people without heart disease

Causes/Risk Factors:

• Usually viral (coxsackievirus, enterovirus, adenovirus)
• Parasites - Trypanosoma (Chagas disease, S America), toxoplasmosis, trichonosis
• Rarer – CMV, HIV, fastidious bacteria
• Hypersensitivity myocarditis: Anticancer drugs, SLE, inflammatory myopathies, cardiac allograft rejection
• Sarcoidosis

Clinico-Pathological Features:

• Inflammatory process of the myocardium that causes biventricular failure Diffuse myocardial degeneration and necrosis with inflammatory infiltrate
• T cells are cytotoxic to infected myocytes
• Flabby, pale, hemorrhagic, mottled, dilated heart
• Abscesses with PMN infiltrate if bacterial
• Edematous with infiltrate of lymphs and monos if viral
• Giant cell Myocarditis – presence of giant cells; progresses rapidly
• Causes severe CHF, symptoms of dilated cardiomyopathy, and lethal Arrythmias
• If HS Myocarditis, will see eosinophils

*Dallas Criteria

Deflection Waves of ECG

• P wave - initial wave, demonstrates the depolarization from SA Node through both ATRIA; the ATRIA contract about 0.1 s after start of P Wave
  
• QRS complex - next series of deflections, demonstrates the depolarization of AV node through both ventricles; the ventricles contract throughout the period of the QRS complex, with a short delay after the end of atrial contraction; repolarization of atria also obscured
  
• T Wave - repolarization of the ventricles (0.16 s)
  
• PR (PQ) Interval - time period from beginning of atrial contraction to beginning of ventricular contraction (0.16 s)
  
• QT Interval - the time of ventricular contraction (about 0.36 s); from beginning of ventricular depolarization to end of repolarization

Marfan's Syndrome is an inherited (autosomal dominant) disorder, caused by a defective gene involved with the production of fibrillin. Fibrillin makes up part of connective tissue in the body, such as the blood vessels, eye lenses, and ligaments.

Signs and Symptoms

• Patient has long, thin arms, legs, fingers, and toes.
• Chest wall protrudes
• Reduced vision and severe near-sightedness
• Mitral valve prolapse
• Aortic aneurysms (a bulge in the wall or the aorta, resembling a weak spot that bulges in an imperfect automobile tire) -- can have no symptoms; or might have fatigue, lightheadedness, and/or chest pain. Death may occur if the aneurysm ruptures.
• Aortic Dissection (a torn area between the layers of the aortic wall, allowing blood to seep between the layers of the wall) -- can cause chest pain, tearing/ripping back pain, or death
• Aortic Regurgitation -- chest pain, shortness of breath
• Spontaneous Pneumothorax -- Collapsed Lungs may occur (severe, sudden shortness of breath)

Diagnosis

• Mutations may be seen in chromosome 15, but no single test establishes the diagnosis.
• Echocardiogram is performed to evaluate the patient's chest for an aortic aneurysm.
• See section on Aortic Dissection for work up and management.
• Ophthalmologic evaluation reveals lens dislocation and severe near-sightedness

Gene	Disease	Comments…
beta-globin	Sickle cell & thalassemia
5p-	Cri du chat	Catlike cry, microcephaly.
Adenosine deaminase	SCIDs	PCR detectable, bubble boy.
bcl-2 t14:18	Follicular lymphoma	Inactivates apoptosis.
bcr-abl t9:22	CML; ALL	Philadelphia chromosome. Translocation  abnml gene.
Blood group A	Stomach CA	Association.
Blood group O	Peptic ulcer disease	Association.
chromosome 1 - N myc	Neuroblastoma
chromosome 11	Wilm's tumor	WAGR complex, hemihypertrophy.
chromosome 13	Wilson's disease: Hepatolenticular	Corneal Kayser-Fleischer rings, copper metabolism.
chromosome 13 - Rb	Retinoblastoma. Osteosarcoma.	Two-hit. Normally a suppresor gene, gets inactivated
chromosome 13 - trisomy	Patau's
chromosome 15	Angelman's; maternal.	Microdeletion. Mental retardation. Bursts of laughter.
chromosome 15	Prader-Willi; paternal.	Microdeletion. Mental retardation.
chromosome 16 - APKD-1	Adult Polcystic Kidney Disease
chromosome 17	Pancreatic CA	Home of p53.
chromosome 17 - BRCA-1	Breast CA. Ovarian CA.	Home of p53, and BRCA-1.
chromosome 17 - NF 1	Acustic neuroma	Normally a suppresor gene. Gets inactivated.
chromosome 17 - p53	25-50% lung, colon, breast…	Normally a suppresor gene. Gets inactivated.
chromosome 18 - trisomy	Edward's	Rocker bottom feet, micrognathia.
chromosome 21	Alzheimer's	-amyloid
chromosome 21 - trisomy	Down's	Simian crease, brushfield's spots.
chromosome 22 - NF 2	Meningioma	Normally a suppresor gene. Gets inactivated.
chromosome 3 - VHL	von Hippel-Lindau	Renal cell CA, adenomas, cysts…
chromosome 4	Huntington's	Choreiform mvmnts, caudate. Triple repeats.
chromosome 5 - APC	Familial Polyposis Coli; Gardener's	100%  CA. Suppressor gene gets inactivated.
chromosome 6	Hemochromatosis	Bronze diabetes
chromosome 6	HLA genes
chromosome 7 - CFTR	Cystic fibrosis	Sweat test, lungs, pancreas. Inability to fold protein.
c-myc onc t8:14	Burkitt's lymphoma	Increases transcription. EBV.
erb-B2/neu	Breast CA, SCC of lung	Increases growth factor receptors; gene amplification.
FMR 1	Fragile X syndrome	CGG repeat
HER-2/neu	Breast CA
HLA-A3	Hemochromatosis	Bronze diabetes.
HLA-A3, B7, DR2, DW2	Multiple sclerosis	Geographic distribution.
HLA-B27	Ankylosing spondylitis
HLA-B8	Myasthenia gravis
HLA-B8, Dr3	Sclerosing cholangitis; Celiac disease	Associated w UC.
HLA-B8, DW3	Celiac disease	Gluten Ab.
HLA-DR2	Ulcerative colitis	Rectum and left colon.
HLA-DR3	Graves'	Hyperthyroidism.
HLA-DR3,4	IDDM
HLA-DR4	Rheumatoid arthritis
HLA-DR5,B5	Hashimoto's thyroiditis	Hypothyroidism.
LDL -R	Familial hypercholesterolemia
piZZ	Panacinar emphysema	alpha 1-antitrypsin.
raf onc		Cytoplasmic protein kinases.
ras onc	30% of all CA. Colon CA.	Point mutation. Produces GTPs. p21 proteins.
sis onc	Carcinomas; astrocytoma	Produces its own growth factor.
src onc		Produces membrane tyrosine kinases.
XO	Turner's	Amenorrhea, webbed neck.
XXY	Klinefelter's	Atrophic testes, tall, female fat distribution.
XYY		Criminals, tall, acne.

Autosomal Dominant
von Willebrand's	125
familial hypercholesterolemia	500
Adult polycystic kidney disease	1250
IHSS	1500
Huntington's	2500
Neurofibromatosis	3000
Congenital spherocytosis	5000
familial Polyposis	8000
intermittent Porphyria	10000
Marfan's	20000
von Recklinghausen's
von Hippel-Lindau

Autosomal Recessive
alpha 1-antitrypsin deficiency
Thalassemia
Glycogen storage disease
Alcaptomuria
Homocystinuria
Hemochromatosis	400
Sickle cell anemia	625
Cystic fibrosis	2500
Tay-Sachs	3600
Phenylketonuria	10000
21-hydroxylase	14000
Albinism	18000
Mucopolysaccharidase	25000
Galactosemia	57000

Determination of race is a very important question in cases of accidents in traveling by air, railway or sea when fatalities occur simultaneously in persons of different races traveling together

The main original races are:

• Caucasian, Negroid, Mongoloid.

• North Africans are part of the Mediterranean race which is a subdivision of the Caucasian race.

• The main identification characteristics regarding the Egyptians are between the Caucasian and the Negroid.

Mongolian race includes Chinese, Japanese, Indians and American Indians.

Race can be determined from:

a. Complexion (color of the skin).

• The skin is black in Negroes, yellow to brown in Indians and fair in the Europeans.

b. The color and characters of hair:

• Negroes: The hair is frizzy, spiral, stiff, black and cut section is flattened and elliptical.
• Europeans: The hair is fair, straight, smooth waxy and wavy.
• Asiatic: the hair is dark brown, straight, smooth & rounded cut surface.

c. Facial characters:

• Negroes are characterized by flattened nose, delayed union of the frontal suture, parallel alveolar ridges & prognathism (protrusion of the maxilla). Their lips are thick and slightly everted.

d. Bones (skull features) and body measurements & ratios: see before

e. Blood:

• By identification of abnormal Hb, some of which only occur in Negroid race

• Hbs: normal 10%, but in Negroid 30%.

• Fya-b- (lacking both antigens) of duffy system occurs in black peoples.

Identification of stature:

• Height = span (distance between the outstretched upper limb).

• Pearson's formulae (see before)

Identification of the social state

• From personal care for clothes, hair, teeth, nails, etc.

Identification of the occupation

• From the clothes.
• Callosities, stains, dyes on the fingers and under nails
• Wax of ears usually retains dust and organic particles for long time.
• Plain x-ray chest may reveal byssinosis and asbestosis in cotton fiber workers

Identification from congenital anomalies, birth marks, moles

Identification from acquired peculiarities e.g. occupational marks, operation scars and tattoo marks.

• Tattoo marks: It is done by injecting certain coloring material (e.g. aniline) into the dermis to be permanently fixed by histocytes.

Tattoo marks


Estimation of time passed since death

* It can be estimated from changes in soft tissues as well as skeleton

• Indicating the name, address, religion, birth date and place of the person.
• Giving an idea about the environmental and social background of the person e.g. tattoo marks is generally practiced in lower class of society. In addict persons, they are practiced to conceal the injection sites.
• Removal of tattoo marks by either surgery or caustic substance will leave a scar.

A) In civil cases:

• Identification of a living person is very important in cases such as: marriage, inheritance, or in case of people impersonating somebody else to obtain unlawful property.

• Identification of living body follows all the points mentioned for the dead with the addition of certain features as:

  1. Character of voice, the expression, hand writing (right or left handed).

  2. Standard of education, the intellect and the accent.

  3. Any mannerism in speech and movements of the hands during talking and any tics.

  4. Any peculiarities in the gait during walking.

  5. Photographs: side view and face view, but they can often be misleading by accidental reversing of a negative to find that wounds which were on the left side of the face appear to be on the right side.
     

B) In criminal cases:

Personal identification of living persons in criminal cases is essentially the work of the police, depending on:

• Anthropometry:
• Bertillon system Anthropology:
• (Anthropos = man and metron = measurement)
• It deals with the measurement of various parts of the human body. The system is applicable to adults only because the human body does not alter after about the age of 21 years and that no two persons show the same measurements in all respects.
• Finger Prints (Dactylography).
• Foot prints, palm prints, lip prints, iris prints, and voice prints
• DNA fingerprints

• 2 weeks: i.e. newborn
• MLI: Crime of infanticide if infant is below this age.
• Identification:
  
• 6 years (age of admission to school)
• MLI: Compulsory education starts at 6 years of age.
• Identification:
• Eruption of first permanent molar tooth.
• Union of pubic and ischeal rami.
• Ossific centre of the upper end of the radius.
• 7 years (age of discrimination):
• MLI: Child is criminally irresponsible and cannot discriminate below this age.
• Identification:

• Eruption of central permanent incisor.

• Ossific centre at lower end of radius reaches 2/3 the breadth of the epiphysis.
  
• 14 years:
• MLI: Below this age the male is considered that he can not commit the crime of rape.
• Identification:
• Union of trochlea and capitulum
• Signs of puberty in males:
  
• Appearance of pubic and axillary hair and moustache and development of testes and penis.
• Signs of puberty in females:

• Remodelling of hip and shoulder.

• Enlargement of breast.

• Start at menstrual cycle .

• Pubic hair start to appear and become thicker and longer.

• Later 13-15 year axillary's hair will appear.
• 15 years:
• MLI: The child under 15 years is partially criminally responsible
• N.B.: Between ages of 15 and 18 years:
• - No capital sentence.
• - No imprisonment for life.
• - The period of imprisonment should not be more than 18 years.
• Identification :

• Union of capitulum and trochlea with shaft.

• Complete union of the Y-shaped suture in hip bone
• 16 years:
• MLI:

• Legal marriage for females.

• Age of having identity card.

• Age of eligibility of having license of motor cycle driving.

• Identification :
• In males

• Fusion of lateral epicondyle of humerus with shaft in males.
• Fusion of upper end of ulna in males
• In females

• Head of femur with shaft .
• Lower end of tibia with shaft.
• Epiphysis of metacarpals and phalanges with shafts.
• 18 years
• MLI:

• Legal marriage for males.

• Age of consent in cases of rape for females.

• Age of eligibility of having license of driving motor cars.

• Age of first call for military service.

• Age of employment in government.

• Age of voting in elections

• Age of full criminal responsibility(below this age the child is tried in front of juvenile courts )
• Identification :
• In males

• Union of epiphyses of metacarpals and phalanges with shaft (in male).

• Head of femur with shaft (in male).

• Lower end of tibia with shaft (in male
• In females :

• Head of humerus with shaft (in female).

• Lower end of radius with shaft (in female).
  

• 21 years:
• Identification :
• In males

• Lower end of femur with shaft,

• Upper end of tibia and fibula with shaft,
• Epiphysis of ischial tuberosity with ischium.
• In females

• Epiphysis of iliac crest with ilium,

• Medial end of clavicle with shaft

• Basiocciput with basisphenoid in females..
• 30 years
• Identification:

• Closure of saggital suture

• The medullary cavity of humerus reaches the surgical neck (in male).In female it approaches the anatomical neck .
• 40 years:
• Identification :Union of xiphoid process with the body of sternum .
• 60 years:
• MLl: Age of retirement.
• Identification: Union of manubrium with body of the sternum.

Examination for sex is important in:

• Civil law e.g. marriage and inheritance of a case of inter sex.
• Criminal law, in exchange of babies in hospitals, sexual perversions, in criminals who conceal their sex.

Inter sex states:

These are conditions in which male and female characters (e.g. gonads, physical form and sexual behavior) coexist in varying proportions in the same individual. These are:

1. Gonad agenesis: here testes and ovaries have never developed (nuclear sexing is negative).

2. Gonad dysgenesis: The testes or ovaries are present but at puberty they fail to develop e.g.: in Klinefilter syndrome where sex chromosome pattern is XXY (47 chromosomes) and in Turner syndrome where chromosomal pattern is XO (45 chromosomes).

3. Hermaphrodite: which is either:

   1. True hermaphrodite: the same individual possesses both non functional testicles and ovaries.

   2. False (pseudo) hermaphrodite: There is lack of clear cut differentiation of the external genitalia while the internal genitalia are isosexual. It is either:

* Male (masculine or testicular) hermaphrodite:

• The person has testicles that are present in abdominal cavity.

• The general features are mixed of both feminine and masculine characters.

• The external genital organs resemble those of the female but not well developed e.g. cul-de sac vagina without uterus.

*Female (feminine or ovarian) hermaphrodite:

• The gonad is the ovary.

• The external configuration and external genital organs resemble those of a male.

In examination for sex (in dead and living), the following steps are followed:

Clinical examination:

• Clothes cannot be relied upon as any person can wear any type of clothes of the other sex. This entails:

1. Presumptive data.

- General features where males are usually more heavily built and larger body dimensions than females.

- Deposition of fat especially in gluteal area is more in females than males.

- Hair distribution where in males there is beard & moustache. Pubic hair in male extends up to the umbilicus while in female it is straight.

- Males have prominent large larynx than females, also, their voice is harsher than females.

2. Highly presumptive data:

• Presence of vagina, uterus, prostate, seminal vesicles and penis. This is due to the presence of certain operations to change sex with reconstruction; here sex chromatin test defines the origin of the person

3. Certain data:

• Presence of the ovaries in females and testicles in males.

N.B: In mutilated bodies, non pregnant uterus and prostate resist putrefaction longer than abdominal organs

Sex chromatin test

• In females, any nucleated cells as the epithelial cells of buccal mucous membrane and hair root cells and tooth pulp show one or more tiny nodes of chromatin attached to the inner surface of the nuclear membrane (Barr bodies). In polymorphs, there is Davidson's body as a bud of chromatin on nucleus, it takes drum stick appearance.
• In males, chromosomal examination for Y chromosome by quinacrine dye.

Sex chromatin test is a good helpful aid in the identification of sex in forensic medicine which assists in resolving many medico-legal problems either in living or dead persons.

1. Determination of the actual sex in cases of change of sex from male to female or the reverse, or in cases of intersexuality such as hermaphrodites,

2. Determination of sex from human specimens found at the scene of a crime or on a weapon.

3. In case of confusion about appropriate sex assignment to babies with ambiguous external genitalia and as a result, poor assignment of sex may lead to medico-legal problems.

4. Identification of parts of dead bodies. It was shown that sex chromatin bodies remain visible for sometime after death, but the length of time is variable depending on the type of tissue and organs examined and on the environmental conditions under which the tissues were left.

Gonadal biopsy: This is conclusive

DNA examination and X-ray to certain bones:

Identification of sex in advanced decomposed or mutilated bodies is detected by

• using the polymerase chain reaction (PCR) of the sex chromosome specific locus , X-Y homologous gene Amelogenin

• examination of the bones (skull, sternum and pelvis).
  

Definition:

• It is an event in which ten or more persons are injured or killed.

Examples:

• Floods
  
• Earthquakes
  
• Transportation fatalities.

Aims of mass disaster investigations:

1. Examination of the bodies of the victims is necessary for 3 main reasons:

• To identify each body.

• To establish the causes of death for legal purposes so that a death certificate can be issued.

• To discover evidence relating to the disaster itself.

• The cooperation of pathologists and police can be considered in 3 phases:

• The first phase: At the accident site.

• The second phase: At the mortuary.

• The third phase: Comparison of previous records with the available results of investigations.
  

The first phase: At the accident site:

There are many procedures that should be carried out at the site of the accident including:

1. Location of the bodies to help in identification e.g. in a room of a hotel etc.

2. Labeling the bodies with numbers.

3. Photographing them in situ.

4. Preparing a plan of the disaster site.

Then bodies are placed in containers to be transferred to the mortuary. Clothing's and associated properties or even parts of the bodies that have become detached in the process of handling must be placed in the same container.

The second phase: In the Mortuary:

Bodies should not be dispersed to numerous small mortuaries as this will make the task of coordination of the investigations very much difficult:

1. Visual identification of the bodies by police or relatives if the bodies intact with minimal external injuries.
2. Then the body which is selected for examination is brought to the autopsy table.

The following steps should be carried out:

• Photograph the body before autopsy.
• Look at the general appearance as regards heights, weight, approximate age, color of skin, hair and eyes, physical deformities birthmarks, old scars, ect.
• Examine clothes for laundry or other marks or tickets.
• Finger prints are examined and compared with known ones for individual ridge characteristics as bifurcation, trifurcation, dots, island, bridge & angle.
• Dental examination is helpful if finger prints, physical characters and clothes are damaged.
• Examination of any fragments of bodies and matching these fragments with the bodies from which they originated thus:

• Muscle attachments should be similar and symmetric as regards size and location.
• Articular surfaces should match in size and general contour.
• Viewing the skeletal remains under ultra violet light as bones of different skeleton reflect U.V. light in distinctive patterns that help to segregate the bones.
• Microscopic examination of cross sections of long bones as regards variation in resorption and number of arrest lines.
• Examination of blood for ABH grouping and other genetic markers to help in matching the separate remains with their corresponding bodies.
  

The third phase:

• Investigations are completed by comparing the results of examination with previous records. Interpol recently produced a disaster victim identification form, which is very useful when there is relatively small number of victims.

1. Typing of blood group systems: They are red cell surface antigens that are permanent throughout life except some temporary changes after blood transfusion, so don’t do blood grouping except after at least 3 months post-transfusion.

They include:

1. ABH system:
1. There are 3 antigens (A,B,H) giving 4 phenotypes (A, B, AB, O) and 6 genotypes (AA, AO, BB, BO, AB, OO) as every individual has two genes on each chromosome. ABO system locus is located on chromosome 9.
2. Other blood group systems:

• RH system: It is present in 85-90% of persons hence they are expressed as Rh +ve, the remaining are Rh -ve. Their specific locus is located on chromosome 1. There are 6 antigens (C,c, D,d, E,e). RH+ve type should have at least one of (C or D or E). The most important is D antigen. RH-ve type don’t have these antigens.

• MN system: These are 3 groups M, N and MN and are present at birth. They are inherited as a Mandelian dominant so M or N does not appear in blood of child unless present in one parent at least. There are 2 antigens (M&N) giving 3 phenotypes (M, N, MN), 3 genotypes (MM, NN, MN). Ss and MN are closely linked but separate gene loci on chromosome 4. Several instances of recombination between the loci have been observed. They are 4 antigens (M, N, S, s) giving 9 phenotypes (MS, MSs, Ms, NS, NSs, Ns, MNS, MNSs, MNs).

• Kell (K) system. There are 2 antigens (K, k) giving 3 genotypes (KK, Kk, kk).
• Duffy system: Two antigens (Fya, Fyb) giving 3 genotypes (Fya+b+, Fya+b- & Fya-b+). Fya-b- type is found in black people (lacking both antigens)
• Kidd system: There are 2 antigens (JKa, JKb) giving 3 genotypes (JKa+b+, JKa+b-, JKa-b+).

2. Typing of red cell isoenzymes:

They are a group of enzymes present inside RBCs which catalyze various vital biochemical reactions. They show polymorphism i.e. they are present in different forms in different people hence the term isoenzymes. e.g:

• Phosphoglucomutase (PGM): It is located on chromosome 1. Two antigens (PGM1, PGM2) giving 3 genotypes (PGM1, PGM2 & PGM2-1).

• Adenylate kinase (AK): has 3 genotypes (AK1, AK2 & AK2-1).

• Acid phosphatase (AP).
• Estrase D
• Glutamate pyruvate transaminase (GPT).
• 6 phosphogluconate dehydrogenase (6 PGD).
• Carbonic anhydrase (CA).

3. Typing of serum protein systems e.g.:

• Haptaglobins: Two antigens (HP1, HP2) giving 3 genotypes (HP1-1, HP 2-2 & HP 2-1).

• Group specific components (GC): Two antigens (GC1, GC2) giving 3 genotypes (GC1, GC2 & GC1-2).

• Transferrin (Tf)

• Protease inhibitor (PI).

• Immunoglobulin markers (Gm, Km).

• The third component (C3)
  

• Protease inhibitors as > antitrypsin

4. Typing of hemoglobin:

• Fetal hemoglobin (HbF) present in the fetus and very young infants.

• Sickle cell hemoglobin (HbS) which is responsible for sickle cell anemia, it is almost exclusively present in blacks and Hispanic people.

• HbC: normally present in black people, less frequently in Hispanic people, never in other ethnic groups.
  

• Hb D, E, A (adult Hb).

5. HLA typing (Human leucocyte antigens or complex)

• This system consists of protein substances (about 50 antigens) on the surface of all cells including leucocytes on which they were first discovered.
• HLA- A, B, C, D, DR and DQ constitute the major human leucocyte antigens i.e. major histocompatibility complex (MHC) which is related to immunity. It has been assigned to the short arm of chromosome 6.

(good +ve test).

- DNA is the basic genetic material contained in all living cells (human, animal, plants, fungi, bacteria and viruses). It is a structure that guides the cell in its production of proteins.

It is the material of which the chromosomes are made. It is double helix twisted strings tightly wrapped into chromosomes.

Structure of DNA:

DNA is formed of sugar-phosphate backbone consists of units named as nucleosides, to each one a nitrogenous base is attached forming nucleotides. There are four nitrogenous bases of the DNA that are arranged in pairs [Adenine (A) pairs with thymine (T), while cytosine (C) pairs with guanine (G)] in a particular order (the DNA sequence), encoding all genetic instructions for an organism. The two DNA strands are held together by hydrogen bonds between the bases.

• Human DNA is formed of about 3 billion of base pairs arranged in triple (codons), each code for certain amino acid.

• A strand of DNA contains genes, areas that regulate genes, and areas that either have no function, or a function yet unknown

• The genetic code that determines the individual characteristics depends on the sequence of bases on DNA molecule that is extremely different in every individual except in identical twins.

DNA Under an electron microscope