UPA II GOVERNMENT UNDER LEADERSHIP OF MR.GULAM NABI AZAD ,A VETERAN POLITICIAN AND CLOSE TO MRS.SONIA GANDHI IS CONTINUOSLY STRIKING NAILS AND NAILS IN THE COFFIN OF MEDICAL PROFESSION ,FIRST ROBBING THE AUTONOMY OF "MEDICAL COUNCIL OF INDIA" BY BRINGING AN ORDINANCE THROUGH THE OFFICE OF PRESIDENT THROGH MEETING IN COUNCIL OF MINISTERS AFTER ARREST OF MR.KETAN DESIA ,PRESIDENT OF MCI THROUGH CBI N THE CHARGE OF ACCEPTING BRIBARY FOR ISSUING NO OBJECTION CERTIFICATES TO FEW PRIVATE MEDICAL COLLEGE IN PUNJAB.
GOVERNMENT IS NOW SAYING THAT DR.KOHLI,PRESIDENT OF "DENTAL COUNCIL OF INDIA" AND MR.R.DILIP BABU.PRESIDENT OF "NUSING COUNCIL OF INDIA" ARE TOO ENGAGED IN MALPRACTICE AND HAVE EARNED HUGH MONEY,CBI IS SEEKING PERMISSION TO IVESTIGATE THESE FOLLOWS AND CENTRAL HEALTH MINISTER WILL BRING AN ORDINANCE EITHER IN THIS PARLIAMENT SESSION OF OTHERWISE THROUGH COUNCILOF MINISTER'S MEETING ORDINANCE THRROUGH PRESIDENT'S OFFICE TO SCRAPE AUTONOMY OF THESE TWO COUNCILS AS DONE TO MCI.
AS INDIAN CITIZEN,NO BODY IS INTERESTED TO PROTECT THE CULPRIT IF PRESIDENT OR VICE PRESIDENT OR FEW MEMBERS OF THESE COUNCILS HAVE DONE ANY CORRUPTION THEN THEY MUST BE PUNISHED BUT LIKE 'SEBI,COMMON WEALTH GAME OR BCCI OR IPL OR OYMPIC OR FOOTBALL ASSOCIATIONS,CULPRIT CORRUPT OFFICIALS SHOULD BE REMOVED NOT THE WHOLE AUTONOMOUS BODY IF SUCH ACTION IS BEING DONE THEN OUR PARLIAMENT SHOULD DISSOLVE ALL THESE AUTONOMOUS BODIES AND PARLIAMENTARY COMMITTIES ON DIFFEREN MATTERS AND MINSTERS AND BUREAUCRATS OF THESE MINISTRY SHOULD BE MADE INCHARGE OF EVERY SUCH BODY BUT WE KNOW THAT IN THIS CASE CORRUPTION WILL REACH TO PEAK AND EVERYTHING WILL BE A POLITICAL PARTY GAME AND MANY SCAMS WILL EMERGE AND HARDLY ANY POLITICIAL WILL BE PUNISHED AS COMMON PRACTISE IN OUR COUNTRY. THE REASON SUCH BODIES ARE UNDER CHARGE OF CORRUPTION BECAUSE THEY HAVE FEW PRESIDENT AND MEMBERS WHO ARE THERE FOR MANY YEARS BY BLESSING OF POLITICAL BOSSES ,MANY POLITICIANS WHO NEVER PLAY ARE HEAD OF SPORTS AUTHORITIES ,FEW DOCTORS ARE RUNNING THESE MEDICAL COUNCIL FOR YEARS,IT IS NEEDED THAT OUR PARLIAMENT SHOULD MAKE RULE THAT NO PRESIDENT OR MEMBER SHOULD BE IN THESE COUNCIL FOR MORE THAN 03 YRS EITHER REPRESENTATIVE OF CENTRAL GOVERNMENT OR STATE COUNCIL OR REPRESENTATIVE OF UNIVERSITY OR ELECTED FROM ANY OTHER ASSOCIATIONS,PRESENCE OF FEW SUCH CORRUPT PERSONS CANNOT BLAME THESE IMPORTANT AUTONOMOUS BODIES NEEDED VERY MUCH FOR SMOOTH RUNNING OF OUR MEDICAL AND HEALTH EDUCATION.FEW UNTRAINED IAS OFFICERS AND SENI OR OTHERWISE EDUCATED POLITICIANS CANOT JUSTICE WITH THESE AUTONOMOUS BODIES,MERE SELECTION OF FEW EXPERTS BY THESE PERSONS WILL BRING THEIR WELL WISHERS AND CATORIE PEOPLE AND DEMOCRACY WILL BE STRANGULATED IN THESE ORGANISATION AS IF WE READ BELOW PARAGRAPHS WE SHALL KNOW HOW WISELY THE CONSTITUTION OF THESE ORGANISATION HAS BEEN WRITTEN .
MEDICAL COUNCIL OF INDIA,DENTAL COUNCIL OF INDIA AND NURSING COUNCIL OF INDIA ARE STATUTORY BODIES TO REGULATE MEDICAL,DENTAL AND NURSING EDUCATION AND SERVICE IN THE COUNTRY.MEDICAL COUNCIL OF INDIA WAS ESTABLISHED IN YEAR 1934 UNDER MEDICAL COUNCIL OF INDIA ACT 1933,IT WAS AMENDED POST INDEPENDENCE IN 1956.IT WAS FURTHER AMENDED IN YEAR 1958,1964,1993,2001 AND 2004.iN YEAR 2009 'MCI' CELEBRATED ITS PLATINUM JUBLEE IN YEAR 2009.IN YEAR 2002 HON'BLE SUPREME COURT CONSTITUTED A BODY OF THREE EMINENT DOCTORS DR.TANDON, DR.MRS.KANTHA AND DR.RANGABHASYA TTO MONITOR FUNCTIONING OF MCI AND THEY SUGGESTED THAT MCI SHOULD BE EMPOWERED MORE AND MORE BUT STILL GOVERNMENT REJECTS MANY ITS PROPOSAL TO START NEW MEDICAL COLLEGES BECCAUSE AS PER 1956 ACT,GOVERNMENT ONLY CONSTITUTES AND REGULATE MCI BY MAKING RULES .GOVERNMENT NOMINATES ITS 37 MEMBERS DIRECTLY CAN CONSTITUTE ANY ENQUIRY IF MCI IS NOT WORKING PROPERLY,CENTRAL GOVERNMENT REGULATE POST GRADUATION COURSE DIRECTLY AND MCI CANNOT START ANY MEDICAL COLLEGE WITHOUT PERMISSION FROM GOVERNMENT.MCI FINANCE IS AUDITED BY CONTROLLER AND AUDITOR GENERAL OF INDIA AND WHOLE MCI IS UNDER SCAN OF PARLIAMENTARY COMMITTEE OF HEALTH AND FAMILY WELFARE.
ITH HAS GOT MEMBERS FROM MEDICAL PRACTITIONERS FROM ALL OVER INDIA REGISTERED IN STATE MEDICAL COUNCIL ,BESIDES MEMBERS FROM STATES AND UNIVERSITIES.PRESIDENT AND VICE PRESIDENTS ARE ELCTED,BUT IT HAS A SEPARATE JURISTIC PERSONALITY ,IT IS NOT A MERE MOUTH PIECE OF GOVERNMENT,GOVERNMENT CANOT INTERFEE DIRECTLY INITS AFFAIS,REMOVE OFFICE BEARERS AND GUIDE AND SUGGEST THEM UNDER PRESSURE ,THIS THE REAL PROBLEM OF MCI AND GOVERNMENT ,NO DOUBT ITS OFFICE BEARERS HAVE DONE SOME MISTAKES BY ON THIS BOARD FOR YEARS AND MANIPULATION GOVERNMENT THROGH BACKDOOR INFLUENCING AND EARNING HUGH MAKING SUCH BODIES AS THEIR CORPORATE HOUSES BUT HERE IS A FAULT OF BBOTH MCI AND GOVERNMENT WHY GOVERNMENT FOLLOWED THERIR RECOMMENDATION AND ALLOWED THEM AT THESE PLACES FOR YEARS.THIS ORDINANCE 2010 IS FOR ONE YEAR AND HAVE STARTED A FIVE MEMBER BOARD OF GOVERNORS TILL NEW COUNCIL IS ELECTED.THIS ORDINANCE ITSELF IS CONTOVERSIAL FOR A STATUTORY BODY LIKE MCI AS ITS PARENT LAW DOESNOT PERMIT FOR SUCH DISSOLUTION ,GOVERNMENT OF INDIA HAS INTRODUCED A BILL IN PARLIAMENT ON 3RD MAY2010 "NATIONAL ACCREDITATION ANDREGULATORY FOR HIGHER EDUCATION INSTITUTIONAL BILL 2010"UNDER WHICH IN MANY UNLAWFUL CONDITION GOVERNMENT CAN DISSOLVE ANY STATUTORY EDUCATION BODY AFETER GIVING ENOUGH TIME TO REPRESENT.PREVIOUSLY FORMER HEALTH MINISTER DR.A RAMDOSS ALSO WANTED TO DISSOLVE MCI THROUGH AN ORDINANCE BUT PMO SEND IT TO PARLIAMENTARY COMMITTEE WHO REJECTED IT.
GOVERNMENT 'S HRD MINISTRY HAS BROUGHT A BILL NAMED AS "NATIONAL COMMISSION FOR HIGHER EDUCATION(NCHER) AND WANT MEDICAL EDUCATION LIKE ALL EDUCATION UNDER IT BUT HEALTH MINISTRY HAS ADVOCATED 'NATIONAL COUNCIL FOR HUMAN RESOUCE AND HEALTH(NCHRH) TO RETAIN MEDICAL EDUCATION UNDER THIS MINISTRY ,THERFORE WE CAN ASSUME HOW TWO DEPARTMENTS/MINISTERS ARE FIGHTING TO KEEP THIS GOLD MINE UNDER ITS REGULATION AND HERE INTEREST OF MEDICAL EDUCATION,SERVICE AND STATUS WILL BE COMPROMISED AND POLITICIANS AND BUREACRATS WILL EARN IN CRORES DISSOLVING THESE COUNCILS .AS PAST PRESIDENT OF THESE BODIES MIGHT EARNED HUGH EDUCATION IS ON SALE FOR STARTING NEW MEDICAL COLLEGE AND DENTAL COLLEGES AND NURSING COLLEGES WHERE A STUDENT HAVE TO PAY LAKHS IN WHITE AND LAKHS IN BLACK TO GET ADMISSION UNDER DIFFERENT QUOTAS IN GRADUATE COURESE AND CRORES FOR POST GADUATION IF SUCH HIGH FEES ARE BLOCKED BY GOVERNMENT CORRUPTION WILL GO AWAY FRO MEDICAL COLLG OR DENTAL COLLEGE OR NURSING COLLEGE.EVEN VERY WEAK STUDENTS ARE ADMITTED EITHER AS SPECIAL OR NRI QUOTA AND THESE WEAK REMAIN WEAK FOR YEARS AS THEY ALSO GET THROUGH BY BRIBERY IN THESE PRIVATE MEDICAL COLLEGE,GOVERNMENT SHOULD STOP ALL THESE THINGS AND STOPS COPMLETE CAPITATION AND BACK DOOR ENTRY FEE BUT THESE WILL NOT BE STOPPED BY GOVERNMENT BECAUSE OTHERWISE HOW THESE POLITICIANS AND BUREAUCRATS WILL EARN CRORES OF RUPEES.
THERFORE IT IS NEEDED THAT THESE COUNCILS ARE NOT DISSOLVED BUT SHOULD BE MADE MORE ACCOUNTABLE,TRANSPARENT AND FUNCTIONAL TO RAISE MEDICAL EDUCATION AND PRODUCE ENOUGH DOCTORS,DENTIST AND NURSES TO IMPROVE OUR HEALTH EDUCATION AND SERVICE TO OUR FELLOW CITIZENS AND TO CREATE MOR CHECK AND BALANCES SOTHAT NO BODY CAN BE HERE FOR YEARS AND USE IT AS ONE'S BUSINESS HOUSE OR CORPORATE BODY.
DR.D.R.NAKIPURIA
AMBIKA CHIKITSHALYA
29 AGRASEN ROAD
SILIGURI-734005,09434143550

Revised lecture at the meeting of the Nobel Laureates on June 30, 1966 at Lindau, Lake Constance, Germany

by Otto Warburg Director, Max Planck-Institute for Cell Physiology, Berlin- Dahlem

Dr. Otto Warburg, twice Nobel Laureate, awarded the Nobel Prize for Physiology or Medicine in 1931 for his research on cellular respiration, explains:

“The growth of cancer cells is initiated by a relative lack of oxygen. Cancer cannot live in an oxygen-rich environment…Cancer has only one prime cause. It is the replacement of normal oxygen respiration of the body’s cells by an anaerobic (i.e., oxygen deficient) cell respiration.”

Going into greater detail in The Prime Cause and Prevention of Cancer, he writes: “…the cause of cancer is no longer a mystery, we know it occurs whenever any cell is denied 60% of its oxygen requirements.

Cancer, above all other diseases, has countless secondary causes. But, even for cancer, there is only one prime cause. Summarized in a few words, the prime cause of cancer is the replacement of the respiration of oxygen in normal body cells by a fermentation of sugar. All normal body cells meet their energy needs by respiration of oxygen, whereas cancer cells meet their energy needs in great part by fermentation.

All normal body cells are thus obligate aerobes, whereas all cancer cells are partial anaerobes.” Compare Otto Warburg On The Prime Cause & Prevention of Cancer: Respiration of Oxygen in Normal Body Cells vs. Fermentation of Sugar in Cancer Cells.

Please download here the full Cancer Protocol of Otto Warburg (56 page pdf):
http://new-planet.net/pdf/O-Warburg-CancerProtocol.pdf

INTRODUCTION:
Opportunistic infections (OI) are the hall mark of immunodeficiency associated with HIV. They include opportunistic protozoan, fungal , bacterial , viral and other infections along with repeated episode of HIV infection. It is important to diagnose OIs, because acute infections are at times life threatening, effective prophylaxis result in better survival. The clinical manifestations are different than normal host. Various studies established the relationship between rising viral load and decreasing CD4+ count and progression of HIV. Timely chemoprophylaxis reduce the risk of OIs and effective ART therapy (anti retroviral) decreases viral load, restore immune function, reduce risk of OIs.

Certain patients in the developed and developing world do not have access to care or response to ART due to multiple reasons leading OIS as important cause of morbidity and mortality in HIV-1 infections. The therapy for OIs has changed substantially leading to new strategies for management.

CLASSIFICATION
AIDS (CDC classification category C diseases) is defined by the development of specified opportunistic infections or tumours. There is a correlation between CD4 count and HIV related infections.
TABLE – 1(CD4 COUNT AND ASSOCIATED INFECTIONS)
> 500 cells/mm3 Acute primary infection, Recurrent vaginal candidiasis
<500 cells /mm3 Pulmonary Tuberculosis, Pneumococcal pneumonia, Herpes Zoster, Oropharyngeal candidiasis, Extraintestinal salmonellosis, Lymphoid interstitial pneumonitis
<200 cells/mm3 Penumocystis carinii (jirovecii)pneumonia, Mucocutaneous herpes simplex, Cryptosporidium, Microsporidium, Oesophageal candidiasis, Miliary/extrapulmonary tuberculosis
<100 cells/mm3 Cerebral toxoplasmosis, Cryptococcal meningitis
<50 cells/mm3 CMV retinitis, CMV gastrointestinal diseases, Disseminated mycobacterium avium intracellulare
The Ols can be descried as per the system involved.
1. Pulmonary diseases seen in HIV (OIs)
• Bacterial: Streptococcus penumoniae, H. influenzae, Pseudomonas aeruginosa, Klebsiella penumoniae, Rhodococcus equi, Mycobacterium tuberculisis, Atypical mycobacteria
• Fungal: Penumocystis carinii (Jirovecii), Cryptococcus neoformans, H. Capsulatum, Coccidiodes emitis, Penicillium marneffi, Aspergillosis
• Viral - CMV, EBV, HSV, VZV
• Protozoal – Toxoplasma gondii, Strongyloides stercoralis
2. CNS
• C. Neoformans
• Toxoplasma Gondii
• JC Virus causing PML
• Others : Syphillis, M. tuberculosis, T. cruzi, HTLV – I infection, Acanthamoeba
3. G.I.T
• Fungus – Candidiasis, Histoplasma, Coccidioidomycosis, Penicillisis
• Bacterial – Salmonellosis, Shigella, Campyolobacter jejuni
• Virus EBV – (Oral Hairy leucoplakia)
CMV Colitis, Rotavirus, Adenovirus , HSV
• Protozoal infection : Cryptosporidiasis, Cyclospora, Micosporidiasis, E. histolytica, Isosporiasis, G. lamblia, C. difficile
4. Hepatobiliary – HBV and HCV infection
Fungus – C.immitis, Histoplasma
5. Genitourinary – Syphilis, candidiasis
6. Dermatological Condition
• Seborrheric dermatitis, Herpes simplex / Varicella zoster virus (VZV), Bacillary angiomatosis, Molluscum Contagiosum, Anogenital HPV (Human papilloma virus), Scabies, Syphilis, Fungal folliculitis rash (Fungal – Malassezia furfur), Dermatoplytic infections involving skin, nail
7. Cardiovascular
Cardiomyopathy – Cryptococcosus, Chagas disease, Toxoplasmosis
Pericardial Effusion - Tubercular
8. Rheumatological
Septic arthritis may be due to fungus C. neoformans, H. capsulatum, Sprorothrix schenckii, Systemic mycobacteria – M. haemophillum
9. Endocrine System
Adrenal gland involved in CMV, mycobacterial, cryptococcal, histoplasmosis
Thyroid – involved in P. carinii, CMV, toxoplasma, mycobacterial, cryptococcal
10. Haemopoetic System
Bone marrow suppressed by – Fungal, Mycobacterial and B19 parvovirus
11. Ophthalmic Disease
CMV Retinitis
HSV & VZV
P. Cariniii – Choroiditis
Toxoplasma - Chorioretinitis

Few common Ols are described in the paragraph following.


P.C.P. (Pneumocystis carnii pneumonia):
Very common infection and called as “ AIDS pneumonia”, occurring in 57% of children below 1 year and leading cause of interstitial plasma cell penumonia. It is a protozoan but closely related to fungi. The reservoir and mechanism of transmission is obscure but transmittd by direct air borne. The organism establishes in alveoli where it proliferates as an exracellular parasite producing interstitial oedema, hyaline membranes resulting in progressive hypoxemia and respiratory failure. The symptom tetrads are fever, cough, dyspnoea and tachypnea. Physical examination shows tachycardia, respiratory distress with accelerating tachypnoea and diffuse retraction without any specific auscultatory findings. Extrapulmonary penumocystitis involves L. node, spleen, liver, Thyroid, adrenal gland, kidney. Ophthalmic lesion of choroids, necrotising vasculitis resembling Burger’s disease, bone marrow hypoplasia, intestinal obstruction, heart. Associated with cystic lesion or calcification on CT or Ultrasound. Otic involvement cause polypoid in auditory canal.

Arterial blood gas analysis (ABG) shows progressive hypoxemia, respiratory failure. Chest X-ray shows signs of hyperinflation with peribronchial thickening , bilateral alveolar, interstitial in filtration, which spread outwards from hila. Further progression leads to bilateral airspace disease with air bronchogram, cavities, pleural effusion and spontaneous penumothorax, the last being characteristic.

The diagnosis is confirmed by Wright – Giemsa staining of induced sputum or Broncho-Alveolar Lavage (BAL). Trophozoites and intracystic trophozoites are seen. Prognosis is related to hypoxaemia (Alveolar – arterial O2 gradient - < 35 mm of Hg – Mild, 35-45 mm of Hg moderate and > 45 mm of Hg severe).

Treatment: The treatment is a medical emergency. The treatment of choice is Trimethoprim sulphamethoxazole (TMP-SMX) or Pentamidine. The other alterantive drugs used in adults are Dapsone – TMP, Clindamycin, Primaquine, Atovaquine.
TABLE – 2
Drug Schedule Remark
TMP-SMX 20mg of TMP/Kg/Day in 4 divided doses I/V for 21 days Restore to oral when patient responds
Pentamidine 4mg/Kg/Day,
Single Dose, I/V for 21 Days Reserved who cant tolerate TMP- SMX or no response after 7 days of therapy.
Dapsone – TMP
Clindamycin
Primaquine
Atovaquine
Mortality – 5-40% in treated and 100% in untreated cases.

PREVENTION:
Indication: All HIV infected children from 4 weeks to 12 months of life, in determinate status children from 4 weeks till HIV is excluded (4 months), HIV infected children above 1 year having CD4 count of < 500 (1- 5years) and < 200 (6-12 years). All children who have been treated for PCP.
TABLE – 3
Drug Schedule Side Effect
TMP-SMX • 150 mg of TMP/M2/day. Orally in two divided doses on 3 consecutive days of a week.
• 150 mg of TMP/M2/ day orally divided into 2 doses on 3 alternating days. Aplastic anaemia megaloblastic anaemia, Steven – Johnson’s Syndrome, Neutropenia, Thrombocytopenia
Dapsone 2mg/Kg/Day orally
(Max – 100mg) Methemoglobinemia
Haemolytic anaemia
Pentamidine (inhaled) 300mg of Pentamidine isoethionate inhaler every 28 days Cough, bronchospasm , increased risk of extra pulmonary PCP
Pentamidine (I/V) 4 mg/Kg /Day single dose I/V every 2-4 weeks Hypoglycemia, Hyperglycemia, Hypertension, Hypocalcaemia, rash

Rhodococcus Equi – Gram +ve pleomorphic acid – fast nonspore forming bacillus causing pulmonary or /and disseminated infection. Presents as fever cough. Chest X-ray show cavity or consolidation. Blood culture may be +ve treated with proper antibiotic.

TUBERCULOSIS:
In high prevalent areas primary and reactivation of tuberculosis is common due to depressed cell mediated immunity. Drug resistance is also common. The extensive tuberculosis is due to progressive depletion and dysfunction of CD4 cells with macrophage and monocyte dysfunction.

Clinically present as fever, cough, weight loss, night sweat, malaise. Extrapulmonary manifestation like CNS (meningitis), lymphadenopathy, hepatosplenomegaly, genitourinary, mastoid involvement occur. The disease may be extensive (miliary).

Diagnostic difficulty is due to unusual features (Tuberculin – ve) and extrapulmonary manifestation. History of contact, tuberculin test (induration > 5 mm), chest X-ray showing lobar or multilobar infiltration or diffuse interstitial lesion and hilar adenopathy are clue. Isolation of AFB from gastric lavage, BAL, sputum is gold standard test. The samples collected from pulmonary and extrapulmonary tissue subjected to culture and sensitivity to drugs as drug resistance is very high. PCR test on sputum , pleural fluid, CSF is highly sensitive and specific.

Treatment:
1st Line Drugs:
INH – 10-20 mg/kg/day (max 300mg)
Rifampicin – 10-20 mg/kg/day (max 600mg) – (May lower the concentration of antiretroviral drugs as it induces the action of hepatic cytochrome 450).
Pyrizinamide - 30 mg/kg/day
Ethambutol - 15 mg/kg/day
Streptomycin – 20-30 mg/kg/day IM
Rifabutin – 300mg for 4 months
2nd Line Drugs:
Ofloxacin, Ethionamide, Cycloserine, Capreomycin, PAS

Duration of Treatment:
• For pulmonary TB – 6-12 Months
• For extrapulmonary TB – Minimum 12 Months
• DOT (Directly Observed Therapy) may be given during initial phase.
• Children of Mx positive without any other lesion – INH & Rifampicin for 12 months.
• In MDR TB – 6-7 drugs depending on sensitivity for 12-15 months.
To start ART the CD4 count is a guideline (WHO recommendation).
• CD4 count < 200/L – Start ATT first and ART is started as soon as patient tolerate ATT (Takes 2-4 weeks).
• CD4 count 200 to 350/L – Start ATT and add ART after intensive phase –(8weeks).
• CD4 count > 350/L – Treat TB completely and defer ART.

NON-TUBERCULOSIS MYCOBACTERIAL INFECTIONS
Mycobaacterium avium complex (MAC) includes M. kansasii, M. Chelonei and M. fortuitum which are saprophytes present in soil, water, food and infect when CD4 count is below 50 cells/ml. Lung, liver, spleen and lymphnodes, bone marrow and GIT are the common sites. Incidence is less in India. Transmitted by inhalation or ingestion. Lung is an unusual site of infection.

Slow progressive clinically present as high fever, weight loss, anemia, abdominal pain, night sweat, diarrhoea, malaise, hepatomegaly, osteomyelitis, meningoencephalitis, intraabdominal and soft tissue abscesses.

Peripheral smear shows anaemia, neutropenia, chest X-ray shows nonspecific finding like focal, diffuse infiltration, cavity, hilar adenopathy. Culture of blood or tissue by Radiometric assay show +ve in two weeks. PCR can identify the species. Biopsy from liver, L. node or marrow shows AFB bacillus within macrophages.

For treatment Azithromycin (10 mg /kg/day – single dose), Clarithromycin (15 mg /kg/day – 2 divided dosees), Ethambutol (15-20 mg /kg/day – single dose), Rifabutin (5-10 mg /kg/day – single dose) Ciprofloxacin (20-30 mg /kg/day Orally– single dose) Amikacin are given. The regimen includes 2-4 drugs i.e Azithromycin or Clarithromycin with Ethambutol and/or Rifabutin and Ciprofloxacin or Amikacin. Immunomodulators like GM-CSF, G-CSF, Interferon gamma, interleukin –2 are helpful.

For primary prophylaxis any drug is given for periods depending on CD4 count (< 50 – 6years, <75 2 –6 years, < 500 – 1-2 years, < 750 – 12 months). Secondary prophylaxis in patients suffering from MAC is life long including at least two drugs.

TOXOPLASMA GONDII INFECTION
In children manifest as congenital toxoplasmosis and CNS manifestation. Pregnant Mother transmit to fetus.

Congenital toxoplasmosis present as low birth weight, microcephaly, hydrocephalus, hepatosplenomegaly and chorioretinitis. CNS toxoplasmosis present as fever, headache, seizures, psychosis, altered sensorium and focal meurological deficit as hemiparesis, ataxia, cranial nerve palsy, aphasia, cerebral edema, confusion, dementia, coma.
Demonstration of specific IgM and IgA antibodies in serum is diagnostic of congenital toxoplasmosis. CNS toxoplasmosis is diagnosed on clinical ground, presence of IgG antibodies and multiple ring enhancing granulomatous lesion on CT scan or MRI. Brain biopsy is definitive diagnosis.

TREATMENT
Sulphadiazine – Loading 100mg/kg followed by 85-120mg /kg/day in 2-4 divided doses. Pyrimethamine – 1-2 mg /kg/day for 2 days followed by 1 mg/kg/day for 2-6 months and 1 mg /kg/day up to 1 year. Folinic acid (calcium leukovorin) 5-10 mg /kg/day or alt days to prevent megaloblastic anaemia secondary to pyrimethamine. Prednisolone 1 mg/kg/daily orally in active chorioretinitis or CSF protein is > 1gm%. Clinadmycin (20 mg/kg/day in 4 divided doses), pyrimethamine, folinic acid is alternate regimen.
CNS Toxoplasmosis: - The drugs used are pyrimethamine and sulfadiazine or Trisulfapyrimidine. Folinic acid is given to prevent bone marrow suppression. Relapse is common which requires reinstitution of therapy.
An episode of CNS toxoplasmosis requires life long prophylaxis.

VIRAL INFECTIONS
The common viruses are Herpes Simplex Virus (HSV 1 & 2), Cytomegalo Virus (CMV), Varicella Zoster Virus (VZV), Epstein Barr Virus (EBV) and Human Herpes Virus type – 8 (HHV-8). The infections are often chronic, invasive and fatal with HIV infection.
1. HSV 1 & 2: HSV-1 is transmitted through contact with oral mucosa and salivary secretions. HSV2 transmitted sexually and present as anogenital lesion. When CD4 count is > 100/mm3 both present as recurrent self-limited cluster of orolabial ulcers, genital, anorectal ulcers. In lower CD4 count the vesicular lesions are found at other sites. In severe cases there are large, painful ulcer which slowly resolve. Stomatitis follow oral lesions and fissures and fistula follow rectal and genital ulcers. Bacterial infection may supervene. Advanced AIDS cases with low CD4 count may produce systemic HSV-infection producing oesophageal ulcer (odynophagia, chest pain)pneumonia, hepatitis, meningoencephalitis, ventriculitis, shock, sepsis like syndrome and transverse myelitis.
Diagnosis is based on typical clinical lesion, rising antibody titre, isolation of virus from culture, detecting HSV1 & 2 antigen from skin or mucosa by scraping and immunofluorescent stain. In suspected HSV encephalitis HSV DNA in CSF using PCR is useful.
Acyclovir is drug of choice. In neonates and severe HSV infection given in a dose of 30 mg/kg/day in 3 divided doses for 2-3 weeks. Primary gingivostomatitis or genital HSV are treated with oral Acyclovir 80mg/kg/day in 3 divided doses for 10 days. Famcyclovir or Valacyclovir in a dose of 750- 1500 mg/day in 3 divided dose may be used. Foscarnet in a dose of 120mg/kg/day on 2-3 divided doses in Acyclovir resistant cases.
For prophylaxis in HIV patients with frequent or severe relapse or slow healing lesion Acyclovir 200mg tid or 400mg bid orally is given.
2. Vericella Zoster Virus (VZV):
In immunocompromised patients causes greater morbidity and mortality. Clinically presents as fever with generalized pruritic rashes (typical). They may be chronic, recurrent, persistent (appearance of new lesion for > 1 month), sever in advanced cases. In chronic infection the skin lesion become verrucous or necrotic. In severe infection presents as high fever, numerous skin lesion, systemic involvement like pneumonia, encephalitis, hepatitis.
Demonstration of VZV antigen in skin lesion, isolation of virus from vesicle contents, rise in antibody during convalescence and VZV specific IgM antibody confirm the diagnosis. PCR is also extremely sensitive and specific.
In severe cases Acyclovir in a dose of 1500mg /M2/day in 3 divided doses for 7-10 days or till no new lesions appear whichever is later is given. In mild cases Acyclovir is given orally 80mg/kg/day in 4 divided doses.
HIV infected children exposed to chickenpox are given varicella zoster immunoglobulin (VZIM) within 96 hours in a dose of 1 vial/10kg (maximum 5 vials). For recurrent case daily Acyclovir is given.
3. Herpes Zoster:
It is a dormant form of VZV producing painful vesicular lesion affecting dermatomes in immunocompetent persons.
Clinically presents as multidermatomal infection, dessiminated Zoster, bilateral rash, retinitis, rarely penumonitis, consumptive coagulopathy, hepatitis, marked constitutional symptoms and encephalitis. Chronic and relapsing cases and post herpetic neuralgia are common.
Classical dermatomal distribution of painful, vesicular eruption is diagnostic. Confirmed by virus isolation and detection of viral antigen in the skin.
Severe cases or neurologic complications like Ramsey Hunt, Zoster Ophthalmicus, disseminated zoster require Acyclovir 30mg/kg/day in 3 doses I/V. Oral Acyclovir 80mg/kg/day in 4 divided doses hastens healing. Famciclovir and Foscarnet are drugs used in resistant or recurrent cases.

4. Cytomegalo Virus (CMV)
It is very common OIs and carry poor prognosis. Horizontally transmitted through saliva, sexual fluid, urines and vertically by infected mother. More than 90% of HIV pregnant mother are CMV – infected.
Clinical manifestations:-
a. Retinitis: - Chorioretinitis develops in CMV seropositive cases when CD4 count is < 50 cells/l. Blurred vision, floaters and flashes are nonspecific symptoms, which starts with one eye progressing to other. It is painless. It leads to visual loss and retinal detachment. Yellowish white area of retinal necrosis with perivascular exudates and haemorrhage at periphery is characteristic.
b. GI Manifestation :- Oesophagitis produce substernal pain, dysphagia and anorexia, Colonic involvement cuase diarrhoea, abdominal pain, weight loss , anorexia, fever, CMV hepatitis and gastritis are uncommon. In 5-10% cases of AIDs cause colitis.
c. Penumonitis – Cough, dyspnoea, hypoxaemia
d. Encephalitis – Produce sub-acute dementia complex.
Diagnosis:- Retinitis is diagnosed by Fundoscopy. GIT infections on mucosal biopsy shows inflammation and CMV inclusion bodies. On endoscopy oesophagitis shows small and confluent ulcers. Sigmoidoscopy of colon shows diffuse erythmatic, submucosal haemorrhage and multiple mucosal ulcer. Chest X-ray of pnumonitis shows diffuse interstitial infiltration and finding of inclusion bodies in lung tissues or BAL is supportive.

Serological test for CMV are less helpful.
Treatment: Ganciclovir 10mg/kg/day in 2 divided doses I/V over 2 hours for 14-21 days followed by life long maintenance therapy.
Or
Foscarnet – 180mg/kg/day in 3 divided doses I/V over 1-2 hours for 14-21 days followed by life long maintenance therapy with 90-120mg/kg/IV in a single daily dose.
Prophylaxis :- Regualr retinal examination at 4 – 6 weeks interval. Life long prophylaxis with Ganciclovir 5mg/kg/day IV 5 days per week.

Other viral infections:
1. Human Herpes Virus – 8 (HHV – 8): This DNA virus causes Kaposi sarcoma in seropositive cases. Although Ganciclovir , Foscarnet, Cidofovir are active in vitro their use in limited.
2. Progressive multifocal leukoencephalopathy by JC Virus : This is caused by polyoma Virus JC virus. Insidious onset with progressive features like congnitive dysfunction, dementia, seizure, ataxia, aphasia, cranial nerve palsy, hemiparesis, quadriparesis, Coma. CT scan shows single or multiple hypodense, non-enhancing lesion in cerebral, white matter. Confirmed by biopsy. No effective treatment. Majority dies within 3-6 months of symptoms.
3. Human Papilloma Virus (HPV): - Infection in anogenital tract resulting in transient infection, genital wart, condyloma, squamous cell cancer. Dignosed clinically and biopsy. No effective treatment.
4. Hepatitis C Virus (HCV): - High rate of HCV coinfection in HIV- I persons through drug user injection, mother to child or sexual route. HIV – I infection increases the progress of HCV infection leading to end stage liver disease. Acute HCV infection is symptomatic or mild symptomatic. Chronic infection leads to hepatocellular failure. A progressive form called fibrosing cholestatic hepatitis found in HIV- I infection. Anti viral treatment is considered in chronic HCV infection. Avoid alcohol. Two doses of Hepatitis A vaccination is advised.
5. Hepatitis B Virus (HBV): About 90% of HIV – I patients are +ve for some markers of HBV. It is associated with increased risk of chronic HBV. Symptoms of acute infection are nausea, vomiting, jaundice, abdominal pain, Chronic infection presents as fatigue hepatocellular failure. Testing for HBs Ag, Anti HBc, Anti-HBs are used. Detection of HBs Ag  6 months is chronic and should be tested for HbeAg and Antigen HBe. They are increased risk of carcinoma.
Avoid alcohol – Two doses of Hepatitis A vaccination and 3 doses of Hepatitis B vaccination is given. Antiviral treatment is given.
6. Hepatitis A Virus (HAV) – All susceptible, chronic HCV cases. Two doses of Hepatitis A vaccination given. Not seen so frequently
7. Influenza virus : All patients annually – inactivated trivalent influenca virus vaccine – 1 dose yearly. Oseltamivir – 75 mg orally – 4 tims or Rimantidine /Amantidine – 100 mg orally – 4 times are used.
8. EBV – When CD4 is < 300L cause oral hairy leukoplakia along tongue border and adjacent mucosa. Not a premalignant condition. Treated with topical podophyllin or systemic antiherpes virus infection.
9. Coinfection with hepatitis D, E, and G are also common.

Cryptosporidiosis: Protozoa parasite . Infects small and large gut and extra intestinal. In this group C.hominis (previously C. parvum) C. canis, C. felis, C. muris. C. meleagridis . Biliary tract involvement like papillary stenosis, sclerosing cholangitis are seen.
Microsporidiosis: Protists related to fungus, contains several groups of organism. Water borne in origin. Commonly manifest as diarrhoea. Rarely encephalitis, sinusitis, ocular manifestation, myositis and disseminated infection occur.
Bartonellosis: Bacterial infection causing Bacillary angiomatosis of skin. Organisms are B. henselae, B. quintana and others. Common among poor sanitation. Common when CD4 count is < 50 cells and chronic infection involving every organ but typical skin lesion which is papular, red, smooth surface, vascular and bleed on trauma. Diagnosed by biopsy. Serological test may be +ve before clinical disease. Treated with Erythromycin /Doxycycline/ Clarithromycin/Azithromycin for at least 3 months.
Syphilis: The impact of HIV – I infection on syphillis (Treponema pallidum) pathogenesis, severity , response to treatment and long term sequelae is not well documented. However the progress is hastened in immunocompromised state. A variety of rare presentation like lues maligna, an ulcer due to necrotising vasculitis. Most commonly presented as condylomata lata. VDRL is of ambiguous significance.
FUNGAL INFECTION:
A. Cryptococcal Infection: Cryptococcus neoformans – infects when CD4 count is <50. This unusual disease involves brain, meninges, skin, eye. Clinically may present as meningitis, meningoencephalitis. Pneumonia is seen in 50% of cases. Sepsis though rare is fatal. Post infective sequlae like hydrocephalus, seizure, ataxia, cranial nerve involvement is common. Uncommon presentation may be in skin (Molluscum contagiosum), L. node enlargement, palatal, glossal ulcer, myocarditis, prostitis, gastroenteritis.
In CSF fungus is detected by India ink stain, cryptococcal antigen (95-100% specificity and sensitivity), positive culture. A positive latex agglutination test from seum also used in pulmonary cases. CT Scan of brain may show granuloma (cryptococcomas). Chest X-ray may show poorly localized bronchopneumonia, nodular or lobar involvement, pleural effusion , hilar, mediastinal adenopathy.
Amphotericin B ( 0.5 – 1 mg/kg/day IV , once daily) with or without Flucytosine (50-150 mg/kg/day orally in 4 divided doses) for 14 days until clinical improvement is initial treatment. Fluconazole (6-12 mg/kg/day, orally) or Itraconazole (2-5 mg/kg/day, orally) up to 8-10 weeks is follow up therapy. Life long secondary prophylaxis with Fluconazole or Itraconazole or Amphotericin B is required.
B. Histoplasmosis: Dimorphic fungus Histoplasma capsulatum. By inhalation or reactivation of latent infection. Manifest as disseminated multiorgan disease – fever, fatigue, weight loss, respiratory symptoms. CNS, GIT, Skin Manifestation seen in < 10% of cases. Diagnosed by presence of antigen in serum or urine, fungal stain of blood or tissues. Chest X-ray in 50% show diffuse interstitial infiltration or diffuse nodularity. Bone marrow involvement is common causing anaemia, neutropenia, thrombocytopenia. Treated by Amphotericin-B 1mg/kg/daily followed by Iatraconazole.

C. Coccidioidomycosis: By C. immitis causing disseminated diseases or meningitis. Dissemianted present as generalized lymphadenopathy, skin nodule or ulcer, peritonitis, liver, bone and joint involvement. Local meningitis is 10% of cases. Diagnosed by culture or serology of serum or CSF. Pulmonary (nodules, cavity, pleural effusion, hilar adenopathy) and disseminated form is treated with Amphotericin B and meningitis is treated with Fluconazole.
D. Aspergillosis: By Aspegillus fumigatus causing two syndromes – Respiratory (pseudomembranous tracheitis, penumonitis), CNS infection (meningoencephalitis with vascular infarction). Diagnosed clinically and demonstration of organism. Treated with Amphotericin B or Variconazole.
E. Candida Infection: Oral candidiasis (thrush) and diaper skin are common. Thrush may be extensive. Painless, creamy white plaques over buccal , oropharyngeal, or tongue which can be easily scrapped off. Angular chelosis may be seen. Oesophageal candidiasis may present as substernal or abdominal pain, dysphagia, weight loss. Disseminated infection present as sepsis or shock. Vulvovaginal candidiasis present as creamy to white yellow vaginal discharge with mucosal burning or itching, dysuria, dysparenia. Vaginitis may be due to trichomonas or bacterias also.
Oral candidiasis are typical and confirmed by presence of pesudohyphae on KOH stained specimen. Oesophageal involvement is diagnosed by clinical, endoscopy and biopsy. Blood culture may be +ve.
For oral candidiasis Nystatin, Amphotericin-B and Azoles are used. Oral Azoles are used when topical application fails. For oesophageal candidiasis. Fluconazole and for disseminated Amphotericin B is the choice.
TABLE
Condition Drug Dose & Duration
Oral Candidiases • Nystatin – Suspension, Lozenge
• Amphotericine B oral Suspension
• Clotrimazole
• Fluconazole
• Ketoconazole
• Itraconazole • 1-2 Lak U orally 4 times – 14 day
• 1 mg orally 4 time – 14 day
• 10mg orally 4 times – 14 day
• 3-6 mg/kg orally once – 14 day
• 5-10mg/kg Orally once – 14 day
• 2-5 mg/kg Orally once – 14 day
Esophageal Candidiasis • Fluconazole
• Itraconazole
• Amphotericine – B • As Above
• As Above
• 0.5 – 1 mg/kg/daily IV – 14 days
Disseminated Candidiasis • Amphotericine – B • As Above

Oral Fluconazole is given as prophylaxis is recurrent cases.
E. Other Fungus: Cause meningoencephalitis – Naegleria, Achanthamoeba.

DERMATOLOGIC DISORDERS:
Seborrheic Dermatitis: Seen in 50% of HIV cases. Aggravated by Pityrosporium , a yeast like fungus. Ttopical antifungal treatment is useful.
Eosinophillic pustular folliculitis: Multiple urticarial perifollicualr papules associated with mite infection which respond to topical anthelminthics.
Norwegian scabies: Hyperketatotic psoriasiform lesion.
VZV: Reactivation in 20% cases of HIV, Visceral involvement is rare. Involve several dermatomes Acyclovir, Famciclovir, Foscarnet are used.
HSV: Recurrent oroabial, genital, perianal lesion as part of reactivation. Perirectal is associated with proctotis.
Molluscum Contagiosum: Flesh coloured umbilicated lesion, regress with ARV.
Erythematous Nodules: Due to Atypical microbacteria, fungus, bartonella, Aconthamoeba.

OPHTHALMIC DISEASES:
CMV retinitis: Painless, progressive visual loss with blurred vision. Retina shows perivascualr haemorrhage and exudates.
HSV & VSV: May cause bilateral necrosizing retinitis called Acute Retinal Necrosis Syndrome or Progressive Outer Retinal Necrosis (PORN). There is pain, keratitis, iritis , associated with orolabial HSV or trigeminal zoaster. Fundus shows pale gray periphery. Complicated by retinal detachment.
Other infections: P. carinii- Choroid lesion- Bilateral elevated yellow white plaque. Toxoplasma – Chorioretinitis associated with CNS lesion.

RECURRENT BACTERIAL INFECTIONS:
Recurrent bacterial infections within 2 years period is peculiar to HIV patients. The clinical presentation depends on the system involved.

TABLE
Site of infection Common Organism Clinical Manifestation Diagnostic Evaluation
Meningitis S. penumonia
H. influenzae
N. meningitides Fever, Headache, Vomiting, Altered sensorium, Neck rigidity CSF – examination and culture
Pneumonia S. penumonia
H. influenzae
Ps.aeruginosa
N. aosteroides Fever, cough, chest pain, tachypnea, crepitation Chest X-ray, Sputum Culture
Bacteremia S. penumonia
H. influenzae
Salmonella species Fever Or Hypothermia , Features of Multiorgan Dysfucntion Blood Culture
Oesteomyelitis Staphylococci Fever, pain, swelling or redness at local site Bone scan, Radiograph
Sinusitis S. penumonia
H. influenzae Persistent nasal discharge , fever, cough, Maxillary sinus – common Radiograph
Central venous catheter infection Staph aureus & epidermidis.
K. penumonae
Acinetonbacter species
Pseudomonas Species Redness and tenderness at local site Culture
Skin, ear and upper respiratory tract S. penumonia
H. influenzae
Group A beta fever, Haemolytic URTI Skin- Pyoderma
Ear- Pain, Discharge
URTI- Cough Culture from specimen

Treatment depends on culture sensitivity. Empiric broad spectrum antibiotic may be started taking into account the site of infection, nuetropenia, in dwelling catheter and other risk factors.

For prophylaxis immunization against organism and proper hygiene is to be maintained. Daily TMP-SMX may be used. Intervenous immunoglobulin monthly may boost the immunity.


DIARRHOEA:
Chronic diarrhoea is very common, which may be due to various organisms and side effects of drugs.
TABLE
Organism Species
Bacteria Salmonella, Shigella, Campylobacter, Clostridium difficile & MAC
Virus CMV, Adenovirus, HIV, HSV, Rota Virus
Protozoa Isopora belli, Cryptosporidium parvum, Microsporidia, E. histolytica, G. lamblia, Cyclospora
Fungi Histoplasma, Coccidiodomycosis, Penicilliosis

Peritonitis is seen in C.immitis.
Clinically presents as large watery stool, abdominal pain associated with fever, dehydration, anorexia, wasting and cachexia. Biliary tract involvement (cholangitis, cholecystitis) is seen in Isospora, Microsporidium, Cryptosporidium and Cyclospora.

DIAGNOSIS AND TREATMENT
Organism Diagnosis Treatment
Isospora Oocyst in stool after acid fast stain TMP SMX – 3-4 weeks Pyrimethamine with folinic acid
Cyclospora Oocyst in stool in acid fast stain Orally TMP SMX for 7 days
Microsporidia
Examiantion of concentrated stool,small intestine biopsy on EM or PCR Albendazole
Cryptosporidium
Stool examination in acid fast stain, Immunoflucoscent assay and stool ELISA Fluid supplementation, Paramomycin- Spiramycin, Azithromycin, Clarithromycin
E. histolytica Stool , trophozoite & Cyst, Serological test - +ve with tissue invasion, Endoscopy and biopsy For gut – Iodoquinol, diloxanide furoate, paramomycin
Invasive – Metronidazole, Dehydrometine
Hepatic – Chloroquine
G. lamblia Trophozoite and cyst in stool or duodenal aspirate, Giardia antigen in stool Metronidazole, Furazolidine, Tinidazole
Adenovirus Sigmoidoscopy – Patchy erythema & raised white lesion
Mucosal Biopsy – Intranuclear inclusion , Virus may grow Supportive treatment
Rotavirus ELISA in stool sample Supportive treatment
Camphylobacter Stool culture or blood culture.
Immunological test – IF, LA
Serology – ELISA for IgG, IgM, IgA level Azithromycin, Clarithromycin, Erythromycin, Ciporfloxacin, supportive therapy
Shigella Endoscopy – Deep mucosal ulcer and pseudomembrane
Stool Culture Ampicillin , cefixime, ceftriazone, Quinolones, Supportive care
Salmonella Stool Culture
LA and Fluorescence test
PCR Duration of treatment is 14 days
Cefotaxime /Ceftriaxone, Ciprofloxacin
Cl. difficile Stool Examination
Toxins detected by ELISA Supportive
Metronidazole
Vancomycin

Special Geographical OIs:
1. Penicilliosis: By dimorphic fungus Penicillium marneffei seen in Thailand, China. Infect when CD4 is less than 50 and high mortality if untreated. Presents as fever, weight loss, with skin, lymph node, bone marrow and hepatic involvement. Cutaneous lesions are papullar with central umbilication over face, ears and extremities. Fungus can be demonstrated. Treated with Amphotericin B for 2 weeks followed by Itraconazole for 10 weeks.
2. Leishmaniasis: It is an obligatory intracellular protozoa seen worldwide. May present as localized or diffuse cutaneous, mucosal or visceral disease, the last being common in AIDS (70%). Demonstration of Leishmania from lesion and antibody is diagnostic. Treated with pentavalent antimony.
3. Paracoccidiodomycosis: Dimorphic fungus P. brasiliensis, seen in central and South American. Few cases in HIV – I presenting multisystemic involvement. Treated with Amphotericin B or Azoles.
4. Isosporiasis: the Protozoa I.belli present in Caribbean & Africa and Worldwide. Presents as diarrhoea with systemic symptoms of fever, weight loss, abdominal pain. Treatment is supportive. Pyrimethamine or TMP-SMX are tried.
5. Chaga’s disease (American Trypanosomiasis): A flagellated protozoa T. cruzi. Among HIV-I infected persons with immunosuppression the reactivation is increased. Present as fever, headache, vomiting, seizure. Single or multiple ring enhancement in subcortical area (Vs toxoplasma – deeper). CSF may show increased cell and proteins. Organism found in blood or tissue. Treated with Benzimidazole (2.5 mg/kg BID) or Nifurtimox ( 2 mg/kg/QID) for 60 days followed by maintenance therapy for life with either drug in a dose of 5 mg /kg thrice a week.
6. Microsporidia: Small unicellular, obligate intracellular parasite, reside in the cytoplasm of enteric cells. The main species is Enterocytozoon bieneusi. Detected by light microscope with chromotobe bases stain. E/M of stain. In contrast to cryptococcal it is seen in other tissue like eye, muscle, liver . Albendazole is treatment.
7. Cryptosporidia: Symptoms range from self limiting, intermittent to sever life threatening diarrhoea. Assoiciated with nausea, vomiting, crampy abdominal pain. Associated with cholangitis and cholecystitis. Diarrhoea is non-inflammatory. Stool containing occyst stain with acid fast.

SUMMARY
• Opportunistic infections due to various organism are associated with HIV infection at some stage or other.
• They can be classified depending on the CD4 count or system involved.
• PCP is commonest form of pneumonia though there is a six-fold rise of pneumonia incidence due to other bacterias.
• The incidence, complications and resistance of M. tuberculosis is more in HIV cases. ATT is modified according to immune status of the patient.
• Atypical mycobacteria specially MAC incidence is common.
• Toxoplasma gondii infection of CNS leads to various clinical presentation.
• The common viral infections are HSV, CMV, VZV, EBV, HBV and HCV. CMV products commonly retinitis and GI complications.
• Fungal infections like candida, cryptococcal and histoplasma are common producing various complications.
• Dermatological and Ophthalmic complication due to various infections are vary often encountered.
• Due to low immune status recurrent bacterial infections give rise to varied clinical manifestations.
• Chronic diarrhoea due to multiple microogransim is a constant problem.
• Depending on the geographical distribution of some organism the infection predominantly seen.

CONCLUSION

With high prevalence of AIDS in developing and underdeveloped Countries the risk of OIs due to organisms is a menance. The clinical presentations are quite different than normal host. Wherever possible attempts are to be made to obtain tissue or specimen to establish a definitive diagnosis. Various studies have proved the relation between CD4 count and progression of HIV and OIs. Timely diagnosis and treatment and chemoprophylaxis have reduced the mortality and morbidity. Additional ART successfully decreases the organism load and restores the immune function reducing the development of OIs.

CLINICAL FOCUS
• OIs due to various microorganism go hand in hand with infection.
• The clinical presentation somewhat differ from normal host.
• Depending of CD4 count the HIV related infections are different.
• PCP is commonest infection in children and adult having high fatality if untreated.
• Depressing cellular immunity is responsible for high incidence of tubercular infection where the treatment modality depends on CD4 count.
• Atypical mycobacteria specially MAC is quite common giving rise to various systemic complications.
• Toxoplasma infection is another treatable neurological infection.
• Various viral infections are common out of which CMV carry poor prognosis as it involves multisystems.
• EBV produces hairycell leukoplakia.
• Incidence of HBV is about 90% of HIV cases,
• Fungal infections like Cryptococcus, Histoplasma present as disseminated multiorgan disease.
• Oral, oesophageal and vulvovaginal candidiasis are common and can be properly treated.
• CMV retinitis causes progressive permanent blindness.
• Recurrent bacterial infections are common giving rise tp various diseases.
• Chronic diarrhoea is very common, due to organism or drugs.

DENGUE FEVER
INTRODUCTION:
Dengue fever (DF) is an acute febrile viral infection presenting with intense headache, bone ache, rash, leucopenia. Dengue haemorrhagic fever (DHF) is associated with pneumonia and circulatory failure leading to Dengue Shock Syndrome (DSS). Currently it poses a threat to 2.5 billion people in over 100 tropical and subtropical areas of World. International travel, new serotype to susceptible populations are a threat. Proper epidemiological and laboratory surveillance is needed to further control, prevent and treat the cases.
Dengue is a Spanish phrase “Ke denga Pepo” meaning “Cramp like seizure caused by evil spirit” during Carribean out break in 1827-1828. Worldwide incidence is 100 million. In India outbreak occurred in 1993, 1996, 2003 and 2006. In recent outbreak there were 167 death out of which at Delhi there was 61.
THE VIRUS
Belongs to family Flaviviridae (Genus – Flavivirus, species – Dengue) having 4 sero subtypes (DEN-1,2,3,4) distinguished by serological method. The virus has a single standard RNA genome surrounded by icosahedral nucleocapsid and covered by lipid envelope. The virion is about 50nm diameter. The genome is about 11 kilobases in length, the genome sequence of all 4 types are known. The genome is composed of 3 protein genes core (C), membrane associated (M) and envelope (E) and seven nonstructural protein genes. Infection by one serotype produces lifelong immunity against same serotype by partial or temporary immunity against other serotypes.
VECTORS:
The mosquito Ae aegypti found around the globe in tropical and subtropical region usually between latitude 350N and 350S and altitude of 100meters. The mosquitoes invade in warm season and die in winter. Because of its high anthropophilic nature and close proximity to human and indoor efficient vector for arbovirus. Its eggs can withstand long period of desiccation even more than a year.
Other Aedes mosquitoes for dengue are Ae albopictus, Ae polynesiensis, several species of Ae scutillaris complex.
The mosquito is known as Tiger mosquito as it has white strips on black body. It is a fearless biter. The biting hour is 2 hour after sunrise and few hours before sunset. It can fly upto 10 meters. The mosquito breads on artificial accumulation of water like discarded tin, flower pot, cocoanut shell, earthen pots, cooler water etc.,
HOST
All 4 serotypes infect human. At different settings DEN-2, DEN-3 and DEN-4 has been responsible for epidemics. The acute phase of infection following an incubation of 3-14 days lasts about 5-7 days and followed by immune response. Usually high viraemia in human leads to greater percentage of infection to feeding mosquitoes.
PREDISPOSING FACTORS:
. The commonest age group is below 12 years.
. Females suffer more than male
. Race – Caucasian> Black
. Nutritional status – Poor nutritional status is protective.
TRANSMISSION:
Once infected the Ae aegypti mosquito remain infected lifelong and transmit to human during probing and feeding. Infected female mosquito transmits to next generation by transovarian transmission. Though human is the commonest amplifying host, monkeys at some places may be the host. The virus circulates during fever and viraemia. The virus develops in the biting mosquito for 8-10 days before infecting a healthy human. This extrinsic incubation period depends on environmental factors.
PATHOGENESIS OF DHF/DSS
The two main pathophysiological changes in DHF/DSS are:
. Increased vascular permeability giving rise to plasma loss, haemoconcentration, low pulse pressure and signs of shock.
. Disorder of haemostasis involving vascular changes, thrombocytopenia coagulopathy.
Activation of complement system with decrease of C3 and C5 levels are seen. Mediators of vascular permeability and bleeding phenomena are not clear. Platelet defects are quantitative and qualitative. There is enhanced viral replication in macrophages by heterotype antibodies. The secondary infection by a different serotype , cross reactive antibodies may increase the number of infected monocytes as dengue virus antibody complexes are taken into these cells. This results in increase of CD4+ and CD8+ cytotoxic antibodies. Activation of T cells releases cytokines rapidly. Lysis of infected monocytes mediated by cytotoxic lymphocytes result in plsma leakage and haemorrhage.
Sequence of infection:
. Serotype 1 Serotype 2 more dangerous
. Serotype 4 Serotype 3 Less dangerous
. Serotype 2  Most dangerous.
PATHOLOGY OF DHF
In autopsy it has been found in order of incidence - skin and S.C. tissues, G.I mucosa, heart , liver. Subarchnoid and cerebral haemorrhage are rare.
Serous effusion (exudative) seen in pleura, peritoneum, rarely in pericardium. The capillaries and venules of involved organs show perivascular bleeding , monocyte and lymphocyte infiltration, intravascular clot.

In liver there occurs focal necrosis of hepatic cells , swelling , councilman bodies hyaline necrosis of Kupffer cells. Mononuclear proliferation occurs commonly in sinusoids and rarely in portal areas.
In autopsy viral antigen commonly seen in liver, spleen, thymus, lymphnode, lung cells. Virus has been isolated from bone marrow, brain, heart, kidney, liver, lung, lymphnode, GIT.
In nonfatal DHF the bone marrow shows depression of all haemopoitic cells which improve after fever subsides. Kidney shows mild immune complex type glomerulonephuits which resolve after 3 weeks without any residue. Biopsy of skin rash shows perivascular oedema of the terminal microvasculature of dermal papillae with infiltration of lymphocytes and monocytes. Phagocytes bearing antigen have been found in this area. Deposition of serum complement, immunoglobulin and fibrinogen on vessels has been detected.
CLINICAL PRESENTATION
Dengue infection may present as asymptomatic, undifferentiated fever, DF, DHF and DSS.
I. Dengue fever:
. The clinical features depends on age. Infants and young children have febrile illness with maculopapular rashes.
. Older children and adult may have mild febrile syndrome or classical disease by high fever of abrupt onset sometimes with 2 peaks (sadodle backed) severe headache, pain behind eyes, muscle, bone , joint pain (break bone fever), nausea, vomiting, rash. Petechial skin lesions are common. Leucopenia and thrombocytopenia is common. Recovery is associated with fatigue and depression. In some epidemics may have bleeding complications like epistaxis, gum bleeding, GI bleeding , haematuria, monorrhagia.
. The case fatality is < 1%.
. Haemorrhage in DF is to be differentiated from DHF where there is haemoconcentration.
. DF is to be differentiated from Chikungunya fever a similar vector borne viral disease with similar epidemiology and overlapping distribution.
II. Dengue Haemorrhagic fever (DHF)
. The 4 typical manifestations are high fever, haemorrhagic phenomena, hepatomegaly and circulatory failure.
. Moderate to marked thrombocytopenia with haemoconcentration distinguish it form DF. So also plasma leakage giving rise to serous effusion and hypoproteinemia.
. Commonly sudden high fever accompanied by facial flush and various nonspecific symptoms and signs may occur like anorexia, nausea, vomiting, constipation, diarrhoea, abdominal pain, infected pharynx, rhinitis , maculopapular rash, myalgia, arthralgia, enanthema, abnormal reflex, palpable spleen, febrile convulsion (children) coma.
. Common haemorrhagic phenomenon is a positive tourniquet test, easy brushing and bleeding from venepuncture site. Discrete fine petechiae over extremities, axillae, face , soft palate are seen during febrile period. Epistaxis, gingival bleeding are infrequent and GI bleeding may occur during fever.
. Liver is palpable in early febrile phase and varies in size but does not correlate with severity though hepatomegaly is more in shock syndrome. Liver is tender without jaundice. Splenomegaly is common in infants.
. The course – In severe cases after 2-7 days of fever, rapid fall of temperature, circulatory disturbances. In less severe cases mild symptoms reflect less plasma leakage. Many patients recover spontaneously after fluid and electrolyte correction. In severe cases patient may go to shock and death.
. DHF can be graded as per severity of symptoms and signs
Grade – I: Fever , nonspecific constitutional symptoms. Only haemorrhagic sign is +ve , Tourniquet test and /or easy brushing.
Grade – II: Grade I symptoms with spontaneous bleeding manifestation of skin and other sites.
Grade – III: Circulatory failure in form of rapid, thready pulse , hypotension, cold , clammy skin and restlessness.
Grade – IV: Profound shock with undetectable pulse and BP.
. During convalescence from DHF sinus bradycardia, arrythmia, confluent petechial rash with small round normal skin are seen. Maculopapular rash are less common in DHF than DF. The course of DHF is usually 7-10 days.
III. Dengue shock syndrome (DSS)
Sudden deterioration of patient after 2-7 days of febrile illness when sudden fall of temperature with signs of circulatory failure like cold, clammy skin, circumoral cyanosis, rapid, thready pulse and low pulse pressure, hypotension. Initially lethargic later may be restless. Acute abdominal pain may proceed shock. If not timely treated patient passes to profound shock stage with imperceptible BP and pulse. But consciousness is intact throughout. The duration of shock is short. The patient dies within 12 – 24 hours or recovers following volume replacement. Pleural effusion and ascites may be detected clinically or radiologically.
Uncorrected shock can give rise to complications like metabolic acidosis, severe bleeding from GIT and other organs with poor prognosis. Convulsion may occur in intracranial haemorrhage and may be comatose. Encephalopathy may occur due to metabolic, electrolyte disturbance and intracranial bleeding.
Convalescence in corrected DSS is short and uneventful. Reviving from shock patient recovers within 2-3 days with adequate urination and appetite. Ascites and pleural effusion may recover later.
COMPLICATION AND UNUSUAL MANIFESTATIONS
The unusual manifestations like CNS involvement giving rise to convulsion, spasticity, altered sensorium , transient paresis. Febrile convulsion may occur in children. Encephalopathy may be due to hypotonic solution replacement or DIC. Intracranial bleeding and brainstem herniation due to cerebral edema may occur.
Some iatrogenic complications like sepsis, pneumonia, wound infection and overhydration may occur.
Liver failure may occur in serotype1, 2, 3 with both primary and secondary infection. Hepatic necrosis with detectable dengue antigen in hepatocytes. The cause of liver damage is not known. Renal failure is a terminal event.
Other unusual manifestations are acute renal failure, haemolytic uraemic syndrome (in cases of haemoglobinopathy and G6PD deficiency). Simultaneous infections like leptospirosis , Hepatitis B, typhoid fever, chicken pox, melioidosis contribute to unusual manifestations.
LABORATORY DIAGNOSIS
1. Thrombocytopenia and haemoconcentration is a constant finding of DHF.
A. Platelet count < 100000/mm3 found between 3-8th day, often along with or before changes in Haematocrit.
B. A rise in Haematocrit is always present more so in shock. A rise of 20% or more is definite evidence of increased vascular permeability and plasma leakage.
C. A relation of drop in platelet and rise in Haematocrit is unique of DHF and occur before defervescence and onset of shock.
D. The WBC count is variable at onset ranging from leucopenia to mild leucocytosis but leucopenia with fall of neutrophil is common at the end of febrile illness. Ralative lymphocytosis with atypical lymphocytes is common before shock.
E. A transient mild albuminuria with +ve occult blood in stool is seen.
F. Coagulation profiles may show reduced fibrinogen, prothrombin, factor VIII, IX and antithrombobin III.
G. Reduced  antiplasmin seen in some cases, serum albumin reduced.
H. In severe liver dysfunction reduced level of Vit K dependent factors like factor V, VII, IX, X are seen. Prothrombin time and partial thromboplstin time is prolonged in 30-50% cases of DHF. Thrombin time is prolonged in severe cases. BT and CT are prolonged..
I. Platelet function is impaired and reduction of complement specially C3 is seen.
J. Other common findings are – Hypoproteinaemia, hyponatraemia and raised serum asparate aminotransferase. In shock there is metabolic acidosis with raised blood urea nitrogen.
K. X-ray chest may show pleural effusion (right side). In shock there is bilateral pleural effusion.
2.Virus and serological test
L. Isolation and detection of virus – Since all patients have a period of viraemia, the virus can be isolated in the course of the disease.
Detection of dengue virus by culture is definitive diagnostic test though practically it has many limitations. As antibody develops within days and the virus being heat labile collection and transport of specimen need care. Detection of dengue RNA using specific oligonucleotide primers, reverse transcriptase and thermostable polymerase – a test known as reverse transcription polymerase chain reaction (PCR) amplification assay is useful. The plasma , serum or cell can be used for this. Determination of virus and antibody type is preferable. Inoculation of clinical specimen to adult or larval mosquito is used for virus culture.
M. MAC ELISA Test: In primary and secondary dengue infection ELISA can measure the rise of specific IgM collected in the acute phase. Four fold rise of Ig G and IgM antibody is diagnostic.
N. Haemagglutination inhibition (HI test) – useful for diagnosis.
O. Neutralization Test: Most sensitive and specific test is serum dilution, virus constant, plaque reduction test. Following primary infection specific neutralizing antibody is seen in early convalescence. Following secondary infection high titre neutralizing antibody is produced against at least 2 or all 4 serotypes.
P. Dot bolt immuno assay: Now technique under consideration.
Q. Complement Fixation Test (CFT) : Though less sensitive it appears later than IgM or HI antibody but more specific . Useful for confirmation in later period. A 4 fold rise of CFT antibody where the interval between acute and convalescent is < 2 weeks signifies secondary seroresponse pattern.
R. Dengue virus antigen is autopy tissues may also be detected by immunohistochmistry, immunofluroscence.
DIFFERENTIAL DIAGNOSIS
In the early febrile phase DHF/DSS a wide spectrum of viral, bacterial, parasitic infections are to be taken into consideration. Chikungunya fever is difficult to differentiate from dengue clinically. But by 3-4 days the laboratory findings will establish dengue. Shock never occurs in Chikungunya. Thrombocytopenia and haemoconcentration excludes endotoxic shock.
Chikengunya fever (compared to DF)Duration of fever - < 7days
Haemorrhage - Less
Gn bleedig - 0
Haematemesis /Melana - 0
Shock - 0
Coma - 0
Abnormal reflux - 0
Hepatomegaly/palyarthralgia - more
TREATMENT
. The major pathological abnormality in DHF/DSS is increased vascular permeability leading to loss of plasma volume. The major haemostatic changes in DHF are vascular changes (due to short acting mediators), thrombocytopenia and disorder of coagulation which leads to DIC and haemorrhagic complications.
. Early and effective replacement of plasma by plasma expander or fluid and electrolyte correction leads to favourable outcome even DSS may be reversible. Resuscitation from shock, correction of acidosis have good prognosis.
. Repeated Haematocrit and platelet count during illness is essential to assess signs of deterioration.
. DHF – Oral hydration with electrolyte is encouraged. Antipyretics are to be avoided to prevent acidosis, bleeding and Reye and Reye like syndrome. Paracetamol is preferable. Parenteral IV fluid is indicated if vomiting or hypotension. Bicarbonate containing IV fluids should be avoided initially. Vital signs, urine output are to be monitored.
. Calculation of maintenance of IV fluid
Body Weight Maintain volume (ml) over 24 hours
10 Kg 100/kg
10-20 Kg 1000+50 for each kg in excess of 10
>20 Kg 1500+20 for each kg in excess of 20
Total fluid required = +10ml /1% normal body weight loss

. DSS
It is a medical emergency. Immediate IV fluid or plasma expander are given. Hyponatremia and metabolic acidosis are to be corrected. Sedatives may be indicated if patients is restless. Avoid hepatotoxic and long acting drugs. A single dose of chloral hydrate (12.5 –15mg /kg) orally is preferable. Oxygen therapy is given if needed. Blood transfusion – indicated when there is internal haemorrhage. Fresh whole blood is preferable. Fresh frozen plasma or concentrated platelets indicated is coagulopathy
. To be given or done - Rest, Fluid/Electrolyte and Acetaminophen.
. Not to be done or given - Aspirin, Brufen, IV therapy before haemorrhage, Blood transfusion, Antibiotic, No injection and No steroid.
PREVENTION AND CONTROL
. Killing of adult mosquitoes by space spray. Theramal fog (insecticide +oil), ULV aerosal (cold fog) and mist. Insecticide used as – Malathion, Fenitrothion, Fenthion, Pyrethroids
. Control of mosquito bite: using repellant oil, use of full clothing, mosquito net
. Eliminate breeding site: Spray larvicides like Temephos sandgranules and insect growth regulator Methoprine in form of brequets.
. Biological control by using Bacillus thurigienisis – H-14 BTI.
. No vaccine yet available.
. Health education,environmental sanitation is best way for prevention.
SUMMARY:
Dengue fever is one of the commonest arthropod borne viral haemorrhagic fever found in tropical or subtropical countries worldwide. The vector has close proximity to human. The virus has 4 serotypes out of which serotype 2 is dangerous. Dengue fever may lead to DHF or DSS depending on the serotype, adequate early treatment and host response. Dengue fever may simulate other fevers specially Chikungunya fever. The pathophysiology of DHF and DSS is increased vascular permeability, haemoconcentration and disorder of haemostasis including thrombocytopenia. The diagnosis depends on clinical symptoms and signs with laboratory findings and commonly thrombocytopenia, rise in haemotocrit value. Virus can be detected on culture. Different serological test are helpful to establish the diagnosis. The treatment is symptomatic with special emphasis in maintaining fluid and electrolyte balance. The measures to eradicate the vector is best prevention.
CONCLUSION:
In tropical and subtropical countries the menance of Dengue is a constant feature. Epidemics occur very often with high morbidity and mortality . Early proper diagnosis, adequate management of DHF and DSS decreases the mortality. Control of mosquitoes and environmental sanitation is best way to prevent the disease.

TUMOR MARKERS

INTRODUCTION :-
Tumor markers are biochemical substances usually proteins released by tumor cells either due to cause or effect of malignant process. Some are specific while others are seen in several cancers. Many are also seen in non-cancerous conditions. They may be intracellular seen in tissues or released into circulation. Search for suitable markers in serum, tissues or body fluids during neoplastic process is of clinical value. Though an ideal marker should be highly sensitive, specific, reliable with high prognostic value and correlate with staging none of the markers identified so far has all the features. However they are helpful to monitor in risk groups, diagnose the probable source, staging the cancer, determine prognosis, guide & monitor treatment and detect recurrence.

CLASSIFICATION :- Broadly they may be classified as :-
1. Oncofetal antigens:-α-fetoprotein(AFP), carcinoembryonic antigen (CEA), pancreatic oncofetal antigen, fetal sulfoglycoprotein etc.
2. Tumor associated antigen/Cancer antigen e.g. CA-125,CA-19-9,CA 50 etc.
3. Hormones e.g. β human chorionic gonadotrophin, calcitonin, placental lactogen etc.
4. Hormone receptors e.g. estrogen & progesterone receptors.
5. Enzymes and isoenzymes e.g.-PSA(prostate specific antigen),PAP(prostatic acid phospatase),NSE(neuron specific enolase),TDT(terminal deoxy nucleotidyl transferase ),PALP(placental alkaline phospatase), lysozymes, alpha amylase etc.
6. Serum&tissueproteins-β2microglobulin,monoclonalimmunoglobulin/paraproteins, GFAP(glial fibrillary acid protein), proteinS-100, ferritin, fibrinogen degradation products etc.
7. Other biomolecules e.g. polyamines.
Some are commonly in use while others are less common.
IDEAL TUMOUR MARKER An ideal tumor marker should have---
1. Highly sensitive and less false negative.
2. Highly specific and less false positive.
3. Should have high +ve &-ve predictive value.
4. 100% accuracy in differentiating healthy & cancer patients.
5. Differentiate between neoplastic & non-neoplastic conditions showing +ve correlation with tumor volume and extent.
6. Predict early recurrence and have prognostic value.
7 . Clinically sensitive to detect in early stage.
8. Level should precede neoplastic process to screen early.
9. Should be universal to all or specific to one malignancy.
10. Easily assayable , able to indicate all changes during treatment.

DESCRIPTION:-
1.Alpha fetoprotein(AFP)— It is a major fetal serum globulin with a molecular weight of 65000. In fully matured fetus the AFP gene is completely repressed leading to its disappearance soon after birth. Though abundant in fetal blood, in normal adult the value is 15ng/ml. A value of serum AFP >500ng/ml indicate malignancy besides pregnancy. During fetal life AFP is synthesized in liver (main), yolk sac and GI tract. Fetal liver produce AFP about 30mg/day. In first trimester amniotic fluid contain yolksac derived AFP (Concanavalin-A non reactive). Later increased portion of AFP is liver derived(Concanavalin-A reactive). AFP reaches a peak between 30-32 weeks of pregnancy and decline suddenly before term. Clinical significance of AFP level is of value in prenatal diagnosis of open spina bifida, anencephaly, atresia of esophagus and multiple pregnancy.AFP level also aid in diagnosis,prognosis and monitoring primary hepatocellular carcinoma, hepatoblastoma, non seminomatous testicular germ cell tumors like embryonal carcinoma, teratoma, choriocarcinoma, yolksac carcinoma, germ cell tumors of ovary and extragonadal germ cell tumors. Most well differential and highly anaplastic hepatomas do not produce AFP, as AFP synthesis is associated with degree of liver cell differentiation. Significant rise of AFP is rarely seen in malignancy of GIT, pancreas, lungs, kidney and breast etc. Moderate rise of AFP is seen in viral hepatitis, chemical hepatic injury, hepatic necrosis, liver surgery. AFP < 400ng/ml is seen in 10-15% cases of acute and chronic hepatitis, cirrhosis, secondary malignancies. Serial AFP estimation shows steady and progressive rise in malignancies in contrast to fluctuation in nonmalignant condition. Pure seminomas are nonsecretor of AFP whereas in nonseminomatous germ cell tumors the AFP indicate progress, monitor treatment and recurrence. Dysgerminomas are AFP nonsecretors while highly malignant endodermal sinus tumours show raised AFP. Measurement of serum AFP is helpful in diagnosis, prognosis, and monitoring efficiency of chemotherapy, radiotherapy, surgery and recurrence of all malignancies discussed. Yolk sac and liver AFP synthesized during fetal and adult life are immunologically cross reactive but different. Because of their affinity to lectin AFP can be resolved to concannavalin A reactive(R con A) and non-reactive (NR con A) fraction. Quantitive as well as qualitative evaluation of AFP vaiant reveal two types, one specific to liver and other to yolk sac.

2.Human chorionic gonadotrophin(βHCG):- HCG, A marker of germ cell tumors and trophoblastic disease, is 45KD glycoprotein, composed of two dissimilar subunits the αchain(14 KD) and βchain(24 KD). It contains 30% carbohydrate. The beta subunit determines the immunological and hormone specificity. HCG is synthesized by the synctiotrophoblasts of the placenta during pregnancy. The peak HCG concentration is reached between 10th & 12th weeks of gestation. The reference values in serum of healthy men and non-pregnant women are less than 5 IU/ml and post-menopausal women are less than 10IU/ml. HCG is a marker of first choice for gonadal (testes and ovary) choriocarcioma. HCG shows 100% sensitivity for choriocarinoma irrespective of their site in addition to hydatidiform mole. In testicular tumors, the detection of βHCG and AFP correlate with the histological findings and is therefore crucial for the therapeutic procedures with the use of serial determination of βHCG. The biochemical recurrence precedes by 3 months before the patient has symptoms of clinical recurrence/metastasis. The marker also helps in monitoring high-risk group of testicular tumors especially individual with undescended testicle or the healthy monozygotic twin of a testicular tumor patient. High levels of βHCG indicate poor prognosis and frequent assays during therapy level correlate to the clinical response. Serum βHCG levels are rarely elevated in nontrophoblastic tumors such as lung, breast, pancreas and bladder cancers.

3.BETA-2Microglobulin(β2M):- β2M is 11 KD light chain constituent of HLA antigen. The β2M is used clinically as a marker of first choice for B-cell leukemia, lymphomas and multiple myeloma. However, due to its non-specificity its moderate elevation is observed in cases of solid tumors and also in various inflammatory diseases, benign infectious disorders, and primary billiary cirrhosis and in acquired immune deficiency syndrome. It is used routinely for evaluating tumor cell load, disease activity and prognosis. It is also used to monitor efficacy of patient’s response to treatment. Elevated levels of β2M are also reported in cerebrospinal fluid (CSF),in CNS metastasis, acute lymphoblastic leukemia. lymphoma and other lymphoproliferative disorders/diseases. Hence the determination of β2M in CSF helps in identifying and managing CNS metastases. Serum β2M could be clinically relevant marker for Waldenstrom’s macroglobulinemia, secretary and non-secretary multiple myeloma, leukemia and lymphoma. Like other tumor markers, β2M has proven to be the best marker for monitoring therapeutic courses, as it useful serum parameter to monitor tumor progression as well as early biochemical relapse. Serum β2M is the most powerful prognostic marker of monoclonal gammapathies.

4. BRCA 1 &BRCA 2:- BRCA 1and BRCA 2 belong to few tumor suppressor susceptibility genes having high risk to few cancers.BRCA1 predicts high risk for breast, ovary, colon and prostate cancers. BRCA2 gene mutation is seen in 70% of breast cancers in women and men. More than 100 germ line mutations are reported in BRCA gene applying current molecular technology.

5.BTA(Bladder tumor antigen):- Not widely used. Urine level helps in diagnosis and recurrence of bladder tumors. May be raised in kidney stones and urinary tract infection.

6.Carcino-embryonic antigen(CEA): -CEA, is a glycoprotein of 200 KD. Radioimmunoassay (RIA) made it possible to detect very low concentrations of CEA in blood, other body fluids, and also in normal and diseased tissues. It is excreted by certain embryonic and adult tissues in addition to adenocarcinoma of the digestive organs. Extensive studies of patients bearing primary and metastatic colorectal neoplasms have determined that its primary use is in the detection of local and metastatic cancer recurrence after initial resection of the primary tumor, through periodic postoperative analysis of CEA in serum or plasma. The notion that fluids bathing tumors in metastatic sites might contain higher levels of CEA than those found in the blood led to analysis of CEA levels in gallbladder bile from patients bearing colorectal liver metastases. It was observed that CEA levels in gallbladder bile were strikingly higher than those in serum. Furthermore , linear regression analysis of tumor volume versus gallbladder bile CEA levels in patient with liver metastases predicted that tumors as small as 1 cm would produce easily measurable gallbladder bile CEA levels as high as 41ng/ml. This data suggested that measuring biliary CEA levels in patients with primary colorectal lesions might permit detection of small, occult colorectal liver metastasis earlier than now is possible through conventional methods (computed tomography liver scanning, ultrasound, and intraoperative exploration). The results of clinical studies that CEA, although originally thought to be specific for digestive tract cancers, may be elevated in other malignancies and in some nonmalignant disorders. CEA testing is of significant value in the monitoring of patients with diagnosed malignancies in whom changing concentrations of CEA are observed. A persistent elevation in circulating CEA following treatment is strongly indicative of occult metastatic and / or residual disease. A persistently rising CEA value may be associated with progressive malignant disease and a poor therapeutic response. A declining CEA value is generally indicative of a favorable prognosis and a good response to treatment. Clinical relevance of the CEA assay has been shown in the follow-up management of patients with colorectal, breast, lung, prostatic, pancreatic and ovarian carcinoma. CEA testing recommended as a screening procedure to detect cancer in the general population; however, use of the CEA test as an adjunctive test in predicting prognosis and as an aid in the management of cancer patients has been widely accepted.

7.Cancer antigen 125(CA 125):- It is a glycoprotein of more than 200 KD, detected by monoclonal antibody. Healthy women has < 35 U/ml in their serum. It is a first marker of choice in epithelial ovarian carcinoma specially adenocarcinoma (high sensitivity 80% specificity 96%). It is useful for staging, prognosis& recurrence. It may be raised in malignancies of breast, colorectal, gastric, esophagus, liver, billiary tract, pancreas, lungs, and endometrium. After removal of ovarian tumor there is rapid decline within a week and normalize within 3-4 weeks. CA-125 value indicates prognosis, remission or relapse. Nonspecific mild rise may be seen in begin ovarian cyst.(follicular cyst), endometriosis, coelomic epithelium pathologies, cirrhosis, pleural effusion, ascites, peritonitis, pericarditis, during menstruation and last trimester of pregnancy.

8. Cancer Antigen 19-9:- It is a marker of first choice in cancer of pancreas and gall bladder. It is 210 KD glycoprotein antigen having carbohydrate on glycolipid and glycoprotein, detected by monoclonal antibody assay. The antigen is located immunologically in fetal epithelium of colon, small intestine, stomach, pancreas, liver, adult GIT and lung. Appreciable level is seen in mucin rich saliva, seminal fluid, gastric juice, amniotic fluid, urine, ovarian cyst fluid, pancreatic, gallbladder and duodenal secretion. Normal value is < 37U/ml and < 100U/ml is considered as grey zone where malignant and benign disease may overlap. In malignancy value may be > 100,000 U/L. In pancreatic tumor (sensitivity -85%, specificity -95%), cholangiocarcinoma and gall bladder carcinoma ( sensitivity 70%) it is helpful. It may have low sensitivity in colorectal, stomach, primary liver, bronchial, mucinous ovarian, uterus and mammary carcinoma. Besides diagnosis its value predicts recurrence after pancreatectomy. Nonspecific rise may occur after acute or chronic pancreatitis. (8%).

9.CA15-3:- Ca 15-3 is heterogeneous 300 KD glycoprotein antigen. The diagnostic sensitivity of the CA 15-3 for breast carcinoma is low as its elevated level is also observed in benign breast diseases and cirrhosis, acute and chronic hepatitis and in metastatic cancers of pancreas, ovary, colorectal, lung, stomach, uterus.

10.CA72-4:- Its molecular weight is more than 106 KD. This antigen was detected in fetal epithelium and also in serum of patients of various adenocarcinoas. CA 72-4 once emerged as the marker of first choice for gastric carcinoma and is thereby superior to CA19-9 and CEA. The sensitivity of CA 72-4 was found to be 38%. CA 72-4 is considered to be the multiple marker for epithelial cell derived tumors.

11.CA 19-5 & CA-50:- CA 19-5 was found to be associated with colon, pancreatic and hepatocellular carcinoma. Individually both antigens have low sensitivity. However use of both together improves sensitivity in detecting pancreatic and other carcinomas.

12.CA 549:- CA 549 is a high molecular weight circulating glycoprotein antigen associated with breast cancer. Elevated level of CA 549 is observed in serum of advanced breast cancer by using sensitive immunoassay. However, it has very low sensitivity; very low negative predictive value and high positive predict value for early breast cancer.

13.Cytokeratins/Keratins:- Keratins are remarkably diverse, highly resistant and the most conserved cytoskeletal proteins are present in all types of epithelial cells. The composition of keratin filaments ranges from a few polypeptides to 19 different polypeptides ranging from 40 to 68 KD. Keratins have gained importance as marker protein in diagnosis of tumor of epithelial origin. There may be variation in keratin expression compared to normal tissue, depending on degree of differentiation of epithelial tumors. This property of keratin allows their use in combination with other changes as markers for malignant transformation in epithelioid tumors. Keratins has 2 main applications(i)distinguish epithelial from non epithelial tumors and(ii)distinguish type of epithelial tumor. Keratin is reliable marker of (i)undifferentiated and anaplastic carcinoma(ii)infiltrating carcinoma(iii)metastasizing single carcinoma cell in suspension. It may be used for epithelial carcinomas, especially those of stratified and sqamous cell origin e.g. lung , breast, urinary bladder, thymomas and cervical carcinoma. As GItract lining from buccal mucosa to rectum including pancreas and gall bladder is of epithelial origin keratin may serve as an useful marker. Keratin has been used as a differential marker in thyroid, GItract, prostate, lung and breast.

14.Cyfra 21-1:- It is used as a marker for non small cell lung cancer (NSCLC),squamous cell carcinoma(SCC), adenocarcinoma and large cell carcinoma. This marker has highest sensitivity for SCC in lung. Both Cyfra 21-1 and CA19-9 have improved detection of adenocarcinoma of lung.
15.Calcitonin:- Calcitonin a low molecular weight peptide hormone secreted from C cells of thyroid is used as a marker, as increased level is seen in malignancies with skeletal metastasis. It is increased in medullary carcinoma of thyroid, bronchogenic carcinoma, small cell cancer of lung, breast, liver, lung, renal and carcinoid tumors.

16.Catecholamines:- Plasma and urinary epinephrine and norepinephrine are raised in Pheochromocytoma.

17.CathepsinD:- Lysosomal aspartyl protease of lysosomes is considered a potential marker for breast cancer metastasis. Cathepsin D predicts early recurrence. It has high prognostic value in node-ve breast cancer than node+ve breast cancer. Patients with low Cathepsin D value have better survival. High level of Cathepsin D enhances metastasis in breast cancer.

18.Chromogranin A:- Chromogranin A(secretogranin 1) belongs to group of closely related secretary acid protein is used as a marker to asses exocytotic sympathoadrenal activity in Pheochromocytoma. In peptide producing tumors it is raised.

19. CA27.29&CA 15-3:- Usually seen in breast cancers. May be +ve in colonic, gastric, hepatic, lung, ovarian, prostatic cancers and breast, liver, kidney diseases and ovarian cyst.

20. Circulating methylated DNA:- Circulating nucleic acids may be used as marker in early detection, follow progression. DNA is a stable molecule and detected by PCR.

21.Epidermal growth factor receptor(EGFR): -EGFR a 170 KD glycoprotein binds to epidermal growth factor(EGF). It is raised in breast cancer, gliomas, lung cancer, SCC and tumors of female genital tract. Absence of EGFR indicates a good response to Tamoxifan therapy.

22.Estrogen receptor(ER),Progesterone receptor(PR):- ER a 70 KD protein is present in mammary and uterine tissues. ER &PR belongs to receptor super gene family including receptors for thyroid hormone, vitamin D3 and retinoic acid. In breast tumor their level indicate benefit of hormone therapy. 55% to60% ER positive primary breast cancer show good hormone response. Following mastectomy high PR&ER positive tumors have longer survival. PR is more sensitive than ER.

23.Ferritin:- Serum ferritin an acute phase reactant is an intracellular protein playing a role in sequestration and storage of iron. Increased ferritin level is seen in cancers in absence of iron overload. It is increased in advanced breast, ovary, lung, colon, esophagus cancer, acute myelocytic leukemia, teratoblastoma and SCC of head and neck.

24.Homovanillic acid(HVA) & Vanillymandelic acid(VMA): -HVA &VMA are acid metabolites of catecholamines. Their increased excretion is observed in neural crest tumors. They also help in detecting and monitoring therapy in Pheochromocytoma & Neuroblastoma.

25.Hydroxy indole acetic acid (5-HIAA):- Urinary measurement helps in indole secreting tumors. Helps in diagnosis and therapy monitoring in Carcinoid tumors.

26.Her-2/neu(also known as HER,erbB-2,EGFR-2):- Seen in 20-30% of advanced breast cancers. It determine prognosis and guide treatment.
27. Human telomerase reverse transcriptase (hTERT):- It is a novel and newly available biomarker for patients with ovarian and uterine cancers. The hTERT mRNA level has a significant correlation with CA-125 and with histological finding in ovarian cancer. Serum hTERT mRNA is useful for diagnosing gynecological cancer and is superior to conventional tumor markers. Up regulation of hTERT may play an important role in the development of cervical intraepithelial neoplasia (CIN) and cervical cancer. So hTERT could be used as an early diagnostic biomarker for cervical cancer in future.

28.Interleukin-2 receptor/Tac antigen(IL-2R):- IL-2 α a 55KD glycosylated protein is seen in some types of lymphoid malignancies like T-cell leukemia. It my monitor treatment.
29. Inhibin:- Inhibin is a peptide hormone normally produced by ovarian granulosa cells. It inhibits the secretion of follicle-stimulating hormone (FSH) by the anterior pituitary gland. It reaches a peak of 772 +/-38 U/L in the follicular phase of the menstrual cycle and is normally undetectable in the serum of menopausal women. Granulosa-cell tumors produce inhibin and its serum levels reflects the tumor burden. Measurement of inhibin can be used as a marker for primary as well as recurrent granulosa cell tumor.The recent availability of markers of ovarian stroma, including melan-A and inhibin- alpha, has provided a means for the positive identification of ovarian stromal tumors, which can manifest in a myriad of histological appearances.The hormonal activity of granulosa cell tumors permits the use of a variety of serum markers in the diagnostic evaluation. Clinically the most useful serum marker for granulosa cell tumors is inhibin. Inhibin exists in 2 different isoforms. Inhibin-A and Inhibin-B. Both isoforms consists of a dimmer of 2 subunits, the alpha and beta subunits. Inhibin usually becomes no detectable after menopause. However, certain ovarian tumors mostly mucinous epithelial ovarian carcinoma and granulosa cell tumors produce inhibin. An elevated level in a postmenopausal women or a premenopausal women presenting with amenorrhea and infertility is suggestive of the presence of a granulosa cell tumor, but not specific. Inhibin levels can also be used for tumor surveillance after treatment to assess for residual or recurrent disease.

30.Lipid associated sialic acid in plasma(LASA-P):- Increased level is seen in malignancies of breast, GItract, lung, leukemia, lymphoma, Hodgkin’s and melanoma(sensitivity vary -77% to97%). Slight increase is seen in many inflammatory diseases indicating poor specificity.
31. Lysophospatidic acid:- It stimulates cancer cell proliferation, intracellular calcium rise and tyrosine phosporylation. It is found in ascitic fluid of ovarian cancer.

32.L1(CAM):- It correlates with stage and grade of ovarian cancer and response to chemotherapy.

33.LDH(lactate dehydrogenase):- Though one of the first marker clinically used may be raised in many cancers. It is currently used in monitoring some leukemias and lymphomas.

34.Monoclonal immunoglobulin/Paraprotein:- Monoclonal immunoglobulin content is of value in diagnosis and monitoring management of plasma cell tumors like Multiple myeloma, Waldenstrom’s macroglobulinemia, plasma cytoma, B cell leukemias and lymphomas.

35.Mitf (Microphthalmia transcription factor):- It is important in melanocyte development and growth. It is tried in determining disease stage and survival, detect sub clinical metastasis and outcome of treatment.

36.Mullerian inhibiting substance(MIS):- MIS is produced by granulosa cells in the developing follicles. It has emerged as potential tumor marker for granulosa cell tumors. As with inhibin, MIS is typically undectable in postmenopausal women. The elevated MIS level is highly specific for ovarian granulosa cell tumors. However, this test is not commercially available for clinical use.

37.Neuron specific enolase(NSE):- NSE, the gamma subunit of enolase enzyme is present in neurons & neuroendocrine cells.NSE is raised in glucagonoma, insulinomas, carcinoid tumor, pheochromocytoma, medullar carcinoma of thyroid, oat cell carcinoma, small cell and other lung cancers. It is marker of 1st choice in SCLC.NSE monitoring is used in assessing prognosis and therapeutic response in85% of neuroblastoma and SCLC.

38.NMP-22:- Not widely used. Urine level helps in diagnosis and recurrence of bladder tumors(>10 units/ml).

39.Oncogene P21 RAS:- RAS ,one of the transformation inducing gene belonging to family of cellular oncogens(c-ras) frequently seen in human solid tumors like colorectal carcinoma, large adenomas, bladder and lung tumors.

40.Prostate specific antigen(PSA):- PSA known earlier as gammaseminoprotein is 34 KD single chain glycoprotein (93% amino acid, 7% carbohydrate) , a monomer made up of 240 amino acid residue. It is a neutral serine protease, having trypin and chymotrypsin like activities belonging to glandular kalkrein family. Synthesized from prostate epithelium. Small amount of PSA released to circulation form complexes with different protease inhibitors detected in serum and seminal fluid. PSA-ACT complex (major immunoreactive form 80-90%), PSA-AT (α-1 antitrypsin) PSA-PCI(protease C inhibitor ) and PSAα2M(α-2 macroglobulin) are different complexes. The remaining PSA are free immunoreactive form(5-15%). PSA is most useful and clinically relevant marker for prostatic cancer. It is useful for early detection, prevention and assay efficacy of treatment. PSA is synthesized in low quantity by normal prostate, mild quantity in inflamed or hypertrophied prostate, prostatic trauma, after ejaculation and in large quantity by malignant prostate. Due to overlap at times there may be difficulty to distinguish between BPH and early cancer. However combined with digital rectal examination and transrectal ultrasound PSA proves useful in adenocarcinoma besides biopsy. The value of PSA also increases with age and there is correlation between total and free PSA. Indian males have low level as compared to other countries. Though the normal cut off value is 4ng/ml it increases with age. Use of age specific reference value will improve diagnostic efficacy. Clinical analysis of molecular forms of PSA, free PSA, or free PSA/total ratio are useful to differentiate begin from malignant conditions. Other markers in prostatic cancer are PAP, Alkaline phosphates (ALP), PSMA,
Zn-alpha-2-glycoprotein, leucine amino peptidase, lactic dehydrogenase.

41.Prostate acid phospatase(PAP):- Acid phosphates activity is 200 times more abundant in prostate tissue than in any other tissue. Acid phosphatase prostatic fraction is useful only in staging apparently localized disease i.e., primary prostate cancer before definitive therapy such as radical prostatectomy. Its activity in serum can be estimated by several synthetic substrates, but now specific antibodies are available for immunoassay. The enzymatic assay appears superior to the immunoassay in this context. Interest in acid phosphates assay in serum as a measure of prostatic cancer staging has decreased with the availability of more sensitive and specific PSA assay.

42. Parathyroid hormone related peptide(PTH-RP):- Elevated plasma level is seen in cancers having hypercalcemia. It helps to differentiate primary hyperparathyroidism, sarcoidosis, vitamin-D, squamous cell carcinoma of renal, bladder and ovarian cancers.
43.PS 2:- PS2, a low molecular weight cysteine rich protein is raised in 50% of breast tumors. Its expression indicates better prognosis than ER and PR. It is also seen in normal stomach mucosa and ulcerative disease of GItract.

44. PSMA (Prostate specific membrane antigen):- Though not used, may rise with age and serum level indicate prostate disease.

45. S-100:- Though not widely used, may help in diagnosis of metastatic melanomas.

46.Tissue polypeptide antigen(TPA):- TPA regarded as a marker of cell proliferation, is a mixture of proteolytic fragments cytokeratins 8,18,and19. These fragments are released during necrosis and lysis of cancer cells. TPA is regarded as a broad spectrum epithelial marker. Moderate elevation occurs in many diseases and pregnancy. Marked elevation is reported in cancers of breast, lung, gastrointestinal, urological and gynecological conditions.TPA though sensitive but not specific. TPA with CEA help in monitoring lung, breast, bladder, colorectal and ovarian carcinomas.

47. Tumor suppressor gene P53:- P53, a 53 KD nuclear phospoprotein acts as tumor suppressor by inhibiting cell proliferation and plays a role in cellular apoptosis.P 53 gene mutation seen in 50% of all cancers like breast, colon, ovary, lung and esophagus.

48.Squamous cell carcinoma(SCC) antigen:- SCC antigen, a 48KD protein is purified from uterine cervix. It is raised in squamous cell cancer of head & neck, lung, esophagus and anal canal. Highest level is found in metastasis. It is elevated in advanced cervical cancer, determine progression or regression following chemotherapy. Combined use of CEA, NSE, SCC antigen increase sensitivity in detection and monitoring lung cancers.

49. Thyroglobulin:- Used after removal of thyroid to find recurrence. It is elevated in many thyroid diseases. In some antibody is formed against thyroglobulin. So level of antithyroglobulin antibody is measured at the same time.

50. Topoisomerase II:- Topoisomerase II expression is detected in tumor samples by immunohistochemistry and has emerged as a promising, clinically relevant biomarker for survival in patients with advanced epithelial ovarian cancer.

51. TA-90:- Recently on trial to diagnose metastatic melanomas. This protein is found on outer surface of melanoma cells. Its use is studied in colon and breast cancer.

52. Other Gynecological markers:- Other markers in many gynecological conditions are-
Urinary gonadotrophin fragment, Tumor associated trypsin inhibitor, Cyclin E, Mesothelin, HE4, Osteopontin, Ineterleukin 8, Vascular endothelial growth factor(VEGF), Macrophage colony stimulating factor, Insulin like growth factor-binding protein-3, OVX, NB70/K, HMFGR (human milk fat globule)

METHODS:- Common methods used to identify tumor proteins are-
1. Immunohistochemistry- Traditionally most methods have used monoclonal antibodies and immunohistochemistry. They can be used directly in tumors or serum, bonemarrow, lymphnodes.
2. Reversed transcriptase and polymerase chain reaction(RT-PCR)


USEFULNESS:- Tumor markers are usually used for--
1. Detection-Screening in asymptomatic cases for early diagnosis.
2. Diagnosis-Differentiating malignant from benign condition.
3. Monitor-Predict effect of therapy and detect recurrence.
4. Prognosis-Choosing therapy and predict tumor behavior.
5. Therapy-Directing cytotoxic agents to marker containing cells.

SUMMARY:-
Tumor markers are biomolecules released or formed during neoplastic process. Though an ideal marker is yet to be identified they aid in detection, diagnosis, monitor response and recurrence. They may be raised in some nonmalignant conditions.
In urinary bladder tumor BTA and NMP-22 are used along with urine cytology and cystoscopy. In advanced cancers CEA, CA-125,CA 19-9 & TPA are raised.
In breast cancers ER,PR and HER/neu are used for diagnosis. In advanced cases follow-up and recurrence are detected by CA15-3, CA 27-29 & CEA.
In colorectal advanced cancers CEA & ca19-9 are elevated, but neither is helpful for screening test. They are used for follow-up and recurrence.
Gestational trophoblastic diseases show elevated βHCG.
In liver cancers AFP is used for screening, diagnosis and follow-up.
In lung cancers no marker is useful for screening. CEA is raised in non small cell cancer and NSE in small cell cancers and used for evaluation of treatment.
Though no marker is useful for screening TA-90, S-100 and other markers help to find metastasis, follow-up and prognosis.
In multiple myeloma immunoglobulins,β2M are helpful.
In ovarian epithelial cancer CA-125 is usually elevated. Others like CA72-4 & LASA-P are raised. In ovarian germ cell tumor βHCG and AFP are raised.
In pancreatic cancer though no marker is helpful for screening CA 19-9 & CEA are used.
For prostatic malignancy PSA is commonly used. Markers like PSMA, chromogranin-A and PAP are also useful.
Though no marker has developed for stomach cancer CEA,CA 72-4 & 19-9 are raised at times.
For testicular tumor βHCG is elevated in seminomas where as AFP or βHCG or both are raised in nonseminomas.

CONCLUSION:-
Though all tumor marker are not ideal biomarkers their judicious use following evidence based medicine are clinically helpful. Inspite of nonspecificity of wide spectrum of available markers, their potential role in monitoring entire cancer therapeutic course is clinically relevant.

CLINICAL FOCUS:-
 Tumor markers are substances which indicate probable presence of malignancies.
 Few are specific, most of them are nonspecific. Many are seen in nonmalignant conditions.
 All of them are classified into various biochemical groups.
 Though tried since long not a single one fulfill the criteria of ideal marker.
 AFP is specific for liver cancers.
 BTA,NMP-22,CEA,CA125,CA19-9, TPA indicate bladder cancer.
 TA-90,S-100 indicate melanoma.
 ER,PR,HER/neu,CA15-3,CA27-29, CEA are indicative of breast cancers.
 PSA,PSMA,PAP are raised in prostatic conditions.
 CEA,CA72-4,CA19-9 are raised in gastric malignancies.
 CEA,CA 19-9 are increased in pancreatic and colorectal cancers.
 CEA,NSE are raised in lung cancers.
 CA-125,βHCG and AFP are raised in ovarian conditions.
 In testicular tumors βHCG &AFP are raised.
 They are detected by immune assay or RT-PCR.
 Few are used for screening asymptomatic cases while others are helpful for diagnosis, staging, prognosis, response to resection or chemotherapy and recurrence.