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BEDAQUILINE – A new drug to treat MDR Tuberculosis

    On March 21st, 2016, the Union Health Minister, Shri J P Nadda, launched Bedaquiline – new anti-TB drug for Drug Resistant TB as part of the RNTCP. Bedaquiline is being introduced at six identified tertiary care centres across India. Bedaquiline has been released specifically to treat TB patients with bacteria that are resistant to rifampicin as well as to isoniazid, another core anti-TB drug, and thus suffer from multidrug-resistant tuberculosis (MDR-TB).

The safety and effectiveness of bedaquiline were established in 440 patients in two phase-2 clinical trials. The last time a drug was introduced specifically for the treatment of TB was in the late 1960s. That drug was rifampicin. Since then, resistance to rifampicin has been increasingly reported in the world. This is a major concern given that it remains among the most effective anti-TB drugs available today.

Mechanism of action

This new class of drug is a diarylquinoline that specifically targets Mycobacterial ATP synthase, an enzyme essential for supply of energy to Mycobacterium tuberculosis and most other mycobacteria. ATP synthase is a critical enzyme in the ATP synthesis of M. tuberculosis. Binding of bedaquiline to the oligomeric and proteolipic subunit-c of mycobacterial ATP synthase leads to inhibition of ATP synthesis, which subsequently results in bacterial death.

Adverse effects

1. Increased risk of death: About 11.4% of patients taking Bedaquiline died during clinical trials compared with 2.5% of those taking placebos. As the drug carries some significant risks, it is mandated to be used only in patients who do not have other treatment options.

2. Cardiac arrhythmias: Bedaquline can affect the heart’s electrical activity causing prolongation of the QT interval, which could lead to an abnormal and potentially fatal heart rhythm.

3. Interactions with other drugs, especially lopinavir and efavirenz (used in the treatment of HIV), ketoconazole, as well as other drugs used in the treatment of MDR-TB (eg moxifloxacin, clofazimine) may be expected.

For these reasons, the WHO and the FDA have approved bedaquiline as part of combination therapy to treat adults with MDR pulmonary TB only when other alternatives are not available.


Approved indications for use (WHO recommendations)

Up to now, bedaquiline has only been approved for use in patients who have MDR-TB and when options to treat this condition using existing drugs have been exhausted (either all fluoroquinolone and/or all second line injectables and extensive drug resistant TB). The drug is to be given in addition to the multidrug treatment regimen recommended by WHO. Given the limited experience on its use, bedaquiline is recommended for use in adults affected with pulmonary (lung) MDR-TB. Special caution is needed when the drug is used in the elderly, in pregnant women, and in persons living with HIV who are taking antiretroviral medication. Bedaquiline should not be used to treat latent TB infection.


1. The use of bedaquiline in the treatment of multidrug-resistant tuberculosis. Interim policy guidance, World Health Organization. 2013

2. Bedaquiline:First FDA-approved tuberculosis drug in 40 years.Rajiv Mahajan. Int J Appl Basic Med Res.2013 Jan-Jun;3(1):1-2

3. WHO guidelines, Frequently asked questions, Bedaquiline available at http://www.who.int/tb/challenges/mdr

4. Press Information Bureau, Government of India, Ministry of Health and Family Welfare.

Fluoroquinolone use and the risk of aortic aneurysm

    Fluoroquinolones are well known to be associated with tendon rupture and this is attributed the antibiotics causing collagen breakdown. According to research from the University of Toronto, Canada, fluoroquinolone use is also associated with an increased risk of aortic aneurysm. A study of 1.7 million patients aged 65 years and over, published in BMJ Open (Nov, 2015), found that, within 30 days of finishing a course of treatment, patients who received fluoroquinolones were 2.2 times more likely to experience aortic aneurysm than other patients. The team concluded that according to the data, fluoroquinolone prescriptions can contribute acutely to aneurysm progression and rupture.

Inhaled steroids for asthma does not increase fracture risk

A systematic review, published in BMJ Open (Nov, 2015), found no association between inhaled corticosteroid (ICS) use lasting one to four years and fractures. Among 18 observational and randomized controlled studies involving patients with asthma, researchers found no link between ICS and the risk of fractures, nor with bone mineral density loss. Researchers say the findings should provide reassurance to prescribers.

Animal studies link painkiller use with infertility in females

Painkiller use in pregnancy may reduce fertility in subsequent generations, an animal study led by the Medical Research Council (MRC) centre for Reproductive Health at the University of Edinburgh and published in the journal Scientific Reports, has found. Preclinical tests in rats found that when a mother was given painkillers during pregnancy, her female offspring had fewer eggs, smaller ovaries and smaller litters of babies than those not exposed to the drugs. Exposed male offspring also had smaller numbers of cells that give rise to sperm in later life even though their reproductive function recovered to normalcy by adulthood. The effects of the drugs were seen within one to four days of the start of treatment. The study also demonstrated the effects in the subsequent generation of rats. The granddaughter rats of the experimental mother rat also had smaller ovaries and altered reproductive function.     This is probably due to the action on prostaglandins which are known to regulate female reproduction and control ovulation, the menstrual cycle and the induction of labour. The findings are significant, say the researchers, given the similarities between the reproductive systems of rats and humans. The team recommends that pregnant women should stick with current guidelines to use painkillers at the lowest possible dose and for the shortest possible time.

Is vitamin K different from vitamin K1?

What’s the difference between Vitamin K and K1? Vitamin K is a fat soluble vitamin and is generally used as a supplement; as antidote to drug induced hypoprothrombinemia; or prophylaxis and treatment of haemorrhagic disease of the newborn. Vitamin K works by promoting the hepatic formation of active prothrombin (factor II), factor VII, IX and X. Vitamin K formulations are classified into 5 subtypes (vitamins K1, K2, K3, K4 and K5) based on their source and/or method of preparation. Vitamin K1 is named as phytomenadione/phylloquinone and is prepared from natural sources. Vitamin K2 refers to a group of compounds (menaquinones) synthesized by bacteria in the intestinal tract. However, the amount synthesized does not usually satisfy the vitamin K requirement. The synthetic forms (water soluble) of vitamin K are vitamins K3 (menadione), K4 (menadiol) and K5. Menadiol is converted in the body to menadione. Since the synthetic water soluble forms (menadiol) do not require bile salts for absorption, they may be used for the prevention of vitamin K deficiency in patients with malabsorption syndromes in whom oral phytomenadione may be inefficiently absorbed. The fat soluble natural vitamin K (phytomenadione) is nontoxic even when large amounts are consumed orally and is recommended preparation for vitamin K supplementation. Though synthetic vitamin K (menadione) can cause toxicity and is not recommended to treat vitamin K deficiency, it continues to be used widely in developing countries like India because of less cost and easy availability. Most countries have switched to Phytomenadione since early 1950s when hemolysis due to high doses of menadione was reported. So, what’s the difference between Vitamin K and K1? Vitamin K may mean any one of K1 to K5. K1 is simply phytomenadione. CMC has Vitamins K1 in injection and tablet form and K3 only in injection form.

Confusion on keeping drugs cool is common

Patients are often confused by looking at the storage conditions mentioned on the product. The product pack recommended that the medicine to be stored in a cool temperature but not to be refrigerated. Proper storage of medications is always an important consideration during periods of extreme cold or heat. Here are few terms related to medicine storage and what they mean.

Store at 2 to 8°C: some products are very heat sensitive but must not be frozen. These are usually kept in the first and second part of the refrigerator (never the freezer).

Keep cool: store between 8 to 15°C (refrigeration is not required). In India, this may not be possible and hence may have to refrigerate them.

Store at room temperature: store at 15 to 25°C.

If storage condition not specified, store the medicine at controlled room temperature (15°C to 30°C).

Source: CMC Pharmacy Bulletin, a publication of the Pharmacy Service (DISH), CMC, Vellore.

Clinical questions – April 2016

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Responses to queries from readers

Myocardial Infarction

1. What is the difference between Troponin T and Troponin I? Which is a more reliable test in case of acute Myocardial Infarction?         Dr. V.L. Ganapathy, Bangalore, Karnataka.


Answer: Cardiac troponin I and T are components of the contractile apparatus of myocardial cells and are expressed almost exclusively in the heart. Hence, both the markers have high myocardial tissue specificity as well as a high clinical sensitivity. An increased troponin concentration is defined as a value exceeding the 99th percentile of a normal reference population [upper reference limit], a value defined by manufacturers.

Suggested reading: Direct comparison of high-sensitivity- cardiac troponin I vs. T for the early diagnosis of acute myocardial infarction. Available at http://eurheartj.oxfordjournals.org/content/ehj/35/34/2303.full.pdf



2. Does a HR of 114-120 require any medication or a just counseling and bed rest sufficient to reduce the HR? What are the best medications for hypertensive with tachycardia? Please give a guideline for treatment of hypertension with tachycardia. Dr. Jyothi Ganapathy, Bangalore, Karnataka.


Answer: Normal sinus rate is considered to be between 60 and 100 beats per minute. Heart rate above 100/min characterizes tachycardia. First step would be to differentiate between sinus tachycardia and other tachycardia such as atrial fibrillation or atrial tachycardia.

Sinus tachycardia is a normal physiologic response to exercise and conditions in which catecholamine release is physiologically enhanced or, less commonly, the parasympathetic nervous system withdrawn. A long list of other factors may be responsible such as generalized anxiety, fever, volume depletion, anemia, hyperthyroidism, stimulants (nicotine, caffeine etc), anticholinergic drugs, beta blocker withdrawal etc. It is important to rule out pathological causes.

Chronic inappropriate sinus tachycardia is an unusual condition that occurs in individuals without apparent heart disease or other cause for sinus tachycardia and is often a diagnosis of exclusion.

Sinus tachycardia will improve or resolve following treatment directed at the underlying etiology. Patients with symptomatic persistent inappropriate sinus tachycardia may be treated with beta blockers or ivabradine.

For hypertensive with tachycardia, always evaluate for secondary etiologies especially in young adult for conditions such as phaeochromocytoma and hypethyroidism. If secondary causes are ruled out, betablockers are ideal choice.

Suggested reading:

  1. NICE guideline available at https://www.nice.org.uk/guidance/cg127/chapter/1-guidance#choosing-antihypertensive-drug-treatment-2
  2. Inappropriate Sinus Tachycardia.J Am Coll Cardiol. 2013;61(8):793-801. doi:10.1016/j.jacc.2012.07.074
  3. What is the best approach to the evaluation of resting tachycardia for an adult? J Fam Pract. 2007 January;56(1):59-61.


3. What are the investigations and line of treatment to be given for a patient (middle aged) – diabetic and hypertensive, coming with chest pain?  How can you pinpoint if it is Myocardial Infarction?  Is Serum Troponin T sufficient to rule out any heart attack even if ECG is normal?       Dr. Jyothi Ganapathy, Bangalore, Karnataka.


When a middle aged patient with risk factors for coronary artery disease presents with chest pain, it is essential to have a stepwise approach for diagnosis regardless of the clinical setting (emergency or outpatient).

 The most common causes of chest pain in outpatient setting are musculoskeletal and gastrointestinal conditions, and approximately 2 to 4 percent have acute myocardial ischemia (including myocardial infarction). Nevertheless, initial diagnostic approach should always consider a cardiac etiology, unless other etiologies for chest pain are apparent. On the right is a table with differential diagnoses for chest pain.

The approach to patients with possible cardiac chest pain.
(William A Parsonage, Louise Cullen and John F Younger. Med J Aust 2013; 199 (1): 30-34.)

Patients who present with ACS (myocardial infarction and unstable angina) have anginal symptoms at rest, new onset angina that is not stable and predictable (eg, with exertion), or progressive symptoms (angina that is more frequent, longer in duration, or occurs with less exertion than previously). Symptoms that are described as pressure, tightness, squeezing, or indigestion or those that are similar to prior ACS events can be considered typical. Elderly and women are likely to present with atypical symptoms such as dyspnea, diaphoresis etc.

If the initial ECG is not diagnostic and the patient remains symptomatic with high clinical suspicion of ACS, it should be repeated at 5 to 10 minutes.

Myocardial infarction is diagnosed using following criteria from ACC/AHA (Third Universal Definition of Myocardial Infarction; Journal of the American College of Cardiology Volume 60, Issue 16, 16 October 2012, Pages 1581–1598):

Evidence of myocardial necrosis in a clinical setting consistent with acute myocardial ischemia. Any one of the following criteria meets the diagnosis for MI:

  • Detection of a rise and/or fall of cardiac biomarker values [preferably cardiac troponin (cTn)] with at least one value above the 99th percentile upper reference limit (URL) and with at least one of the following:
  1. Symptoms of ischemia.
  2. New or presumed new significant ST-segment–T wave (ST–T) changes or new left bundle branch block (LBBB).
  3. Development of pathological Q waves in the ECG.
  4. Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.
  5. Identification of an intracoronary thrombus by angiography or autopsy.

Patients who have typical symptoms, but with normal ECG and enzymes are labeled as Unstable Angina.

Answers provided by Dr. John Jose, DM (Cardiology), Assistant professor, Department of Cardiology, CMC Vellore.


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Your time is a treasure

Our days may come to seventy years,

or eighty, if our strength endures;

yet the best of them are but trouble and sorrow,

for they quickly pass, and we fly away.

Teach us to number our days aright,

that we may gain a heart of wisdom. Psalm 90

The Christ speaks to sadhu Sundar Singh:

    “Many there are who have wasted the precious time given to them for My service, but even now there is an opportunity for them to rouse themselves and make the best use of the time that remains to them. They are like a hunter who, while wandering in the jungle, picked up some pretty stones on the bank of a stream. Unaware of their value he used them one by one in his sling to shoot at the birds seated on the trees near the river, and so one by one they fell into the water and were lost.

    With one still in his hand he returned to the city, and as he passed along the bazaar a jeweller caught sight of it, and told the silly fellow that it was a valuable diamond for which he could get lakhs of rupees. When he heard this he began to bewail himself and say, “Woe is me! I didn’t know their value, and have been using many of these diamonds to shoot at birds by the riverside, and they have fallen into the river and are lost, otherwise I should have been a millionaire. Still I have saved this one, and that is something gained.”

    Every day is like a precious diamond, and though many priceless days have been wasted in the pursuit of fleeting pleasures, and are forever sunk in the depths of the past, you should awake to the value of what remains, and bringing it into the best possible use gather for yourself spiritual riches. Use it in My service, who have given to you life and all its priceless blessings, and by using them to save others from sin and death you will obtain an everlasting and heavenly reward.”

As for man, his days are like grass; he flourishes like a flower of the field;
for the wind passes over it, and it is gone, and its place knows it no more. Psalm 103:15,16

Be very careful, then, how you live—not as unwise but as wise, making the most of every opportunity, because the days are evil. And try to discern what is pleasing to the Lord. Ephesians 5:15-17

From ‘At the master’s feet’ By sadhu Sundar Singh



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MEDICAL NEWS – News from around the world

BMJ editorial recommends reforms in the MCI

    The latest editorial of the British Medical Journal contains a scathing report on the state of the Medical Council of India (MCI) and made recommendations to change the present situation. The report of a committee formed for this purpose lays bare the Medical Council of India’s (MCI) failure to oversee quality and integrity in health services in the country. In 2014, The BMJ launched a campaign against corruption that sparked global interest in the rampant practices of kickbacks for referrals, revenue targets in corporate hospitals, and capitation fees in private medical colleges in India. Recognising the erosion of trust in doctors and inadequacies of the existing health system, the committee makes far reaching recommendations to revolutionise medical education and healthcare in India.

    The editorial of ‘The Hindu’ newspaper reported – “It is a strange incongruity that in a democratic country with over 1.2 billion people, the systems of health-care delivery and medical education are poorly regulated, expensive, opaque and, by the government’s own admission, considerably corrupt. The report is a severe indictment of the Council and the Centre, for failing to stop the sale of medical seats in private colleges for capitation fees going up to Rs.50 lakh, and allowing a single, all-powerful agency heavily influenced by corporate hospitals to provide accreditation to institutions and assess their quality, ignoring blatant conflicts of interest. ”

Some of the recommendations by the BMJ for reform of Medical Council of India

  • Institutional mechanism for better distribution of medical colleges and bottom-up planning of medical staffing to tackle shortage of doctors and skewed urban:rural ratio
  • Nomination rather than election of members
  • Greater diversity through inclusion of non-specialists, academics, community health doctors, NGOs, and patient advocacy groups
  • Soft skills (including ethics) to be a cornerstone of medical curriculum
  • Regulation of fees charged by private medical colleges
  • Promoting postgraduate degree in family medicine
  • A new regulatory framework with the formation of a National Medical Commission with separate departments for undergraduate and postgraduate training, assessment and accreditation, and medical registration.

A radical prescription for the Medical Council of India.
BMJ 2016(Published 31 March 2016); 352, Editorial. The Hindu, 02/04/2016.

Government bans 344 fixed dose combinations

    The Indian Health Ministry, through a gazette notification on March 14th 2016, has banned some single drugs and around 344 fixed dose combination (FDC) drugs. This is a significant move since these are drugs that are widely available in the market and often over the counter. The ban, which comes into effect immediately, follows recommendations of an expert committee formed to examine the efficacy of these drug combinations.

Reasons for the ban:

  1. Many of these drugs are used “irrationally” and have no proven efficacy.
  1. There have been concerns over the safety of drugs that are added to the main drug in the combination. These ‘add-on’ drugs can potentially cause damage to the brain and psyche. There are several reports that cough syrups containing codeine are actually harmful to children and they do not really work. Besides codeine, these drugs often contain alcohol, naturally leading to a better night’s sleep for the child and hence, relieving the exhausted parent.
  2. Also, there were concerns about the abuse of these drugs, therefore these were considered unsafe for

    Besides these, very popular cough syrups containing Codeine Phosphate, Chlorpheniramine Maleate, 344 more such fixed-dose combination (FDC) drugs belonging to analgesics, antidepressant and psychotic condition segment were banned by the government.

Some of the single drugs recently banned in India are mentioned below:

  1. Weight loss drugs:
    Fenfluramine and dexfenfluramine: were used to treat obesity. However, they were withdrawn due to reports of diseases of heart valves, fibrosis of the heart and pulmonary hypertension. Sibutramine is a weight loss pill that has been recently banned since it caused heart related side effects.
  2. Astemizole and terfinadine: antihistamines that were used to treat allergies. They were banned since they could cause polymorphic ventricular tachycardia and even death when used in high doses or with drugs like erythromycin, clarithromycin and ketoconazole.
  3. Antidiabetic drugs: Rosiglitazone – It has been banned due to an increased risk of heart attacks.
  4. Rofecoxib and valdecoxib: popular painkillers that provided pain relief without causing gastric side effects. However, they were withdrawn due to concerns of heart attack and stroke with their use.
  5. Gatifloxacin: an antibiotic whose use as an oral and injectable drug has been recently banned in India. This is due to its risk for severe hyperglycemia in the elderly.

Sources: TNN, New Indian Express, medindia.net The full list of banned drug combinations is available at:


Facts you should know about Zika

The Zika virus infection has been making news over the last two months but how much do you know about it? Here are some facts.

  1. Zika was discovered incidentally in Uganda in 1947 in the course of mosquito and primate surveillance and had until now remained an obscure virus confined to a narrow equatorial belt running across Africa and into Asia.
  2. The Zika virus is transmitted by Aedes mosquitoes, especially Aedes aegypti, the same mosquito that transmits dengue, chikungunya and yellow fever.
  3. The virus originally circulated predominantly in wild primates and arboreal mosquitoes such as Aedes africanus and even in highly enzootic areas it rarely caused infections in humans.
  4. The ongoing pandemic confirms that Zika is predominantly a mild or asymptomatic dengue-like disease. However, data from French Polynesia documented a concomitant epidemic of 73 cases of Guillain-Barre syndrome and other neurologic conditions in a population of approximately 270,000, which may represent complications of Zika. The Brazilian epidemic of microcephaly, manifested by an apparent 20-fold increase in incidence from 2014 to 2015, has been linked by some public health officials to Zika virus infection in pregnant women. This association is yet to be confirmed by studies.
  5. Commercial tests for Zika have not yet been developed. Moreover, because it is closely related to dengue, serologic samples may cross-react in tests for dengue.
  6. The mainstay of management is bed rest and supportive care.
  7. There are no Zika vaccines in advanced development, although a number of existing flavivirus vaccine platforms could presumably be adapted, including flavivirus chimera or glycoprotein subunit technologies.
  8. Gene detection tests such as the polymerase-chain-reaction (PCR) can reliably distinguish the three viruses.
  9. Indian council of medical research (ICMR) has prepared itself to handle Zika virus outbreak in India. The samples received during the acute phase of the disease will be tested by RTPCR technique.
  10. Indian council of medical research (ICMR) has prepared itself to handle Zika virus outbreak in India. The samples received during the acute phase of the disease will be tested by RTPCR technique.

Source: Pharmacy Bulletin, Department of Pharmacy Services, CMC, Vellore.

Legacy interview – Dr. Mammen Chandy

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Legacy interview – Dr. Mammen Chandy

Bone marrow transplantation and Haematology in India

Dr. Mammen Chandy, an alumnus of the Christian Medical College Vellore, is a pioneer in the field of bone marrow transplantation in India. He was involved in setting up the first sustained bone marrow transplantation programme in the country, in Christian Medical College, Vellore in 1986. Despite initial hiccups, this programme has grown to become the most prominent stem cell transplantation programme in the country in terms of volume, research publications and training. The first bone marrow transplant for Thalassemia in the country was done in CMC Vellore and the Hematology department that he founded has contributed to the training of many of the hematologists in India. After his retirement from CMC, he took over as the director of the Tata Medical Center, Kolkata, where he has set up a bone marrow transplant unit as well. In a candid interview he traces the genesis and growth of the bone marrow transplant programme in CMC Vellore and explains the processes involved in a transplant.

Tell us a little bit about yourself. How did you decide to specialise in hematology?

I joined CMC in 1967 and graduated in 1972, after which I did my sponsorship obligation in Christian Fellowship Hospital, (CFH) Hospital, Oddanchatram for 2 years. Following this I realized that I wanted to do medicine and joined the MD Medicine post-graduation programme in 1975, at Christian Medical College, Vellore. During my undergraduate period, the department of Clinical Pathology had what I would still consider one of the best teaching modules in Hematology. There were brilliant lectures by very eminent personalities like Dr. S.J. Baker, Dr. Cyrus Kapadia, Dr.Robert Carmen, and Dr. A.B.A. Karat. Each lecture was followed by a practical session for two hours. This was absolutely formative in creating a desire to do hematology, even as an undergraduate. This shows that a well structured undergraduate teaching programme can influence an individual, even at that early stage in his life to make a career choice.

While doing my MD post-graduate course, I was involved in treating patients with hematological malignancies like leukemia. I noticed that the treatment of patients with Acute Myeloid Leukemia (AML) in CMC was very inadequate and was not backed by research. The treatment administered was more out of a sense of compassion and duty than based on scientific rigor. This was when I decided that hematology was the field of medicine that I would like to specialize and work in.

Following my MD, I joined the Department of Medicine 1 in CMC as a consultant. At that time, the office of the division of Medicine consisted only of a small room for the secretary and three 4 x 7 feet rooms for consultants. While working there, I looked after hematological patients as well because the unit had a tradition of Hematology teaching by Dr. S.J. Baker who worked in the WELLCOME laboratory. He was an Australian physician working in CMC and was the one who conceived and developed India’s National Anemia Programme in association with Dr. Ramalingaswamy. After working for about a year, I realized that I needed some specialised training in Hematology. However, there was no formal course in clinical hematology in India at that time. With the help of Dr. B.M. Pulimood, I joined the Hematology and Pathology fellowship in Westmead Center, Sydney, Australia and was trained by Dr. Peter Castaldi, who was an eminent hematologist at that time. After completing the fellowship, I returned to Vellore and joined the Department of Medicine 1 in CMC.

    I was initially given one intern to help me. Thus in 1984, the intern and me in one 7 x 4 feet office constituted the Department of Hematology nested within THE Medicine-1 unit. Later on, I was given a small room in the outpatient department to do bone marrow biopsies. The first bone marrow trephine biopsy was done using a Jamshidi bone marrow needle donated by a patient. Initially I began, by seeing general medicine cases along with hematology cases, then slowly restricted myself to only hematological cases. In the beginning, no one would refer hematology cases to me. There were informal queries on management of some cases by post-graduate registrars but no formal referrals. It took some years before hematology cases were referred to me.

I have noticed that when young doctors come back after having studied something new elsewhere, they are often impatient to put their new-found knowledge into practice. My advice to them would be to wait and give it some time. Just keep doing good work quietly and you will surely be noticed and will be able to find enough work to keep you satisfied. After the initial slow start, we found that we were overwhelmed with work and patients were being referred to us even for management of iron deficiency anemia. Gradually, other clinicians who had specialized in hematology joined me and we formed a small team. This was how the Hematology department started and grew. About 5 years after I finished my hematology training, the Department of Hematology was formally inaugurated as a separate unit in 1986.

The concept of component therapy

    When I came back from Australia, I realized that if I wanted to start a new division of Hematology, I would need the help of several other people. Unlike a plastic surgeon who only needs an anesthetist to do his job, a hematologist needs the support of numerous other specialties. The most important of these is the Department of Clinical Pathology. We had an excellent department in CMC Vellore and they formed a good bedrock which supported the growth of the Hematology department. I also needed a good blood bank which would provide the blood components required. In those days, in CMC, blood was still collected in bottles and was not separated into its components. When I introduced the concept of component therapy, I was met with resistance and I realized that I would have to teach and persuade clinicians to use components like plasma, platelets and packed red blood cells rather than whole blood. I started this process by conducting regular academic sessions in the department of Anesthesia (as they used about 75% of the blood from the Blood Bank), showing them for example, that a person who needs two units of whole blood for low hemoglobin would only need two units of packed RBC – the plasma and platelets were not necessary. These components could be used for other patients who needed them. I was successful in getting them to understand, accept and support this. The Blood Bank was the next in line to be convinced of the rationale and utility of blood components.

    The first patient who helped us realize the importance of blood components was a person with Hemophilia who was bleeding from his gastrointestinal tract. Everyone assumed he was bleeding because he had Hemophilia but I rejected this idea because I reasoned that if his Hemophilia was the cause of the bleeding, then he should be bleeding into his joints and other regions as well. I got a gastroenterologist to do an endoscopy on him and he discovered a large Arteriovenous malformation in his gastro-duodenal region – this was why the patient was exsanguinating. To resect this lesion, he would require surgery and there was no Factor VIII available at that time to provide cover during the surgery. The only way we could stop the bleeding was by transfusing a large volume of fresh frozen plasma (It is not possible to transfuse 100 units of whole blood to provide the necessary plasma). In order to do this, we organized 100 medical students and collected blood from them in the blood bags that I had brought back from Australia in my luggage. We then separated the blood into fresh plasma and packed RBC’s. Under the cover of the fresh plasma, Dr. Sitaram and Dr. Prakash Khanduri operated and removed the malformation. The patient is alive today. The case was reported in the Annals of the British Journal of Surgery.

Was the plasma frozen at that time?

    No, we used it as fresh plasma; it was not frozen. This was in 1985. The patient’s total protein went up to 22 gm% but he survived. After this case, the programme took off and today about 99% of blood collected is separated and used as components rather than as whole blood.

Further progress

Once the help of the Clinical Pathology department was harnessed and the blood component programme was initiated, the next step was to develop an HLA laboratory because HLA typing is essential for matching patients for a bone marrow transplant (to see if the donor and recipient are compatible). We were, at that time, sending our samples for HLA testing to a laboratory in the Madurai Kamaraj University where a gentleman with several publications in the field of HLA did the HLA typing for us. To verify the results, I sent the third HLA typing sample that he had sent me, to Australia as well, and the report I received from Australia was that the HLA typing was totally wrong. That particular patient did not survive the transplant. Through Mrs. Pulimood, we therefore invited Dr. Paul Ichiro Terasaki who was a world authority on HLA typing at that time and we had a workshop in Vellore. After this, the blood bank in CMC started doing HLA typing and we had access to reliable HLA typing for the transplant programme.

The Bone marrow transplant programme

When I was in Australia, throughout the period of my training, I was constantly looking for things that I could apply in CMC Vellore, in order to set up a bone marrow transplant unit there. After I came back to Vellore, I approached the Director, Dr. LBM Joseph if I could use two rooms in the private ward for setting up a bone marrow transplant unit. He was gracious enough to grant me the use of the two revenue earning rooms. Once we had the rooms, we started trying to set up a HEPA filtration system for the transplant room. I was naïve; the training abroad does not equip you with engineering knowledge on how to set up a transplant room. Sister Anne Bothamley, who had been trained as a transplant nurse in the Royal Marsden hospital in the U.K, was a great help in this. She also helped in developing and training nurses to look after the transplant unit. In this way, we somehow cobbled together a transplant unit. It constituted of two rooms, with an entry and changing room and a small nursing station. This was the first bone marrow transplant unit and we started the bone marrow transplant programme in 1986.

The first patient

Before the first human bone marrow transplant, we harvested bone marrow on dogs in the Pharmacology Department, just to make sure that we were doing things right. We anesthetized dogs, harvested bone marrow and standardized procedures to ensure that the sample did not clot and was suitable for transplant etc. This helped in reducing the apprehensions regarding the actual harvest.

    The first patient that I took up for transplant was a 26 year old man named Antony from Kerala with Acute Myeloid Leukemia with multiple relapses. He had given up all hope and was ready for anything. We performed the first bone marrow transplant on him; he survived for about 2 weeks and finally died of severe pseudomonas septicemia. This patient taught me several things. The most important lesson was regarding gut sterilization. In Australia, I had learnt that gut sterilization with antibiotics was important before a transplant, but what I realized was that this only killed the drug-sensitive bacteria and allowed the resistant bacteria to survive. Now I do not do gut sterilization in Indian patients.

When was this bone marrow transplant done and was it the first in India?

This was in 1986. Bone marrow transplant was an established procedure in the Western world; it had been in existence for 20-30 years before this. In India, the first allogenic bone marrow transplant was done by Dr. S.H. Advani in Tata Memorial Hospital, Mumbai and CMC Vellore was probably the second. We in CMC, were the first to do a bone marrow transplant in a patient with Thalassemia, and this was the first institution to have a sustained bone marrow transplant programme in the country. The transplant programme in Vellore is the most active one of its kind in India and more than half of the bone marrow transplants in India are done in CMC Vellore.

The second transplant

The second transplant was done on a girl child from Orissa with Chronic Myeloid Leukemia (CML)who had a twin sister (monozygotic twin). The twins were born in a mission hospital in Orissa and their mother died in childbirth. The babies were adopted by the missionary couple who ran the hospital and one of them developed CML. She successfully survived the transplant but subsequently relapsed later.

Disaster, despair and hope

The third transplant was on a person who had acute leukemia, who died because the HLA typing was wrong (the one referred to earlier). This was a disaster. After the third transplant patient died, we were really, really depressed. The nurses were so involved in the programme that they were actually crying. I still remember we were cleaning up the unit (doctors joined in cleaning duties those days), when Dr. Pandey, the head of Nephrology, from the Renal transplant unit just opposite to our unit, walked over and met me. He put his arm around my shoulder and said, “Don’t give up. If you need more money, I will support your programme from the Nephrology fund if necessary, just don’t give up.” This was a great encouragement to us. We continued our work and subsequent to the third transplant, we never looked back and went from strength to strength.

Growth and Development of the Hematology department

As we were expanding the bone marrow transplant programme, I realized that in order to ensure the enduring success of the programme, we would need more research. Dr. Dennison and Dr. Alok Srivastava who were working with me at that time suggested that we should develop a molecular genetics laboratory for blood diseases. They felt that was the only way to move forward. So we approached the Indian Institute of Science and they agreed to train a technician for this purpose. However, when our technician went there, he was asked to sit outside with a book and was not allowed into the laboratory to learn techniques. At that time while at a meeting in Bombay, by serendipity, I met Dr. Krishnamurthy, a research director from the INSERM Laboratory in Paris. After the meeting, he approached me and offered to help me in any way he could.

At that time Dr. Poonkuzhali from Vellore had been working on a research project as part of her Ph.D.to develop an assay to measure Busulfan levels in blood (which is a key agent in preparing a patient for a transplant). Bio-RAD had promised to develop this assay for us but were not able to, so she was sent to Dr Ehninger’s lab in Dresden, East Germany but the results using a published method in his lab proved to be wrong when the same samples were analyzed in the INSERM laboratories in Paris ( with the help of Dr. Krishnamurthy). With the help of Dr Eileen Jaques in Paris she developed an assay for measuring Busufan levels using HPLC. She came back and successfully established the assay in Vellore.

At that time, we had also hired Dr. Shaji to work in the laboratory as a research scientist and he went on to finish his Ph.D. He was very good with techniques and was sent for training to the USA to work with Dr. John Cunningham (who was the head of the molecular biology laboratory in the University of Chicago). He was so good that, during his training, he was offered a tenured position in Chicago. He however, chose to come back to Vellore. Today we have a well established and active research programme in CMC Vellore which has trained many Ph.D students, and which provides a wide range of diagnostic molecular biology tests for blood disorders. I don’t think there is any other department in the country that does this.

DM Hematology

The next step was to start a DM programme in Hematology because there was no formal post graduate training course in this subject in India. So we set up a programme and applied for recognition. A person from Delhi came over for inspection and told us that we could not have the programme. So I replied with a six page rebuttal to the Directorate General of Medical Education, New Delhi, explaining why that assessment was incorrect. I went to Delhi and had a chat with the Director General who said he could grant permission, but wanted another assessment, this time by a person of my choice. The person who I chose said that an assessment was not necessary and was willing to sign the papers even without an assessment, but I insisted that he come: we had another assessment, a report was sent back, and permission was granted for the DM Hematology course, which I believe is the best training course in Hematology in the country today. Dr. Vikram Mathews was the first DM candidate and he is currently the head of the department in CMC. Over the years we have trained many of the hematologists in the country.

What are the notable features of the Hematology department in CMC Vellore and what were the contributions of this department over the years?

    The hematology programme in CMC Vellore is most prominently known for stem cell transplantation. We have completed around 2000 stem cell transplants. We are the largest and most active transplant center in the country and we have contributed significantly to the science of transplant in the world in terms of research publications.

    Second, we are known internationally for the Hemophilia work that is being done here in association with the laboratory in the Transfusion Medicine department, with the Physiotherapy and Orthopedic departments and Dr. Alok Srivastava is spearheading the programme. Today, we are recognized internationally as a Hemophilia reference and training center.

    Under the stewardship of Dr. Vikram Mathews, we are recognized internationally as one of the centers advancing research in Promyelocytic Leukemia. We are also actively contributing to the science and research of Thalassemia through our Thalassemia programme.

    In India, CMC is at the forefront of research and diagnostics in the field of molecular genetics in Leukemia, looking at the various aspects of this

disease. As mentioned earlier, the first bone marrow transplant in Thalassemia was done in Vellore and we have the largest and most active transplant programme in India in terms of training, service and research. In terms of sheer volume, CMC has the most active transplant programme – we do about 10 allogenic and 8 autogenic transplants a month while most centers do about 3 to 4 transplants every month.

Which are the other centers in India where bone marrow transplants are done and what was the role of CMC Vellore in this?

    Bone marrow transplantation was started in Tata Memorial Hospital, Mumbai, but for some reason, the programme never took off initially. CMC Vellore was the second place to start transplant. This programme went on to become the most prominent contributor to bone marrow transplantation in India in terms of volume, training and research. Subsequent to this, the Bombay center started its transplant programme again.     Today bone marrow transplantation is done in other centers as well – in AIIMS, New Delhi, Narayana Hridalaya in Bangalore; there are three centers in Pune and also in many of the corporate hospitals like Apollo hospitals around the country. Many of the hematologists practicing in these centers have had training in CMC Vellore. In the promotion of the science and training in bone marrow transplant, I think CMC Vellore has played a much more important and prominent role than other centers.

What do you think are the possibilities for research in a peripheral medical center? What does it involve and how feasible is it?

    For most of us, research is conceptualized as some scientist sitting in a laboratory doing experiments with test tubes and high-tech equipment. That is a wrong understanding of research. I think research consists of fundamentally three steps 1) analyzing what you are doing: what are you doing in your center for a particular problem? This involves collecting data, documentation, looking at your results and then making a conclusion about what you are doing. 2) The next step is to look at results of research from other centers all over the world and compare it with what you have done. 3) Finally, done with your research and having understood the issue, you work towards applying what you have learnt practically in your context and then make it known to the world. To me that is clinical research and it is possible in any setting whether primary, secondary or tertiary. The tools required for this are dedication to clinical care, measuring and collecting data, analysis of the data and making a conclusion. For example, if you are in Orissa, you probably know the mortality rate due to cerebral malaria. Now, if you perform certain interventions, how much of a difference does it make to the mortality rate – that is research, and it is very feasible as long as you set your mind to it.

Looking back, why did you decide to come back to Vellore after your training abroad?

     I was pretty sure that I would continue working in CMC Vellore after my training.. When I did my undergraduate training in Vellore, there were enough stories of inspiration that made me feel that this was the best place to work. Looking back after retiring from CMC, I am absolutely sure that the choice was right and I wouldn’t have wished it any other way. The immense satisfaction of being able to set up something that was relatively new and making a contribution to this great institution is something that will always be there with me. I don’t think there was any desire to stay back in Australia during my training. The satisfaction of contributing something to your own countrymen, where you are valued much more, is something you will not get by working abroad.

Why do you think you were able to do what you did, while in CMC?

    I think, I was able to do what I did because I enjoyed what I did. At no point of time did I feel that I was ‘sacrificing’ anything to work in Vellore. Anyone who feels that he is giving up a lot to work in a place like Vellore is not correct; he or she should in fact consider it a special privilege. If you enjoy what you do you will go far, and things will work out. Hematology as a discipline enjoys one advantage, in that it involves a lot of molecular biology and genetics. So many cutting edge technologies come quickly into clinical practice, so there is a lot of excitement.

The Hematology department today

The Hematology department in CMC Vellore currently sees about 1200 new outpatients every year and admits about 700 patients every year for inpatient care. These patients come from all over India and cover the whole spectrum of blood diseases. About 30 autologous & 80 allogenic bone marrow transplants / stem cell transplants (SCT) are done annually. The post-graduate course in hematology (D.M.) started in 1999 for the first time in India remains a highly sought after course in the country. The department also offers Ph.D. programmes and post-doctoral fellowships in Molecular Hematology. It remains in the forefront of research in Hematology in the country with significant publications in the field of stem cell transplant, Thalassemia, Leukemia and hemostasis/thrombosis. After his retirement from CMC Vellore, Dr. Mammen Chandy took over as the director of the Tata Medical Center, Kolkata, where he has set up a bone marrow transplant unit as well.


Could you describe in simple terms, the steps involved in a bone marrow transplant?

  • The first step is to identify the person with a hematological problem which cannot be cured by an easier, simpler method. For example, consider a 25 year old person with severe bone marrow failure and an absolute neutrophil count of less than 200, his best chance of survival is with an allogenic bone marrow transplant.
  • The second step is to find siblings or relatives or others who can be potential donors.
  • The third step is HLA typing to match a potential donor to the patient and determine if both are compatible. If a donor’s HLA type is compatible with that of the recipient, the chances of successful implantation of the graft are high.

Conditioning the recipient

Once a HLA matched donor has been identified, the patient is prepared for the bone marrow transplant. A Hickmann catheter is inserted for continuous venous access and the person is conditioned. Conditioning does two things – 1) it destroys the immune system of the recipient so that the graft is accepted and 2) it creates the space for accepting the grafted bone marrow. Today we know that it is not necessary to create space; suppression of the immune system is enough. This process of conditioning is done using certain drugs which destroy most of the hematopoietic cells in the bone marrow.

Stem cell harvesting

The stem cells of the donor are then harvested. One way of doing this is to collect cells from the bone marrow of the donor. This is done in the operating theater under strict aseptic conditions. The bone marrow cells are aspirated from the iliac crest or other suitable sites into a collecting bag. We collect enough aspirate to obtain 300 million nucleated cells/kg of the recipient – this contains enough stem cells for the transplant. This material is obtained through multiple punctures (an average of 60-70 punctures) into the iliac crests on both sides. Three to four ml of aspirate is taken after each puncture; beyond that we would only obtain sinusoidal blood.

The other more elegant way of doing this is through a peripheral blood stem cell transplant. This is done by giving the donor a growth factor (G-CSF) SC daily for four days. This growth factor pushes the stem cells into the peripheral blood. The donor’s blood, which is now rich in stem cells, is collected in a bag using a cell separator which selects only the mononuclear cells and returns the rest of the blood back to the donor. The disadvantage with this procedure is that there are more T cells in this graft and so there is a slightly higher rate of graft vs. host disease.

Infection control measures

The patient who is being conditioned and transplanted is very prone to infections because he is immune-suppressed. To reduce the risk of infections as far as possible, certain precautions are followed. The patient is placed in a HEPA filtered room breathing only filtered air, is given only pressure-cooked food and drinks only filtered water. Even the water he uses for a shower goes through a 0.3 micron filter. The sheets are autoclaved and the doctors and nurses wear autoclaved garments. HEPA (High Efficiency Particulate Air filter) is a system that filters air through a 0.3 micron filter to prevent air-borne viruses or fungi from entering the room. The process of conditioning takes around 8 days and during this period drugs that destroy his immune system are administered. On the 8th day, stem cells from the bone marrow of the donor are collected.

How do you know that the patient has been adequately conditioned and is ready for the transplant?

There is no technology to tell us that. We do not do a bone marrow biopsy to see if the bone marrow is empty. We just assume that the drugs have worked and the patient has been adequately conditioned for the transplant. The bone marrow is usually never completely empty – that takes time, but 8 days of conditioning is sufficient for accepting the graft.

The transplant

Now the stem cells collected from the donor are infused into the recipient just like a blood transfusion. The miracle is that the stem cells have little molecules on their surface that make the cell home into the bone marrow and soon latch on to the remaining stroma of the bone marrow. These molecules are called adhesion molecules (they were called addressins or ‘Mecca molecules’ earlier) and the stem cells latch on to the niche or nest of cells in the bone marrow composed of adipose cells, osteoblasts and fibroblasts. These ‘niche’ cells are not destroyed by the conditioning process.

Post- transplant period

Once the transplanted stem cells establish themselves in the bone marrow, the peripheral blood counts start going up. This takes about 2 weeks and during this period, the patient is a sitting duck for infections of all kinds because he has no cells to confer immunity. During this period, the patient will therefore require several blood components like packed red blood cells and platelets. His white cell count would be almost zero if he got an infection and he would require several antibiotics and anti-fungal agents to combat the infection.

Graft vs. host disease / Graft vs. Leukemia

Once the graft has been accepted and the peripheral blood counts start increasing, the possibility of graft vs. host disease becomes a concern. By doing HLA typing we assume that the donor and the recipient are immunologically compatible; however, we are only looking at the tip of the iceberg. There may be several other molecules which the donor cells consider as foreign and this leads to the graft cells attacking the cells of the host. The skin, the liver and the intestine are the commonly involved organs. There are grades of graft vs. host disease from 1 to 4. If you have grade 4, your skin looks like you have had a third degree burn all over your body. The patient may have diarrhea, jaundice and other symptoms.

Today we abort graft vs. host disease using cyclosporine and methotrexate and it is rare to see grade 4 disease. The commonly seen grades are 1 or 2. This is good because it is the immunological differences between the recipient and the host cells that help to kill the remaining leukemic cells. Chemotherapy is not the only way the marrow is cleared of leukemic cells. This is called Graft vs. Leukemia reaction. The immune system of the donor helps in preventing a relapse of the disease. This is why in a transplant between two identical twins, the chances of relapse are high in case of malignancies – because of a lack of this Graft vs. Leukemia reaction. This is usually not an issue if transplantation is done between twins for bone marrow failure.

Today, most bone marrow transplants for malignancies are done using peripheral blood stem cell transplant because the Graft vs. Leukemia reaction is desirable. This process is also technically easier and approximately 3 out of 4 transplants are done using this method even though there is a slightly higher chance of Graft vs. Host disease.

Autologous transplants

Autologous bone marrow transplant is a mode of therapy for malignancies. Here the patient’s own stem cells are collected, his bone marrow is killed using chemotherapy and the collected stem cells are re-infused back into his system. This type of transplant can be used for lymphomas and myelomas and they are fairly effective. Here there is no risk of graft vs. host disease with autologous transplants.


Following a transplant, the patient is kept on immunosuppressant agents for about 6 months. Unlike a renal transplant patient who has to be on immunosuppressant agents for his entire lifetime, the drugs are tapered after 6 months and by one year almost all patients who have had a bone marrow transplant are off immunosuppressants. Children with Thalassemia can now go to school; they need no transfusions – they can lead a normal life.



PDF Version


Case 1

A 60 year old male presented with 3 month history of low grade, intermittent fever, dry cough, loss of appetite, and significant weight loss (since 2014). He was diagnosed to have HIV infection 6 months earlier. On general examination he was found to have oral candidiasis and multiple enlarged, non- tender cervical lymph nodes. His respiratory system examination revealed right supra clavicular bronchial breath sounds. This is an image of one of his nails (similar finding was seen in all the nails in both hands).


  1. Describe the nail finding? What is this called?
  2. What is the pathology behind this line?
  3. What are the conditions that may present with this finding?
  4. Name some other similar nail findings?

Case 2

A 39 year old male presented with history of generalized weakness for 1 1/2 years, significant weight loss of 20 kgs over 1 year and hyperpigmentation of skin. He is a known case of diabetes mellitus. These are his CT abdomen images.

CT abdomen axial post contrast showing bilateral enlarged adrenal glands with heterogeneous enhancement and central necrosis. No calcific focus.

CT abdomen coronal section showing bilateral enlarged adrenal glands


1. What are the top three differential diagnoses for the above findings?

2. How will you confirm etiological diagnosis?

3. What is the treatment for this disease?

Case 3:

A 20 year old lady with rheumatic heart disease (severe mitral stenosis, moderate mitral, aortic and tricuspid regurgitation), presented with history of sudden onset left hemiparesis associated with an left upper motor neuron type facial paresis side and slurring of speech. She had been on oral anticoagulation along with digitalis and verapamil for controlling ventricular response in atrial fibrillation. Cardiovascular examination revealed a mid-diastolic and pan-systolic murmur in the mitral area and ejection systolic murmur in the aortic area. A plain computed tomography of the brain showed an infarct in the right parieto- temporal region. An electrocardiograph (ECG) during hospital admission is shown above.


1. Describe the ECG finding? What is this ECG sign called?

2. Does this sign indicate digitalis toxicity? When should I suspect digitalis toxicity?

3. What is the appropriate line of management?


Answers to CME in images

Case 1

  1. Symmetric, narrow white transverse bands parallel to the lunula separated by normal pink nail. It is called Muehrcke’s line. These lines typically disappear on blanching and do not move with nail growth.


2.  The pathology behind this line: These are areas of hypopigmentation which are not palpable. [1] These changes occur in the vascular nail bed following chronic hypoalbuminemic states (i.e, albumin level less than 2 g per dL) and disappear when the protein level normalizes.(2)

3.  This finding may be seen in patients with chronic hypoalbuminemic states like nephrotic syndrome, chronic liver disease, and chronic malnutrition.

  This patient’s chest x-ray showed miliary mottling with right upper zone consolidation. Tuberculosis was confirmed by Xpert TB PCR and culture from his lymph nodes. At the time of admission his CD4 count was 64 cells/microL. Liver function tests showed an albumin of 1.5 and total protein of 4.2. He was initiated on weight based ATT.

4. Other similar nail signs: Beau’s lines and Mees’ lines (1)

How does one clinically differentiate between these lines? Beau’s lines are deep grooves and have actual ridges and indentations in nail plate which make them palpable. Mees’ lines, unlike Muehrcke’s lines do not disappear on blanching. As Mees’ lines represent changes in the nail plate they move with the growth of the nail whereas Muehrcke’s lines do not move with nail growth.3


1. Sharma V, Kumar V. Muehrcke lines. CMAJ Can Med Assoc J. 2013 Mar 19;185(5)

2. Short N, Shah C. Muehrcke’s lines. Am J Med. 2010 Nov;123(11):991–2.

3. Huang T-C, Chao T-Y. Mees lines and Beau lines after chemotherapy. CMAJ Can Med Assoc J , J Assoc Medicale Can. 2010 Feb 23;182(3)

Case contributed by Ajay Kumar Mishra (Department of General Medicine), Anu Anna George, (Department of Dermatology, Venereology and Leprosy), Christian Medical College and Hospital, Vellore

Case 2

1. Three differential diagnoses: 1) Tuberculosis, 2)

Histoplasmosis, 3) Metastasis.

Other rarer differentials are non Hodgkin’s lymphoma, Amyloidosis, Neoplasias such as bilateral pheochromocytoma and adrenocortical carcinoma.

2. Imaging wise, presence of calcification in the mass would point to infective etiology such as tuberculosis or Histoplasmosis. In India, where tuberculosis is still rampant, the first imaging differential diagnosis with the given history would be disseminated tuberculosis; however differentials diagnoses such as disseminated histoplasmosis needs to be considered. Definite diagnosis can be attained by CT guided fine needle aspiration.

    In this case, fine needle aspirate cytology showed periodic acid Schiff positive rounded structures consistent with Histoplasmosis. The final diagnosis is disseminated histoplasmosis.

    Hematogenous dissemination occurs in most patients during the acute infection before cellular immunity develops. Disseminated disease occurs in approximately 1 in 2000 patients with acute infection. Most patients who develop disseminated histoplasmosis are immunosuppressed ( eg. AIDS, solid organ transplantation, treatment with tumor necrosis factor – alpha inhibitors) or are at the extremes of age. In addition, chronic progressive disseminated histoplasmosis occurs rarely in older adults with no known immunosuppressing conditions. This patient had diabetes mellitus.

3. The treatment for disseminated histoplasmosis includes Antifungal agents (Ampotericin B, atraconozole, Fluconozole) and corticosteroids for hypocortisolism

Case contributed by Dr. Hannah Khiangte, Department of Radiodiagnosis, CMC Vellore

Case 3

  1. Rate: Ventricular rate 80-120 beats per minute, Rhythm: Irregularly irregular with absent P waves, varying RR intervals, QRST morphology: ST segment depression with downward sloping pattern, flattened or inverted T wave, left ventricular hypertrophy by voltage.
    This ECG sign is called as the “Reverse tick” sign or “Reversed check mark” sign(1). (See image on right) The ST depression is asymmetric and down sloping and has a characteristic sagging, coved, or scooped appearance.
    2.  Does this sign indicate digitalis toxicity? When should one suspect digitalis toxicity?

    This finding is the typical
    “digitalis effect” on ECG and is not an necessarily an indicator of digitalis toxicity.(1,2). If this ECG finding is present and if the patient also has clinical features of toxicity, then one must consider the diagnosis of digitalis toxicity. The clinical features of digitalis toxicity can be divided into non-cardiac and cardiac. Non cardiac complaints would include nausea, vomiting, vision changes, seeing green or yellow. Nonspecific gastrointestinal symptoms can also be seen in more than 30% of patients.(4) Cardiac complaints can include palpitations and chest pain. Once suspected, an ECG is done in order to confirm the same. Serum digitalis levels can be measured 6 hours after the last intake of the drug, if available. (4)

        Risk factors for digitalis toxicity: Older age [>70 years], female sex, low lean body mass, chronic renal failure and hypokalemia.(3,4) This patient had a lean body mass but her serum potassium was 3.7 mmol/L and her serum creatinine was 0.7 mg%.

    3.   What is the appropriate line of management? In case of the presence of significant T wave inversions or arrhythmias, digitalis has to be stopped. Serum potassium and creatinine has to be measured and corrected as necessary. In the absence of refractory, life threatening arrhythmias, severe hyperkalemia and/or haemodynamic instability, the use of digoxin antibody Fab fragments have no role.(4) In our patient, digitalis was withheld in view of the presence of risk factors and baseline neurological deficits. Her management was optimised with anticoagulation and ventricular rate control with calcium channel blockers.


    1. Cheng TO. Digitalis Administration: An Underappreciated but Common Cause of Short QT Interval. Circulation. 2004 Mar 9;109(9)

    2. Heather Wetherell. Digoxin and the heart. The British Journal of Cardiology. Available from: http://bjcardio.co.uk/2015/08/digoxin-and-the-heart/

    3. Lip GY, Metcalfe MJ, Dunn FG. Diagnosis and treatment of digoxin toxicity. Postgrad Med J. 1993 May;69(811):337–9.

    4. Yang EH, Shah S, Criley JM. Digitalis toxicity: a fading but crucial complication to recognize. Am J Med. 2012 Apr;125(4):337–43.

    Case contributed by Dr. Ajay Kumar Mishra (Department of General Medicine), Christian Medical College and Hospital, Vellore.

Medicine and law- april 2016

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& The Law

‘Medicine and the Law’ is a forum where readers can ask questions pertaining to legal issues they may face during the course of their medical practice. The answers and clarifications are have been kindly provided by D. Samuel Abraham, (M.A., B.L., M. Phil., PGDPM), Legal Advisor to Christian Medical College, Vellore.

Q1. A female patient has come with an allegation against the management stating that she is pregnant in spite of the tubectomy done in 2010. She had caesarean section done for her first and second delivery following which she had got tubectomy done. This was done by a visiting consultant from another unit. We had charged 6000rs and had given 2000rs charity as well  (mentioned in the card). She and her husband are both frustrated  and don’t want any more children. They say they are not willing to raise up the 3rd child. Her brother is a lawyer who  is claiming compensation. Please give us your advice.

Answer: In a recent judgment of the National Commission titled as Parivar Seva Sanstha & Ors. V/s Jagdish & Ors, the Hon’ble National Commission had held that “merely because a woman who has undergone a sterilization operation becomes pregnant and delivered a child, it does not make her entitled to compensation on account of unwanted pregnancy or unwanted child. Any claim in such types of cases can be sustained only if there was negligence on the part of surgeon in performing the surgery and not on account of child birth. A similar view was taken by Hon’ble Supreme Court in the case titled State of Punjab V/s Shiv Ram &Ors. (2005) . The Hon’ble Supreme Court in this case had said that, proof of negligence shall have to be provided. Failure of a surgery due to natural causes would not provide any ground for a claim. Having understood that conception has occurred in spite of the sterilization operation, if the couple opts for bearing the child, it ceases to be an unwanted child. Compensation for maintenance and upbringing of such a child cannot be claimed.

Perhaps her husband’s brother who is a lawyer would have relied upon the Judgement and order of the Supreme Court of India in State of Haryana Vs Smt . Santra which was delivered on 24.4.2000 wherein the Supreme Court held that if there is a new born after tubectomy performed for a woman, automatically it would be viewed as negligence on the part of Medical Professionals. However we wish to make it clear that this judgement has been overruled by the Supreme Court of India in State of Punjab V/s Shiv Ram &Ors case.

    Therefore, you can point out this and need not worry till you receive any summons or notice from Judicial Forum. In Court also, only the complainant has to prove that there is negligence on the part of the Medical Professionals, on successful submission of proof followed by a judicial order, the question of payment comes; there also appeal provision is there. Do not worry now.


Q-2 If a doctor refuses to treat a patient or forcefully refers to another hospital for some reasons (perhaps because the patient cannot afford treatment or patient is not cooperating or lack of treatment systems or because the doctor is not confident with treatment), is it liable for legal action against doctors? What are the legal issues if the doctor is practicing at home without registering his clinic?

Answer: 2 (A) If the Patient is in emergency condition, then the Doctor should try to resuscitate the patient from the emergency condition with his/her competence. As per rule 2.4 of Code of Medical Ethics, 2002, “A physician is free to choose whom he will serve. He should, however, respond to any request for his assistance in an emergency. Once having undertaken a case, the physician should not neglect the patient, nor should he withdraw from the case without giving adequate notice to the patient and his family”.

    Also, when a patient is referred to a specialist by the attending physician, a case summary of the patient should be given to the specialist, who should communicate his opinion in writing to the attending physician. (Rule 3.6 of Code of Medical Ethics). Therefore doctors are not liable for legal actions, if he refers or refuses to give treatment beyond his area of practice.

2 (B) In some states, the Clinical Establishment (Registration and Regulations) Act, 2010, notified by the State Government, registering a clinical establishment is mandatory; otherwise it becomes unlawful. However, there are a few states that have not notified the said act where a doctor can practice medicine in that branch in which he is qualified and registered under the Medical Council Act.


Q-3. There was a fight between two groups of people on the road in front of my Hospital. Someone pierced a sharp instrument into another’s chest. Then everybody left that place. The police brought the injured person to the Hospital for treatment. Suddenly someone called over the phone and demanded that I should not to treat him. What should a doctor do in such a situation? Please advise.

Answer: This appears to be a criminal case. In a criminal case or offence, it is the responsibility of the Sovereign Authority (represented by Police/Public Prosecutors) namely the State, to punish the accused. To punish the accused, all the charges against the accused must be proved before a competent court of law. To prove the charges, (that A has caused an injury to B) , the State has to prove that B sustained the injury by A; for this, the state requires the aid and help of the medical professionals. Such cases are called Medico – legal cases.

    From your version, it appears that the Police brought the victim to your hospital for treatment. Therefore, by law you have to extend all medical facilities to the victim according to your competence. If the victim requires specialised service which you do not have, you can inform the Police in writing accordingly so that they will take further action and you will be absolved from any further responsibilities.


Q- 4. (a) What are the preventive insurance covers against CPA/legal suits (CPA= Consumer Protection Act)? (b) Is there any validity of a bond signed by attendant/patient that CPA is not admissible due to low cost treatment (like token fees in Govt. hospital)? (c) Is it mandatory to take medical experts’ opinion in passing verdict in CPA against doctors? (d) How is compensation is calculated in CPA?

Answer: 4(a)- Insurance is available to safeguard and protect the Medical Professionals. This is called Professional Indemnity Errors and Omissions Policy. Any notice or summons received from court in connection with Medical Negligence and claim of compensation addressed to doctors / hospital will be handed over to Insurance Company. If there is any award of compensation ordered by a Court, it will be paid by the Insurance Company. In short, the hospital would be indemnified.

4 (b) There is no validity of a bond signed by attended patient that CPA is not admissible due to low cost treatment if you are charging fees from another patient in your hospital. In other words, even if you are treating free for one or a few patients, while charging others, your hospital and its services are amenable under CPA (whereas the Government hospital will come under civil law not consumer law) Any bond which goes against the spirit of existing law would be invalid.

4 (c) It is not mandatory to take medical expert opinion for passing verdict in all CPA cases, however in a complicated question of fact, at the discretion of Presiding Officer, a case can be referred for expert opinion from other 3rd competent person.

4 (d) Compensation is calculated, generally, according to the age, economical status, and family responsibilities of the patient or patient who died. Normally, the persons who receive less earning without family would receive less compensation whereas a person who is earning good salary coupled with many years of further service with large dependant family members would receive more. Therefore, doctors and eminent lawyers under the aegis of the Institute of Medicine and Law have requested the Union Government to fix a cap to the maximum limit for awarding compensation.

Q-5. In a school dormitory, a parent bashed up a young teenager while separating 2 boys who were fighting. The boy needed suturing and medical care by the school doctor. Does the doctor have to report to the police or go through the school administration?

Answer: This case comes under Medico Legal area. Even though the doctor is appointed as an employee or a consultant engaged by a School to take care of health requirements of a school boys, he would be considered as an independent Medical Professional inrespect of treating a victim under Medico legal arena. One way service – wise he is under the administrator of the School whereas automatically he is a doctor who is attending a Medico – Legal case. If the affected party (student) with great influence reports this matter to Police later, the doctor would be held responsibility under relevant provisions of criminal law. Therefore, the best course is you can send a Medico- legal intimation to the Police through the management of school and a copy may be forwarded to Police directly.




(Source: Human Resource Management in Hospitals by D. Samuel Abraham, (J.R. Publications).

1. Once a claim is made to provide certain medical facilities in a clinic/hospital, the time limit should be mentioned. This time limit implies that the necessary equipment, manpower and medical and paramedical staff are all available during this specific period.

2. The responsibilities of the Medical Practitioner extend to the post-operative period also; therefore, he should ensure that he mentions the date for the patient to report to the hospital in post-discharge examination while issuing a discharge summary.

3. Certain types of negligence like leaving behind sponges, wires or instruments inside the patient’s body attract compensation/damage only to the surgeon; therefore such negligence should be avoided.

4. Medical assessment should be made only in an objective manner guided by extensive tests and examinations.

5. When attending to a patient for the first time, the medical professional must not be influenced by the results of the tests conducted in a diagnostic centre earlier. Such results must be corroborated by conducting other tests.

6. Pregnancy should be ruled out before subjecting the patient to X-ray.

7. The medicine and the dosage should always be checked before administering to a patient.

8. The site of injection must be ascertained.

9. While dealing with an agitated patient, steps must be taken to calm him down before administering injection; otherwise, a broken needle may be a valid ground for claiming compensation.

10. While doing tubal ligation or sterilization, the patient should be told that there is no guarantee for non-pregnancy.

11. To avoid false claims at a later date, test for HIV/Hepatitis B should be arranged before treating the patient especially before blood transfusion or surgery.

12. The medical professional must continuously update his knowledge by reading textbooks/journals, reports of semi-nars/association meetings etc.

13. If a doctor feels that he cannot treat a patient , the

patient must be referred to specialist. A record to this effect should be kept.

14. If a decision is made to take advice from other units after holding discussions about treatment procedures, it should be recorded clearly in the chart.

15. In accident cases, statements given by patients or people who brought them to the hospital should not be recorded. Such cases should be reported to the police, facts verified from them and then only recorded. In many cases, the statement given by those who brought patients to the hospital, proved to be false later.

16. The doctor’s instructions to a nurse about a specific

matter should be recorded in the Nurse’s chart so that relieving Nurse will know about such instructions.

17. The history of any allergy must be recorded so that other consultant/doctor will become aware of it.

18. The names of drugs should be written clearly. Wrong interpretation of illegible handwriting has led to wrong administration of drugs thereby causing death of the patient caused huge monetary damage to the hospital in many instances.

19. If the patient is uncooperative in following the prescribed medications/tests/treatment, this must be recorded in the chart, getting it in writing from him in the local language and the patient discharged.

20. The medical records of patients who underwent major operations/eye operation should be preserved for at least 7 years; the three year mandatory period is not enough. This is in the larger interest of the hospital.

21. The medical professional must not hesitate to treat emergency cases as it is life which is at stake. The patient should be treated with the available facilities at the treating hospital and referred for specialist care if required. Fees can be claimed later.

22. A neatly designed consent form with proper means of recording is necessary for each and every major treatment/examination. Always a legally valid consent form designed by professionals must be used.

23. If a medical doctor receives legal/court notice, he should always consult a lawyer before replying to the notice.


Nutrition for Bone Health

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Nutrition for Bone Health

Beyond Classic Nutrients, Calcium and Vitamin D

N.V. Mahendri, MSc, PGCCN, MHRM, M.Phil, RD, Chief-Dietitian & Head, Department of Dietetics
Christian Medical College, Vellore – 632 004

Summary: The key for a strong and healthy skeletal system across life cycle is healthy eating habits by consuming a balanced diet every day. The IOF (International Osteoporosis Foundation) recommends that at every stage of life a nutritious, balanced diet promotes strong, healthy bones. A good diet includes sufficient calories and adequate protein, fat and carbohydrates, as well as vitamins and minerals – particularly vitamin D and the mineral calcium. In childhood and adolescence, good nutrition helps to build peak bone mass (maximum bone density, attained in the 20’s) thereby reducing vulnerability to osteoporosis later in life. In younger and older adults, a nutritious diet helps preserve bone mass and strength. And in those who have had a fracture, it speeds and aids recovery and reduces the risk of having another fracture. Varied and enjoyable eating habits, including calcium-rich foods, are a recipe for a lifetime of strong bones and the high quality of life that comes with them.


Adequate nutrition is essential for the development and maintenance of the skeleton (bone health). Roughly 80–90% of bone mineral content is comprised of calcium and phosphorus. Protein is another crucial nutrient and is incorporated into the organic matrix of bone for collagen formation, upon which mineralization occurs. Besides this, protein seems to be involved in regulation of calcium absorption. Although calcium has been studied most extensively, other minerals such as magnesium, fluoride, zinc, copper, iron, selenium and vitamins D, A, C, K and folate are required for normal bone metabolism. Calcium, phosphate, vitamin D and protein are essential for normal bone structure and functions, but several other nutrients also have essential roles in maintaining bone health. Total energy consumption, fats, carbohydrates and fiber intake, and electrolytes like sodium and potassium, may also, for different reasons, affect bone health.



Adequate energy intake is required to maintain healthy body weight.Very low body weight is associated with lower peak bone mass development in the young and increased bone loss and risk of fractures in older persons


Adequate dietary protein intake is essential for bone health. Protein being one of the major structural components of bone makes up roughly 50 percent of the volume of bone and about one-third of its mass. Insufficient protein intake is detrimental, both for acquisition of bone mass during childhood and adolescence and for the preservation of bone loss with aging (IOF 2007). Protein is essential for intestinal absorption of calcium.

    Dietary protein intake below 0.8g/ kg bodyweight is associated with a probable reduction in intestinal calcium absorption sufficient to cause secondary hyperthyroidism. The long term effect of the low protein diet induced changes on mineral metabolism is not known, but such a diet could be detrimental to skeletal health. Of concern are several recent epidemiological studies that demonstrate reduced bone density and increased rates of bone loss in individuals habitually consuming a low protein diet.

Essential fatty acids (EFA):

EFA’s have also been found to increase calcium deposition in bone, as bone calcification must take place in the presence of phospholipids. It is also been indicated that essentialfatty acids appear to improve bone strength, possibly by generating collagen synthesis(International Osteoporosis Foundation – IOF 2011).


Vitamin A (Retinol)

Vitamin A plays an essential role in the development of osteoblasts, the bonebuilding cells that laydown new bone. A deficiency in vitamin A also limits calcium absorption and metabolism, whichresults in poor bone growth. Beta carotene is the pro-vitamin A found in plant foods

Vitamin D

Vitamin D’s key function is the absorption of calcium. Dietary sources of vitamin D are limited to very few foods – such a as salmon, tuna fish, and sardines. Most of the vitamin D required is produced by the body upon exposure to adequate sunlight. A normal diet alone (without exposure to sunlight) cannot supply the recommended daily vitamin D intake.

Vitamin K

Vitamin K is an essential micronutrient for bone health. Its role in post-translational modification of several matrix proteins, including osteocalcin, is now well established. Osteocalcin, a bone-specific protein made by osteoblasts, requires vitamin K for its posttranslational carboxylation, that is, maturation.

Vitamin C

Vitamin C is necessary for healthy bones; it is involved in the formation of collagen, the main protein in bone.

Vitamin B6

Vitamin B6 plays an important but indirect role in bone metabolism. Vitamin B6 is necessary for hydrochloric acid (HCl) production by the stomach, and HCl in turn is necessary for calcium absorption.

Deficiency of vitamin B6, vitamin B12 and folic acid lead to Hyperhomocysteinemia which has been linked to increased risk for cerebrovascular disease and also found to have adverse effects on bone health.

Vitamin B12 is not found in plants, but is abundant in animal protein. Vegetarians are therefore strongly advised to ensure adequate B12 intake.



Calcium is one of the three major nutrients (calcium and vitamin D and protein) necessary for bone health. Calcium is the major structural component of bone tissue. Ninety nine percent of the calcium in the body is stored in the bone which therefore also acts as reservoir of calcium for maintaining calcium levels in the blood at about 10mg/dl.

Besides the amount of calcium in the diet, the absorption of dietary calcium from the food is also a critical factor in determining the bioavailability of calcium for bone development and maintenance.

    The amount of calcium consumed regulates the efficiency of intestinal calcium absorption. Calcium absorption efficiency is increased when calcium intake is low and decreases when calcium intake is high. Thus calcium is a unique nutrient for which intestinal absorption is auto regulated in a homeostatic mechanism. Calcium deficiency leads to bone diseases like osteoporosis and osteopenia.


More than 50% of the magnesium in the body is found in bone tissue. It is necessary for the conversion of vitamin D into its active form. Magnesium is involved in calcium absorption metabolism and homeostasis and as well as in the formation of hydroxyapatite.

Note: It’s often overlooked that magnesium and calcium function together, so deficiency of one markedly affects the metabolism of the other. In fact, increasing calcium supplementation without magnesium supplementation can actually increase magnesium loss.


Phosphorus combines with calcium to form a mineral crystal that gives strength and structure to bones and teeth. It is important to maintain the ideal ratio of these minerals in the diet that is one part calcium to one part phosphorus.


Potassium is also known as the hidden bone guardian of bone health; this protective role relates mainly to neutralizing the bonedepleting acids that are produced during every day normal metabolic processes.


High sodium intakes, particularly in association with a low calcium intake, can contribute to osteoporosis because they result in increased calcium excretion.

Trace Minerals

Trace Minerals, especially fluoride, iron, zinc, copper, manganese, and boron, function in bone metabolism, but in general their roles in preventing bone loss are not well established.

Boron: Boron appears to be utilized by osteoblasts for bone formation, as demonstrated in both rodent and human studies but whether boron is absolutely required for human bone formation has not been determined.

Chromium: Chromium helps to keep insulin activity in the body efficient, an effect that may be boneprotective inthe following ways: i) by promoting the production of collagen ii) by moderating bone breakdown iii) and lowering calcium excretion


Copper is needed for the cross-linking of collagen and elastin molecules, and it may have roles in other enzymes of bone cells. Like manganese, copper is an essential trace mineral that has only recently been found to play an important role in bone health maintenance. This role is still not fully understood, but it is known that by virtue of a coppercontaining enzyme called lysyl oxidase, copper aids in the formation of collagen for bone and connective tissue and contributes to the mechanical strength of bone collagen fibrils — the long thin strands of proteins that crosslink to one another in the spaces around cells. Copper also helps inhibit bone resorption through a copper and zinccontaining antioxidant calledsuperoxide dismutase. This antioxidant neutralizes superoxide radicals produced by the bone breakdown cells called osteoclasts during bone resorption.

Fluoride: Fluoride enters the hydroxyapatite crystals of bone and within narrow limits, increases the hardness of bone minerals without any adverse effects. At intakes of 2 ppm or greater fluoride is considered to produce bone that is subject to increased micro fractures because of the change in the properties of the hydroxyapatite crystals.

Iron: Iron serves as a catalytic cofactor for the vitamin C – dependent hydroxylations of praline and lysine in collagen maturation. Iron also has other roles in osteoblasts and osteoclasts related to mitochondrial oxidative phosphorylation as well as in other enzymes, similar to the needs of other cells in the body.

Manganese: Manganese is required for the biosynthesis of mucopolysaccharides in bone matrix formation, and it acts as a cofactor in energy-generating reactions. In recent decades research has uncovered the special role manganese plays as a cofactor in theformation of bone cartilage and bone collagen, as well as in bone mineralization

Zinc: Zinc is essential for enzymes in osteoblasts that are responsible for collagen synthesis. In addition, an important enzyme in osteoblasts, alkaline phosphatase, requires zinc for its activity. Proper calcium absorption alsodepends on zinc, and a deficiency prevents full absorption of calcium. It’s essential for bone healing, andincreased amounts are found at the sites of bone repair.Zinc is a constituent of the hydroxyapatite mineral crystals of bone, and plays a role in the regulation of bone turnover. Zinc is also needed for the correct functioning of alkaline phosphatase, which is required for bone mineralization

Silicon: Recent research recognizes silicon as an essential mineral for bone formation.

Non-nutrients that influece bone health:

Dietary Fiber:Excessive dietary fiber intake may interfere with calcium absorption,

Isoflavones: The isoflavones in soybeans, as well as chick peas function both as estrogen agonists and antioxidants in bone cells, may result in the inhibition of bone resorption.

Conclusion: Maintaining optimal bone health is a life-enhancing strategy.Overall diet patterns are likely as important as or more important to growing bone than adequacy of individual nutrients.The whole diet needs to be considered to determine if nutrients needs are being met. The whole diet should contains constituents that can enhance or inhibit nutrient absorption, influence their excretion, or influence bone turnover. The nutrients that are essential for bone health do not function in isolation and all work together to keep one’s bones standing strong all his/her lifelong.

Nutrients Found in the Foods

Grains (cereals)- good source of B vitamins (except B12), vitamin E, magnesium, iron, silica and fiber.(Ragi is a rich source of calcium, iron and manganese)

Vegetables –good source of fiber, folate, potassium, β-carotene (provitamin A), vitamin C and other  antioxidants. Green leafy vegetables also contain  calcium and other minerals and vitamin K.

Fruits – good source of β-carotene (provitamin A), vitamin C, folate, potassium and antioxidants

Milk and Dairy –good source of calcium, vitamin D, protein, phosphorus, zinc, vitamin A, vitamin B12, potassium and essential fatty acids.

Meats –good sources of protein*, zinc, iron, vitamin B12, vitamin B6 and Niacin.

Eggs –good source of protein, riboflavin, vitamin B12, phosphorus and selenium.

Fish and Shellfish -good source of protein, iodine, iron, zinc, niacin and omega-3 fatty acids .

Oily fish (salmon, mackerel, lake trout, herring, sardines, and albacore tuna)contain naturally occurring vitamin D.

Legumes, Nuts and Seeds :

Legumes, (whole grams,dried beans )are a good source of protein, calcium, iron and fiber.

Nuts are a good source of protein, calcium, phosphorus, magnesium, potassium.

Seeds are a good source of protein, calcium and iron.

Mehti seeds(fenugreek) are good source of soluble fiber

Flax seeds are also good source of ALA (15 g meets the RDA for Omega 3 Fatty acids-3g/day)

Choosing variety of foods under each category will ensure variation and nutritional adequacy.


  1. Anderson JJB: Nutrition and Bone health in Krause’s’ Food, Nutrition and Diet therapy, 11th Ed. Elsevier USA, 2000:642-66
  2. Cashman KD. Calcium intake, calcium bioavailability and bone health Br. J. Nutr 2002; 87: Suppl. 2, S169–S177
  3. Heaney MT et al. Effect of dietary protein on bone loss in elderly men and women. The Framingham Osteoporosis study J. Bone Miner Res 2000 15; 2504-12
  4. Ilich JZ, Brownbill RA, Tamborini. C Bone and Nutrition in elderly Women, protein energy and calcium as such determinant of bone mineral density. Eur J Clin Nutr 2003; 57:554-65 Abstract
  5. International Osteoporosis Foundation 2007 and 2011,2014
  6. Krestetter JE et al. Dietary protein, calcium metabolism and skeletal homeostasis revisited Am J Clin Nutr 2003;78 584S-592S
  7. Prentice A. Is nutrition important in osteoporosis. Proc Nutr Soc 1997, 56 : 35767 (Medline)


Cell based model of haemostasis

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Cell based model of haemostasis

Anand Bhaskar, Associate Professor, Department of Physiology, Sukesh C. Nair, Professor, Department of Transfusion Medicine and Immunohematology, Tony Abraham Thomas, Christian Medical College, Vellore

Summary: The complex process of coagulation that leads to hemostasis has been described by several models in the past, the most popular of which was the cascade model. Though the cascade model (with intrinsic, extrinsic and common pathway) was a good description of this process in vivo, it fails to account for several experimental and clinical findings that have come to light in the last few decades. The in vitro activation of the coagulation process (the basis of the cascade model) doesn’t completely represent the global haemostatic process that occurs in vivo, characterised by interactions between tissue factor bearing cells, platelets and the intrinsic and extrinsic pathways. The cell-based model of haemostasis is the currently accepted model as it better reflects the process of haemostasis in vivo. It consists of three overlapping phases – initiation, amplification and propagation phases. It overcomes many of the limitations of the cascade model and is clinically relevant.


    Haemostasis is the process by which bleeding is stopped after an injury by the formation of a clot, while at the same time, maintaining blood in a fluid state elsewhere. Injury to a blood vessel results in vasoconstriction and temporary platelet plug formation. This is followed by a coagulation process which arrests bleeding at the site of injury by forming a fibrin clot. The clot formed at the site of injury by the coagulation process can potentially spread to the adjacent normal areas leading to clotting of blood elsewhere. This is prevented by the presence of fibrinolytic system and various natural anticoagulants in the intact blood vessel.

    Our understanding of the process of haemostasis has evolved over years through various models. The cascade/waterfall model of haemostasis (which includes an intrinsic pathway, extrinsic pathway and a common pathway) has been in use for several decades and is the most popular. Although useful in our understanding of haemostasis, this model does not fully explain several clinical and experimental findings. The cell-based model of haemostasis (initially proposed by Hoffman, Monroe et.al.1 and later expanded by K.G. Mann, S. Butenas et al.2), which proposes that clotting occurs not as a cascade, but in three overlapping stages is the currently accepted model of haemostasis that adequately reflects the process of clotting. The current article will update the readers about the cell based model of haemostasis.

Models of haemostasis

    The early understanding of the process of clotting during the times of Hippocrates, Aristotle, Celsius and Galen was that bleeding stopped when blood came into contact with air. They hypothesised that blood cooled on contact with air resulting in the cessation of bleeding3. The formation of blood clots within vessels was described in the early 1720s by the French surgeon Jean-Louis Petit and in 1860, the German pathologist Rudolf Virchow described thrombi and their tendency to embolize 3.

It was only in 1905 however that a model to describe the process of haemostasis was proposed by Paul Morawitz. He described the four factor model of haemostasis where prothrombin was converted to thrombin by calcium. The thrombin formed then converted fibrinogen to fibrin (Figure 1). This model was also known as the classic theory of haemostasis 1. However this model was not able to explain bleeding tendencies in patients who had normal levels of these factors. Later, other clotting factors were discovered in the blood. These clotting factors were assigned Roman numerals based on the order of discovery. Based on these discoveries and identification of bleeding diseases, two independent groups proposed a cascade and waterfall model of haemostasis in 1964 (4,5). These models formed the basis for the intrinsic and extrinsic pathways described in most medical textbooks.

The cascade model of haemostasis

The cascade/waterfall model suggests that clotting factors are in an inactive proenzyme form and they get activated sequentially by a series of proteolytic reactions (in the intrinsic and extrinsic pathways) during the coagulation process to finally generate a burst of thrombin1. These two pathways eventually resulted in the activation of the common pathway (Figure 2).

Intrinsic pathway

The intrinsic pathway was named so because all the factors required for this pathway were present in blood.

The intrinsic pathway is activated when factor XII comes in contact with negatively charged subendothelial collagen which is exposed following injury to the blood vessel and also by cell and platelet derived polyphosphates6. During this process factor XII is converted to its active from factor XIIa.

This is followed by a sequential cascade of activation of Factor XI, IX and X to their active forms XIa, IXa and Xa. Factor Xa along with factor Va, calcium and platelet phospholipids form prothrombinase2 which then results in the formation of fibrin through the common pathway (figure 2).

The intrinsic pathway is tested in the laboratory by measuring activated partial thromboplastin time (aPTT).8

Extrinsic pathway

The extrinsic pathway requires tissue factor present in subendothelial cell membranes.
This pathway is activated when factor VII in blood comes in contact with tissue factor (TF) that is released following tissue injury.2

    Factor VII and factor X are converted into their active forms VIIa and Xa. Factor Xa along with factor Va, calcium and platelet phospholipids form prothrombinase which then results in the formation of fibrin through the common pathway (figure 2).

    The extrinsic pathway is tested in the laboratory by measuring the prothrombin time (PT).8

Common pathway

    The common pathway is similar to the four factor model of haemostasis where prothrombin or factor II is converted to thrombin (IIa) by prothrombinase8. The prothrombinase consists of activated factor X (Xa), activated factor V (Va), calcium and platelet phospholipids. The thrombin that is formed then initiates the formation of a stable fibrin plug.

    The factors in common pathway (factors X, V, II and I) can be tested in the laboratory by measuring the aPTT and PT.8

Limitations of cascade/waterfall model

    The cascade/waterfall model is good for describing the coagulation process in vitro (in the laboratory) where we can selectively activate the intrinsic or extrinsic pathways1. However several clinical observations have exposed its limitations while describing the coagulation process in vivo. Some of the observations are:

  1. It has been observed that individuals with factor XII deficiency do not suffer from bleeding in spite of the requirement of this factor for initiating the intrinsic pathway 9. The aPTT of these individuals are prolonged but they are asymptomatic.
  2. Deficiency of high molecular weight kininogen and pre-kallikrein also do not lead to a clinical bleeding tendency1.
  3. Deficiency of factor XI leads to variable haemostatic deficits in human beings with bleeding seen in some individuals 8.
  4. Individuals with factor IX or factor VIII deficiency have severe bleeding even though their extrinsic and common pathways are normal and should be sufficient to promote clotting.7
  5. Deficiency of factor VII also causes bleeding even though the intrinsic pathway is intact. This means that intrinsic and extrinsic pathways alone cannot bring about haemostasis and an interaction between both pathways is necessary for haemostasis in vivo. This interaction can be explained by the cell based model of haemostasis.

The Cell based model of haemostasis

    The cell based model of haemostasis gives a better description of the process of haemostasis as it occurs in the body and better reflects this process when compared to the cascade model.

    The formation of thrombin from prothrombin is the central event in the process of coagulation which results in clotting of blood. There are several reactions which precede thrombin production. These reactions occur rapidly and do not follow a neat sequence of events as described by the cascade model. For the purpose of understanding these events, the process of coagulation may be divided into three phases which are interwoven and overlap each other.

The phases of coagulation are:

  1. Initiation phase
  2. Amplification phase
  3. Propagation phase

Figure 3: Initiation phase
TF: tissue factor

I. Initiation phase

    Tissue factor (TF) is the initiator of the process of haemostasis. TF is normally present in TF-bearing cells like smooth muscle cells and fibroblasts in the subendothelial layer of blood vessels and a small amount in macrophages, endothelial cells and platelets circulating in the blood(2,6). It is hidden and membrane bound and is expressed on the surface of these cells only after an injury.

    The processes involved in the initiation phase, which takes place on the surface of these TF bearing cells, are as follows: 1,2,8

i. Binding of TF with factor VII

    The coagulation process is initiated by the contact of factor VII (or activated factor VIIa) present in the plasma with tissue factor (TF) exposed on the surface of TF bearing cells.1 This contact occurs when the endothelium is breached by the injury.

ii. Activation of Factor X and IX

    The factor VIIa/TF complex then activates factor X to factor Xa and factor IX to factor IXa2,10 providing interaction between the extrinsic and intrinsic pathways.

iii. Conversion of Prothrombin to Thrombin

    Factor Xa activates the conversion of prothrombin to thrombin (figure 3).

    Only a small amount of thrombin is formed in this phase because of some inhibiting factors – the circulating Xa is inhibited by the binding of endothelium derived tissue factor pathway inhibitor (TFPI)1 and by antithrombin III (ATIII) present on normal endothelium. The TFPI/Xa complex also inhibits the VIIa/TF complex.

    The formation of thrombin during this phase is very inefficient and very little is formed. However this small amount of thrombin is necessary to initiate the amplification phase.

II. Amplification phase

The amplification phase occurs on the surface of platelets. The processes involved are as follows.

i. Activation of platelets

    Platelets now adhere to the injured vasculature and extra-vascular tissues (mediated by von Willebrand factor). The small amount of thrombin formed from the initiation phase on the TF bearing cells acts on these platelets converting them into activated platelets.

Components of platelet activation:

a) Platelets become irregular in shape with multiple pseudopodia that increase surface area for the coagulation process.11

b) Platelets start expressing receptors and binding sites for various clotting factors. This is done by reversing the asymmetry of the phospholipid bi-layer of the platelet membrane. The anionic phosphatidyl serine (PS) found on the inner layer is brought to the outer layer(2,11,12,13)by a process referred to as “flip-flop”. The anionic PS attracts the positively charged Ca2+ ions involved in the formation of tenase complex (described later).

c) Platelets start releasing serotonin, calcium and ADP from their dense granules. They also release factor V, fibrinogen, von Willebrand factor (vWF) and platelet derived growth factor from their alpha granules.

ii. Activation of Factors V, VIII and XI

  1. The factor V on the platelet surface gets activated by thrombin produced during the initiation phase.14

  2. Thrombin also activates factor VIII present on the platelet surface complexed with vWF. During this process, vWF/VIIIa complex separates and the vWF then mediates further platelet adhesion and aggregation. Activated factor VIIIa will remain on the platelet surface.

  3. Thrombin also activates Factor XI present on platelet surface (figure 4).

    The activated platelets and factors Va, VIIIa and XIa on the platelet surface thus set the stage for the next stage of the amplification phase which is characterized by the formation of two coagulation complexes – tenase and prothrombinase11.

iii. Formation of tenase complex

    The activated factor IXa combines with factor VIIIa (along with calcium and phospholipids) on the platelet surface form the tenase complex (VIIIa/IXa) which converts the inactive factor X (substrate) into activated factor Xa.2

iv. Formation of prothrombinase complex

    Activated factor Xa now forms a complex with factor Va (along with calcium and phospholipids) on platelet surface to form prothrombinase complex (figure 5).

v. Formation of thrombin

    The prothrombinase (Xa/Va) converts prothrombin (substrate) into large amounts of thrombin11. When compared to factor Xa (in the initiation phase), prothrombinase is about 300,000 times more active in the formation of thrombin from prothrombin.14 This large scale formation of thrombin is often referred to as ‘burst of thrombin’.

Fig. 4 – Amplification phase

Figure 5: Formation of tenase and prothrombinase complex

III. Propagation phase

Further production of thrombin:

    Factor XIa that was formed in the initial part of the amplification phase (inactive factor XI activated by thrombin) in turn activates factor IX to factor IXa which enables the formation of tenase complex leading to the formation of thrombin (The amount of thrombin formed during the amplification phase could be sufficient for clot formation, in which case this phase of thrombin formation may not be critical.)

Formation of thrombin and fibrin plug:

    The prothrombinase initiates a burst of thrombin formation from prothrombin. The thrombin converts fibrinogen to fibrin monomers. These fibrin monomers, in the presence of factor XIIIa, interweave with each other and platelets to form a stable fibrin plug that seals the wound and stops bleeding.

Control and Termination of clotting

    If the process of thrombin production is not controlled, the thrombin that is formed at the site of injury can spread to the adjacent normal areas and cause coagulation in surrounding normal areas. The process of thrombin formation is therefore under tight control by various mechanisms mediated by factors like TFPI (through processes described earlier) and natural anticoagulants like Protein C, Protein S and Antithrombin III which activate the fibrinolytic system. The activated antithrombin III complex can inactivate thrombin and other clotting factors like IX, X, XI and XII.

    Drugs like streptokinase, tissue plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) act by activating the fibrinolytic pathway and are useful in lysing clots in patients with myocardial infarction, ischaemic stroke, deep vein thrombosis and pulmonary embolism.

Clinical implications

  1. Normal haemostasis requires normal vascular function, normal platelets and coagulation factors. Blood vessel abnormalities and a decrease in platelet count or platelet dysfunction can lead to bleeding tendencies. Coagulation factor deficiencies can also lead to bleeding disorders like haemophilias.
  2. Deficiency of factor VII can lead to bleeding as it is important in the initiation phase of haemostasis.
  3. Haemophilia A or classic haemophilia is due to deficiency of clotting factor VIII. Deficiency of clotting factor IX results in Haemophilia B or Christmas disease. Both haemophilia A and B are inherited as X linked recessive disorders. Usually males are affected and females are carriers. Haemophilia A and B are common in communities that promote consanguineous marriage. Factor VIII and IX deficiencies lead to severe bleeding as they are important for the amplification phase of haemostasis.
  4. Haemophilia C is due to deficiency of factor XI and is inherited as an autosomal disease. Factor XI deficiency causes variable bleeding tendency with bleeding seen in only some individuals. This is probably because factor XI in the propagation phase may not be needed for haemostasis if adequate thrombin is generated in the amplification phase.
  5. Deficiency of von Willebrand factor (vWF) can result in von Willebrand disease. vWF binds to subendothelial collagen and helps in platelet adhesion by binding to glycoprotein GP1b present on the platelet surface. VWF is also important for maintaining normal levels of factor VIII. VonWillebrand disease is more common when compared to haemophilias.


    The cascade/waterfall model of haemostasis is useful in explaining the in vitro haemostatic process initiated in the laboratory. The intrinsic pathway and common pathway are tested by the aPTT and the extrinsic and common pathways are tested using prothrombin time. The in vitro activation of coagulation process doesn’t completely represent the global haemostatic process happening in vivo with interactions between tissue factor bearing cells, platelets and the intrinsic and extrinsic pathways. The in vivo process of haemostasis is better explained by the cell based model of haemostasis where the process is initiated in cells expressing tissue factor and propagated on the surface of platelets. This two compartment model also explains better, the underlying processes behind many of the clinical conditions due to deficiency of clotting factors.


1.     Hoffman M, Monroe DM. A cell-based model of hemostasis. Thromb Haemost. 2001 Jun;85(6):958–65.

2.     Mann KG, Brummel-Ziedins K, Orfeo T, Butenas S. Models of blood coagulation. Blood Cells Mol Dis. 2006 Apr;36(2):108–17.

3.     Riddel JP, Aouizerat BE, Miaskowski C, Lillicrap DP. Theories of blood coagulation. J Pediatr Oncol Nurs Off J Assoc Pediatr Oncol Nurses. 2007 Jun;24(3):123–31.

4.     Davie EW, Ratnoff OD. Waterfall sequence for intrinsic blood clotting. Science. 1964 Sep 18;145(3638):1310–2.

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Anticoagulation in atrial fibrillation – BRIDGE Trial

Source: Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation. James D. Douketis et al, for the BRIDGE Investigators. N Engl J Med. 2015 Aug 27;373(9):823-33.

Clinical question: Is bridging anticoagulation necessary for patients with atrial fibrillation who need an interruption in warfarin treatment for an elective invasive procedure.

Authors’ conclusion: Bridging anticoagulation is not necessary in patients with atrial fibrillation requiring a short interruption in warfarin treatment

Back ground:

The role of bridging anticoagulation during perioperative interruption of warfarin treatment in patients with atrial fibrillation is not clear. [1] As mentioned in the above case scenario, at present warfarin treatment is stopped 5 days before an elective procedure. It is resumed after achieving complete hemostasis. During this entire period of 5 to 10 days heparin is used as a bridging anticoagulation.[2] Whether heparin is truly needed during interruption of warfarin therapy before and after an operation or other invasive procedure is not known. The BRIDGE trial was designed by Douketis et al to answer this key question in patients with atrial fibrillation.[3]

Methodology: The BRIDGE trial was a multi- centric, randomized, double-blind, placebo-controlled trial involving 108 centres in United States and Canada. It included patients who were eighteen years or older, and had a proven chronic atrial fibrillation or flutter, (with one of the CHADS2 risk score factors), on warfarin therapy for at least 3 months or longer and was planned for an elective operation or invasive procedure requiring interruption of warfarin therapy. This study included a total of 1884 patients over a span of 65 months [2009 to 2014].

    Patients were randomly assigned to receive bridging anticoagulation therapy with low-molecular-weight heparin or matching. Both LMWH (100 IU of dalteparin per kilogram of body weight) and placebo were administered subcutaneously twice daily, from 3 days before the procedure until 24 hours before the procedure and then for 5 to 10 days after the procedure. Warfarin treatment was stopped 5 days before the procedure and was restarted within 24 hours after the procedure. Both the placebo and LMWH were restarted within 12 to 24 hours of a low bleeding risk procedure (minor) and 48 to 72 hours after a high bleeding risk (major) procedure. Study drug administration was continued until the INR was 2.0 or higher on one occasion. Patients recruited were followed-up for 30 days after the procedure. The primary outcomes of this study were arterial thromboembolism like stroke, systemic embolism or transient ischemic attack and major bleeding (safety outcome), which was assessed 37 days after the procedure.


  • There was no significant difference in the incidence of arterial thromboembolism between the two groups. (0.4% in the no-bridging group and 0.3% in the bridging group.
  • There was a higher incidence of major bleeding in the bridging group (1.3% in the no-bridging group and 3.2% in the bridging group).
  • There was no significant difference between the secondary outcomes (rates of acute myocardial infarction, deep-vein thrombosis, pulmonary embolism, or death) between both the groups


A systematic review and meta-analysis of 34 observational studies including 12,278 patients published in 2012 had shown that there was no difference in thromboembolic events among both the subgroups of patients. It had also shown that patients receiving bridging heparin had higher rate of all and major bleeding. [4] However the above meta- analysis concluded that requirement of randomized clinical trials to confirm need of perioperative bridging. The BRIDGE trial filled that gap and confirmed that for patients with atrial fibrillation requiring temporary interruption of warfarin treatment for an elective operation or other elective invasive procedure, a strategy of forgoing bridging anticoagulation was not inferior to perioperative bridging with low-molecular-weight heparin for the prevention of arterial thromboembolism. This strategy of forgoing bridging treatment also decreased the risk of major bleeding in these subsets of patients.


1.Gallego P, Apostolakis S, Lip GY. Bridging evidence-based practice and practice- based evidence in periprocedural anticoagulation. Circulation 2012; 126: 1573-6.

2. Baron TH, Kamath PS, McBane RD. Management of antithrombotic therapy in patients undergoing invasive procedures. N Engl J Med 2013; 368: 2113-24.

3. James D. Douketis et al, for the BRIDGE Investigators.N Engl J Med. 2015 Aug 27;373(9):823-33. doi: 10.1056/NEJMoa1501035. Epub 2015 Jun 22

4.Siegal D, Yudin J, Kaatz S, DouketisJD,Lim W, Spyropoulos AC. Periprocedural heparin bridging in patients receiving vitamin K antagonists: systematic review and meta-analysis of bleeding and thromboembolic rates. Circulation 2012; 126: 1630-9.

Experts Comments: Dr. Cijoy K Kuriakose, Asst. Physician, Dept. of Medicine, CMC Vellore

The study question seems to be relevant and specific as increasing number of patients are encountered in routine clinical practice who are on anti-coagulation and require elective surgical procedures for various reasons. On review, the study design stands up to scrutiny in terms of randomization, allocation concealment, comparable baseline characteristics, blinding and placebo-controlled nature of the study.

    The Bridge trial has clearly shown that it is not really necessary to use bridging anticoagulation for patients with AF on anticoagulation prior to selected surgical procedures. It has also shown that this strategy helps in preventing bleeding complications. A caveat is that this study excluded patients who were undergoing cardiac, intra-cranial and intra-spinal surgeries and also of patients who have mechanical heart valves implanted already.

Is this study clinically applicable?

According to this trial, for every 100 patients who are on anticoagulation for atrial fibrillation, 2 major bleeding complications can be prevented by not using bridging anti-coagulation, without causing any significant increase in the thrombotic complications. This could be applied in most of the practice situations except for those patients who have mechanical heart valves or are undergoing cardiac, intra-cranial or spinal surgery.