Subclinical Hypothyroidism



By Gabe Mirkin MD, May 28, 2012  —  Several studies suggest that people who have subclinical hypothyroidism (blood tests demonstrating low thyroid function, but have no symptoms of low thyroid disease) should be given thyroid replacement medication.

THE NORMAL THYROID: The brain produces a hormone called TSH that stimulates the thyroid gland to produce thyroid hormones. To keep the thyroid gland from producing too much thyroid, the thyroid hormone called T4 keeps the brain to from producing more TSH.

TESTS TO DIAGNOSE LOW THYROID FYUCNTION: A blood test called TSH is the most dependable test to diagnose low thyroid function. People with low thyroid function usually have low blood levels of thyroid hormones, and very high levels of the brain hormone, TSH. Doctors diagnose low thyroid function when people have very high levels of the brain hormone, TSH and low levels of thyroid hormones.

SYMPTOMS OF LOW THROID FUNCTION: Most people who have high blood levels of TSH have signs of low thyroid function including tiredness, weakness, weight gain, and decreased deep tendon reflexes.

SUNBCLINICAL HYPOTHYROIDISM: Some people have high blood TSH levels, normal levels of thyroid hormones, and they also have no signs or symptoms of low thyroid function. Doctors call this subclinical hypothyroidism and they usually do not prescribe thyroid replacement pills. Now it appears that these people should also be treated with thyroid hormones, even if they have no symptoms of low thyroid function.

WHY PEOPLE WITH SUBCLINICAL HYPOTHYROIDISM SHOULD BE TREATED: A report from the University of Nebraska shows that people with an abnormal TSH thyroid test should receive thyroid pills, even if they have no symptoms of low thyroid function (1). This study showed that people with low TSH tests and no symptoms can have abnormal cholesterol levels as the only sign of low thyroid function.. See report #G171.1). Treatment with thyroid hormone was associated with fewer heart attacks and death during an eight-year period of observation in 40- to 70-year-old individuals with subclinical hypothyroidism, but not in those who were older than 70(2).

1) Effects of subclinical hypothyroidism and its treatment on serum lipids. Annals of Pharmacotherapy, 2003, Vol 37, Iss 5, pp 725-730 BA Ineck, TMH Ng. Ng TMH, Univ Nebraska, Med Ctr, Dept Pharm Practice,986045 Nebraska Med Ctr, Omaha,NE 68198 USA
2) Archives of Internal Medicine April 24, 2012

Checked 5/26/12

Hypothyroidism is a condition characterized by abnormally low thyroid hormone production. There are many disorders that result in hypothyroidism. These disorders may directly or indirectly involve the thyroid gland. Because thyroid hormone affects growth, development, and many cellular processes, inadequate thyroid hormone has widespread consequences for the body.

This article will focus specifically on hypothyroidism in adults.

What are thyroid hormones?

Thyroid hormones are produced by the thyroid gland. This gland is located in the lower part of the neck, below the Adam’s apple. The gland wraps around the windpipe (trachea) and has a shape that is similar to a butterfly – formed by two wings (lobes) and attached by a middle part (isthmus).

The thyroid gland uses iodine (mostly available from the diet in foods such as seafood, bread, and salt) to produce thyroid hormones. The two most important thyroid hormones are thyroxine (T4) and triiodothyronine (T3), which account for 99% and 1% of thyroid hormones present in the blood respectively. However, the hormone with the most biological activity is T3. Once released from the thyroid gland into the blood, a large amount of T4 is converted into T3 – the active hormone that affects the metabolism of cells.


Thyroid hormone regulation- the chain of command

The thyroid itself is regulated by another gland that is located in the brain, called the pituitary. In turn, the pituitary is regulated in part by the thyroid (via a “feedback” effect of thyroid hormone on the pituitary gland) and by another gland called the hypothalamus.

The hypothalamus releases a hormone called thyrotropin releasing hormone (TRH), which sends a signal to the pituitary to release thyroid stimulating hormone (TSH). In turn, TSH sends a signal to the thyroid to release thyroid hormones. If a disruption occurs at any of these levels, a defect in thyroid hormone production may result in a deficiency of thyroid hormone (hypothyroidism).

Hypothalamus – TRH


Pituitary- TSH


Thyroid- T4 and T3

The rate of thyroid hormone production is controlled by the pituitary gland. If there is an insufficient amount of thyroid hormone circulating in the body to allow for normal functioning, the release of TSH is increased by the pituitary gland in an attempt to stimulate more thyroid hormone production. In contrast, when there is an excessive amount of circulating thyroid hormone, TSH levels fall as the pituitary attempts to decrease the production of thyroid hormone. In persons with hypothyroidism, there is a persistent low level of circulating thyroid hormones.



T3 Thyroid Hormone to Treat Depression


The thyroid is a butterfly-shaped gland in the front of the neck. It produces hormones that control the speed of your metabolism — the system that helps the body use energy. Thyroid disorders can slow down or rev up your metabolism by disrupting the production of thyroid hormones. When hormone levels become too low or too high, you may experience a wide range of symptoms.



By Gabe Mirkin, MD, May 28, 2012  —  . If you are tired much of the time, your doctor will order blood tests for the two thyroid hormones called T3 and T4 and for the brain hormones called TSH and prolactin. If your TSH is high and your prolactin is normal, you are probably hypothyroid and need to take thyroid hormone to give you more energy and prevent heart and blood vessel damage.

Doctors treat people with low thyroid function with thyroid pills called T4 (Levothroid, one brand name is Synthroid). Many doctors think that a person needs only T4 because the thyroid gland makes T4 and then it is converted to T3 in other tissues. However, some people become depressed when they take just T4 and their depression can be cured when they take both thyroid hormones, T3 and T4.

When a depressed patient comes to me and is taking thyroid hormone, T4, I immediately order a blood test called TSH to check if he or she is getting the correct dose. If the TSH is normal, I reduce the dose of T4 by 50% and add a very low dose of T3 (brand name, Cytomel) because it safer to prescribe too low a dose, rather than too high a dose. Overdoses cause shakiness, irritability, irregular heart beats, clots, and osteoporosis. The patient returns in one month for a blood test, TSH, to see if the total thyroid dose is correct. If the TSH is too high, the thyroid dose is too low and I raise the T3 (Cytomel) dose by 5 to 10 m5 each month until the TSH is normal. Then once a year I check TSH blood levels to make sure that the person’s requirements for thyroid hormone are being met.

For example, the usual replacement dose for low thyroid function is 100 micrograms per day. If a depressed patient has a normal TSH, I reduce the T4 dose to 50 mcg/day and add 5 mcg of T3 per day. One month later, if the TSH blood is still too high I raise the T3 dose to 10 or 20 mcg and continue to increase the T3 level each month until the TSH is normal.

Exciting research shows that the thyroid hormone called T3 can help treat depression (1,2,3). Psychotherapy often fails to control depression. Sigmund Freud, the father of psychotherapy, proposed theories about depression, that many psychiatrists do not accept because his writings were his opinions and not presented as scientific data supported by controlled experiments. The dominant theory today is that depression is caused by low brain levels of the neurotransmitters, serotonin and norepinephrine. The drugs such as Paxil, Prozac and Zoloft that treat depression are supposed to raise brain levels of these neurotransmitters. Doctors can also raise brain levels of serotonin by prescribing pills containing T3, a hormone produced by peripheral tissue from T4, which is produced by the thyroid gland. (1) They also prescribe T3 by itself or together with antidepressants. Depression is common among people who have too much or too little thyroid hormone. Doctors usually treat low thyroid function with T4 also known as Levothroid and many people become even more depressed. They treat this depression by prescribing T3 as well as T4.

An article in the Journal of Clinical Psychiatry shows that T3 can be used to treat post traumatic stress disorder, commonly seen in soldiers and people who have been through other causes of terrible emotional trauma (13).

Try to balance T3 and T4 so you will not be taking too much thyroid and harm yourself. 1)If you now take 100 mcg of Levothroid (T4): 2) Lower T4 (Levothroid) to 50 mcg and add Cytomel (T3) 5 mcg each day. 3) One month later, have your doctor draw blood for TSH. 4) If it is normal, you are on the correct dose and should get blood tests TSH once a year. 5) If TSH is too high, increase Cytomel to 10 mcg and hold Levothroid at 50. 6) Draw monthly TSH until it is normal. Keep on raising Cytomel by 5 mcg until TSH is normal.


In some cases, hypothyroidism results from a problem with the pituitary gland, which is at the base of the brain. This gland produces thyroid-stimulating hormone (TSH), which tells the thyroid to do its job. If your pituitary gland does not produce enough TSH, your levels of thyroid hormones will fall. Other causes of hypothyroidism include temporary inflammation of the thyroid or medications that affect thyroid function.



Treating Hypothyroidism

If you are diagnosed with hypothyroidism, your doctor will most likely prescribe thyroid hormones in the form of a pill. This usually leads to noticeable improvements within a couple of weeks. Long-term treatment can result in more energy, lower cholesterol levels, and gradual weight loss. Most people with hypothyroidism will need to take thyroid hormones for the rest of their lives.



With the exception of certain conditions, the treatment of hypothyroidism requires life-long therapy. Before synthetic levothyroxine (T4) was available, desiccated thyroid tablets were used. Desiccated thyroid was obtained from animal thyroid glands, which lacked consistency of potency from batch to batch. Presently, a pure, synthetic T4 is widely available. Therefore, there is no reason to use desiccated thyroid extract.

As described above, the most active thyroid hormone is actually T3. So why do physicians choose to treat patients with the T4 form of thyroid? T3 [liothyronine sodium (Cytomel)] is available and there are certain indications for its use. However, for the majority of patients, a form of T4 [levothyroxine sodium (Levoxyl, Synthroid)] is the preferred treatment. This is a more stable form of thyroid hormone and requires once a day dosing, whereas T3 is much shorter-acting and needs to be taken multiple times a day. In the overwhelming majority of patients, synthetic T4 is readily and steadily converted to T3 naturally in the bloodstream, and this conversion is appropriately regulated by the body’s tissues.

  • The average dose of T4 replacement in adults is approximately 1.6 micrograms per kilogram per day. This translates into approximately 100 to 150 micrograms per day.
  • Children require larger doses.
  • In young, healthy patients, the full amount of T4 replacement hormone may be started initially.
  • In patients with preexisting heart disease, this method of thyroid replacement may aggravate the underlying heart condition in about 20% of cases.
  • In older patients without known heart disease, starting with a full dose of thyroid replacement may result in uncovering heart disease, resulting in chest pain or a heart attack. For this reason, patients with a history of heart disease or those suspected of being at high risk are started with 25 micrograms or less of replacement hormone, with a gradual increase in the dose at 6 week intervals.

Ideally, synthetic T4 replacement should be taken in the morning, 30 minutes before eating. Other medications containing iron or antacids should be avoided, because they interfere with absorption.

Therapy for hypothyroidism is monitored at approximately six week intervals until stable. During these visits, a blood sample is checked for TSH to determine if the appropriate amount of thyroid replacement is being given. The goal is to maintain the TSH within normal limits. Depending on the lab used, the absolute values may vary, but in general, a normal TSH range is between 0.5 to 5.0uIU/ml. Once stable, the TSH can be checked yearly. Over-treating hypothyroidism with excessive thyroid medication is potentially harmful and can cause problems with heart palpitations and blood pressure control and can also contribute to osteoporosis. Every effort should be made to keep the TSH within the normal range.


What are the symptoms of hypothyroidism?

The symptoms of hypothyroidism are often subtle. They are not specific (which means they can mimic the symptoms of many other conditions) and are often attributed to aging. Patients with mild hypothyroidism may have no signs or symptoms. The symptoms generally become more obvious as the condition worsens and the majority of these complaints are related to a metabolic slowing of the body. Common symptoms are listed below:

As the disease becomes more severe, there may be puffiness around the eyes, a slowing of the heart rate, a drop in body temperature, and heart failure. In its most profound form, severe hypothyroidism may lead to a life-threatening coma (myxedema coma). In a severely hypothyroid individual, a myxedema coma tends to be triggered by severe illness, surgery, stress, or traumatic injury. This condition requires hospitalization and immediate treatment with thyroid hormones given by injection.

Properly diagnosed, hypothyroidism can be easily and completely treated with thyroid hormone replacement. On the other hand, untreated hypothyroidism can lead to an enlarged heart (cardiomyopathy), worsening heart failure, and an accumulation of fluid around the lungs (pleural effusion</A.).< p>



How is hypothyroidism diagnosed?

A diagnosis of hypothyroidism can be suspected in patients with fatigue, cold intolerance, constipation, and dry, flaky skin. A blood test is needed to confirm the diagnosis.

When hypothyroidism is present, the blood levels of thyroid hormones can be measured directly and are usually decreased. However, in early hypothyroidism, the level of thyroid hormones (T3 and T4) may be normal. Therefore, the main tool for the detection of hyperthyroidism is the measurement of the TSH, the thyroid stimulating hormone. As mentioned earlier, TSH is secreted by the pituitary gland. If a decrease of thyroid hormone occurs, the pituitary gland reacts by producing more TSH and the blood TSH level increases in an attempt to encourage thyroid hormone production. This increase in TSH can actually precede the fall in thyroid hormones by months or years (see the section on Subclinical Hypothyroidism below). Thus, the measurement of TSH should be elevated in cases of hypothyroidism.

However, there is one exception. If the decrease in thyroid hormone is actually due to a defect of the pituitary or hypothalamus, then the levels of TSH are abnormally low. As noted above, this kind of thyroid disease is known as “secondary” or “tertiary” hypothyroidism. A special test, known as the TRH test, can help distinguish if the disease is caused by a defect in the pituitary or the hypothalamus. This test requires an injection of the TRH hormone and is performed by an endocrinologist (hormone specialist).

The blood work mentioned above confirms the diagnosis of hypothyroidism, but does not point to an underlying cause. A combination of the patient’s clinical history, antibody screening (as mentioned above), and a thyroid scan can help diagnose the precise underlying thyroid problem more clearly. If a pituitary or hypothalamic cause is suspected, an MRI of the brain and other studies may be warranted. These investigations should be made on a case by case basis.


What causes hypothyroidism?

Hypothyroidism is a very common condition. It is estimated that 3% to 5% of the population has some form of hypothyroidism. The condition is more common in women than in men, and its incidence increases with age.

Below is a list of some of the common causes of hypothyroidism in adults followed by a discussion of these conditions.

  • Hashimoto’s thyroiditis
  • Lymphocytic thyroiditis (which may occur after hyperthyroidism)
  • Thyroid destruction (from radioactive iodine or surgery)
  • Pituitary or hypothalamic disease
  • Medications
  • Severe iodine deficiency

Hashimoto’s Thyroiditis

The most common cause of hypothyroidism in the United States is an inherited condition called Hashimoto’s thyroiditis. This condition is named after Dr. Hakaru Hashimoto who first described it in 1912. In this condition, the thyroid gland is usually enlarged (goiter) and has a decreased ability to make thyroid hormones. Hashimoto’s is an autoimmune disease in which the body’s immune system inappropriately attacks the thyroid tissue. In part, this condition is believed to have a genetic basis. This means that the tendency toward developing Hashimoto’s thyroiditis can run in families. Hashimoto’s is 5 to 10 times more common in women than in men. Blood samples drawn from patients with this disease reveal an increased number of antibodies to the enzyme, thyroid peroxidase (anti-TPO antibodies). Since the basis for autoimmune diseases may have a common origin, it is not unusual to find that a patient with Hashimoto’s thyroiditis has one or more other autoimmune diseases such as diabetes or pernicious anemia ( B12 deficiency). Hashimoto’s can be identified by detecting anti-TPO antibodies in the blood and/or by performing a thyroid scan.

Lymphocytic thyroiditis following hyperthyroidism

Thyroiditis refers to inflammation of the thyroid gland. When the inflammation is caused by a particular type of white blood cell known as a lymphocyte, the condition is referred to as lymphocytic thyroiditis. This condition is particularly common after pregnancy and can actually affect up to 8% of women after they deliver. In these cases, there is usually a hyperthyroid phase (in which excessive amounts of thyroid hormone leak out of the inflamed gland), which is followed by a hypothyroid phase that can last for up to six months. The majority of affected women eventually return to a state of normal thyroid function, although there is a possibility of remaining hypothyroid.

Thyroid destruction secondary to radioactive iodine or surgery

Patients who have been treated for a hyperthyroid condition (such as Graves’ disease) and received radioactive iodine may be left with little or no functioning thyroid tissue after treatment. The likelihood of this depends on a number of factors including the dose of iodine given, along with the size and the activity of the thyroid gland. If there is no significant activity of the thyroid gland six months after the radioactive iodine treatment, it is usually assumed that the thyroid will no longer function adequately. The result is hypothyroidism. Similarly, removal of the thyroid gland during surgery will be followed by hypothyroidism.

Pituitary or Hypothalamic disease

If for some reason the pituitary gland or the hypothalamus are unable to signal the thyroid and instruct it to produce thyroid hormones, a decreased level of circulating T4 and T3 may result, even if the thyroid gland itself is normal. If this defect is caused by pituitary disease, the condition is called “secondary hypothyroidism.” If the defect is due to hypothalamic disease, it is called “tertiary hypothyroidism.”

Pituitary injury

A pituitary injury may result after brain surgery or if there has been a decrease of blood supply to the area. In these cases of pituitary injury, the TSH that is produced by the pituitary gland is deficient and blood levels of TSH are low. Hypothyroidism results because the thyroid gland is no longer stimulated by the pituitary TSH. This form of hypothyroidism can, therefore, be distinguished from hypothyroidism that is caused by thyroid gland disease, in which the TSH level becomes elevated as the pituitary gland attempts to encourage thyroid hormone production by stimulating the thyroid gland with more TSH. Usually, hypothyroidism from pituitary gland injury occurs in conjunction with other hormone deficiencies, since the pituitary regulates other processes such as growth, reproduction, and adrenal function. Medications

Medications that are used to treat an over-active thyroid (hyperthyroidism) may actually cause hypothyroidism. These drugs include methimazole (Tapazole) and propylthiouracil (PTU). The psychiatric medication, lithium (Eskalith, Lithobid), is also known to alter thyroid function and cause hypothyroidism. Interestingly, drugs containing a large amount of iodine such as amiodarone (Cordarone), potassium iodide (SSKI, Pima), and Lugol’s solution can cause changes in thyroid function, which may result in low blood levels of thyroid hormone.

Severe iodine deficiency:

In areas of the world where there is an iodine deficiency in the diet, severe hypothyroidism can be seen in 5% to 15% of the population. Examples of these areas include Zaire, Ecuador, India, and Chile. Severe iodine deficiency is also seen in remote mountain areas such as the Andes and the Himalayas. Since the addition of iodine to table salt and to bread, iodine deficiency is rarely seen in the United States.



Eat Only When You Are Active


By Gabe Mirkin MD, May 28, 2012


More than a third of all North Americans are obese and will die prematurely because of their excess fat. WHEN you eat may be even more important than HOW MUCH you eat. Never eat and go to bed. The safest time to eat is just before and after you exercise. Resting after you eat is an invitation for higher blood sugar and insulin levels, more weight gain, and increased risk for diabetes and heart attacks. The current obesity epidemic may well be caused by staying up later at night to snack and watch television.

MICE ALLOWED TO EAT ALL DAY LONG ARE FATTER. Mice that are placed on a high-fat diet gain far more weight when they are supplied with food 24 hours a day than when they can eat only for 8 hours a day, even though they eat the same number of calories per day (Cell Metabolism, published online May 17, 2012). Besides weighing more, the mice that could eat all day long had higher blood sugar and insulin levels, more liver damage, and higher blood levels of CRP, the blood test that measures inflammation.

MICE FED ONLY DURING SLEEPING HOURS ARE FATTER THAN THOSE FED DURING WAKING HOURS. Mice that were allowed to eat only during the 12 hours that they normally sleep gained significantly more weight (48 percent weight increase) than mice eating the same type and amount of food during the 12 hours they are normally awake (20 percent weight increase). Both groups ate the same total amount and type of food and were equally active (Obesity, published online Sept. 3, 2009).

HUMANS WHO SNACK SUFFER MORE DIABETES AND PREMATURE DEATH. Scientists at Karolinska Institutet surveyed 4,000 60-year-old, men and women. Compared to those who ate only breakfast, lunch and dinner, those who snacked between meals had larger waist circumferences and higher blood sugar, insulin, triglyceride and cholesterol levels than people who ate regular meals with less snacking (Obesity, 2008;16 (6):1302). These are all signs associated with metabolic syndrome, diabetes, heart attacks, and premature death.

STAY ACTIVE AFTER YOU EAT. Resting muscles are inactive and draw no sugar from your bloodstream. On the other hand, contracting muscles pull sugar from the bloodstream. They do not even require insulin to do this. If you eat and stand or walk, the contracting muscles can pull sugar from your bloodstream. However, when you eat and sit or lie down, your muscles draw no sugar from your bloodstream and blood sugar levels rise higher to increase risk for cell damage.

• HIGH INSULIN LEVELS: Your pancreas tries to lower the high blood sugar level, so it puts out ever increasing amounts of insulin.

• INCREASED RISK FOR HEART ATTACKS: Insulin constricts the arteries leading to your heart, to increase risk for a heart attack.

• HIGH TRIGLYCERIDES: When muscles are inactive, blood sugar levels rise. The extra sugar goes to your liver and other cells. Once your liver fills up with its own stored sugar called glycogen, it cannot store any more sugar. so all extra sugar is converted to a type of fat called triglycerides.

• LOW GOOD HDL CHOLESTEROL: High triglycerides increase risk for clotting, so your good HDL cholesterol works to save you by carrying triglycerides from your bloodstream to your liver. You use up your good HDL and blood levels of HDL drop.

• FATTY LIVER: The triglycerides accumulate in your liver to cause a fatty liver. A fatty liver cannot clear sugar from your bloodstream.

• DIABETES: Since the liver cannot clear sugar from your bloodstream, you develop even higher blood sugar levels and are now diabetic.

• HEART ATTACKS AND PREMATURE DEATH. Diabetes markedly increases risk for heart attacks, strokes, many cancers, and premature death.


Blood Test for Diabetes Predicts Cancer Risk in Women

By Gabe Mirkin MD, May 28, 2012  —  A blood test that measures blood sugar levels also can be used to predict who is at increased risk for cancer (International Journal of Cancer, April 26, 2012). HBA1C is a blood test that measures how much sugar is stuck on cells. People who have values 5.7 or higher are at increased risk for cancer, even if your doctor has not diagnosed you as having diabetes.

When blood sugar rises too high, sugar sticks to the outside surface of cell membranes. Once there, sugar can never get off. It is converted through a series of chemical reactions to sorbitol that destroys cells. Anything that raises blood sugar appears to increase cancer risk.

To keep your blood sugar low,
1) Avoid being overweight
2) Do not take sugared drinks in any form, including fruit juices, except during prolonged intense exercise
3) Avoid foods with added sugar
4) Avoid fried foods
5) Eat large amounts of fruits and vegetables
6) Do not eat red meat (blocks insulin receptors)
7) Exercise
8) Grow muscle
9) Reduce body fat
10) Keep blood levels of hydroxy-vitamin D above 75 nmol/L



C-Reactive Protein (CRP) and Inflammation



By Gabe Mirkin MD, May 28, 2012  —   Recent research shows that having a high C-Reactive Protein increases your risk of suffering a heart attack or stroke by twice as much as having a high cholesterol. C-Reactive Protein (CRP) is a blood test that measures inflammation, part of the immune reaction that protects you from infection when you injure yourself. It causes redness, pain and swelling, and can damage the inner lining of arteries, and break off clots from arteries to block the flow of blood to cause strokes and heart attacks.

CRP levels fluctuate from day to day, and levels increase with aging, high blood pressure, alcohol use, smoking, low levels of physical activity, chronic fatigue, coffee consumption, having elevated triglycerides, insulin resistance or diabetes, taking estrogen, eating a high protein diet, and suffering sleep disturbances, or depression. If you have none of these known causes, at this time the best ways we know to reduce CRP levels are exercise and a diet that includes omega-3 fatty acids. Statins appear to protect against inflammation as well as to lower cholesterol, but they can cause muscle pain in exercisers.

IF YOU HAVE A HIGH CRP, try to correct the known causes: infection, high blood pressure, alcohol use, smoking, low levels of physical activity, chronic fatigue, coffee consumption, having elevated triglycerides, insulin resistance or diabetes, taking estrogen, eating a high protein diet, and suffering sleep disturbances, or depression.

The most common cause of an elevated CRP is infection. If you have burning on urination, getting up in the night to urinate, urgency when your bladder is full of a feeling that you have to urinate all the time, check for a urinary tract infection. If you have wheezing and a chronic cough or shortness of breath, check for a lung infection. If you have belching and burning in your stomach, get an upper GI series X ray and blood test for Helicobacter. If you have diarrhea, check for an intestinal infection. If you have any of these infections, you have an accepted reason to take antibiotics. Your evaluation should include IGG and IGM antibody blood tests for chlamydia and mycoplasma. If either or both titres are high, I usually recommend taking doxycycline 100 mg twice a day for at least three weeks. Most doctors will not do this because they feel that data aren’t strong enough to warrant antibiotics at this time.




We would like to thank the loyalty and feedback of our over 4,300 readers, some of whom have been receiving ON TARGET since 1995. Several times a year we are asked what Target Health does and what are our accomplishments. The following summarizes what has happened over the last 12 months.


In 2012, Target Health celebrated its 19th year as a New York City-based, full-service e*CRO. Our full-time staff are dedicated to all aspects of the “paperless clinical trial,” complementing our expertise in Drug and Device Regulatory Affairs, Clinical Research Management, Biostatistics, Data Management, Internet-based clinical trials (Target e*CRF®), Medical Writing, and Strategic Planning. We provide turn-key development operations for small and medium size companies and have fully validated software for clinical trials. Patent # 8,041,581 B2 was issued in October 2011 for a System and Method for Collecting, Processing, and Storing Discrete Data Records Based Upon a Single Data Input (Target e*CTR®; eClinical Trial Record).


Highlights of the last 12 months include:


1. Regulatory approval of 3 NDAs and 1 PMA
  a. Gaucher disease – May 2012
  b. Cystic Fibrosis – May 2012
  c. Head Lice – February 2012
  d. Companion Diagnostic for NSCLC Drug – August 2011

2. Implementation of 3 paperless eSource clinical trials under 2 US INDs, using Target eCTR® (eClinical Trial Record; patent issued), the “electronic health record” for clinical trials
3. Publications:
  a. Mitchel, J, Kim, YJ, Choi, JH, et al. Evaluation of Data Entry Errors and Data Changes to an Electronic Data Capture (EDC) Clinical Trial Database. Drug Information Journal, 2011, 45:421-430.
  b. Morrison, B, Cochran, C, Giangrande, J, et al. Monitoring the quality of conduct of clinical trials: a survey of current practices. Clinical Trials, 2011; 8:342–349.
  c. Mitchel, J. and Schloss-Markowitz, J. Time for Change. International Journal of Clinical Trials, February 2011; 22-29.
  d. Tantsyura, V., Grimes, I., Mitchel, J. et al. Cost-Effective Approach To Managing Laboratory Reference Ranges For Local Laboratories, DIA Journal (2012, in press)
  e. Mitchel, J., Schloss-Markowitz, J., Yin, H. Lessons Learned From a Direct Data Entry (DDE) Phase 2 Clinical Trial Under a US IND. DIA Journal (2012, accepted for publication)
4. Three original IND submissions
5. Target Health member of the CTTI Steering Committee
6. Release of:
  a. Target e*CTR® v 1.2 (electronic health record for clinical trials; Patent # 8,041,581 B2)
  b. Target e*Studio® v 1.1 (generates Target e*CRF EDC applications
  c. Target Document® v 1.6 (eTMF document management)
  d. Target e*CTMS™ v 1.3 (Clinical trial management system)
  e. Target e*Pharmacovigilance® v 1.0 (Safety monitoring and generation of Form 3500A and CIOMS 1)
  f. Target Encoder® v 1.3 (MedDRA and WHO Drug coder)
  g. Target Monitoring Reports™ v 1.0 (online monitoring reports)


We are also very pleased to announce that Target Health has played a key role in bringing to market 35 new drug or device products. Of these approvals, there are now 25 products marketed world-wide that used Target e*CRF for their pivotal trials:


  1. NDA pancreatic Insufficiency – Cystic Fibrosis – Monitoring; DM; Statistics; Writing; NDA Preparation
  2. NDA – Gaucher Disease – EDC ; Regulatory Consulting, Toxicology, Monitoring; DM; Statistics; Writing, NDA, eCTD
  3. PMA – Companion Diagnostic – EDC
  4. NDA – Head Lice – EDC
  5. NDA/MAA – Hereditary Angioedema –Regulatory Affairs, EDC
  6. NDA Emergency Contraception –- EDC ; Regulatory Affairs, Monitoring; DM; Statistics; Writing
  7. NDA/MAA – Prostate Cancer – EDC
  8. NDA – Head Lice– EDC; Toxicology, Regulatory Consulting, Monitoring; DM; Statistics; Writing; NDA (eCTD)
  9. BLA – Autoinflammatory Disease – EDC
  10. NDA/MAA – Infertility – EDC ; DM; Statistics
  11. NDA/MAA – Infertility – EDC; DM; Statistics
  12. PMA – Periodontal Disease – GEM 21S (Biomimetic Therapeutics) – EDC; Monitoring; DM; Statistics; Writing
  13. Canada – Bone Fractures – GEM 21S (Biomimetic Therapeutics) – EDC; Monitoring; DM; Statistics; Writing
  14. PMA – Surgical Adhesions – REPEL CV (Synthemed, Inc. Approvable) – EDC; Monitoring; DM; Statistics; Writing; PMA (eCopy)
  15. PMA – Ten (10) Diagnostic Approvals (Abbott Laboratories) – EDC
  16. 510(k) – One (1) Diagnostic Approval (Abbott Laboratories) – EDC

Target Health now represents over 30 companies at FDA from all over the world including England, France, Germany, Israel, Korea, Switzerland and the US.
a. Oncology
  i. Bladder cancer
  ii. Colorectal cancer
  iii. Cancer imaging
  iv. Ovarian cancer
  v. Pancreatic cancer
b. Orphan Disease
  i. Gaucher disease
  ii. Cystic fibrosis
  iii. Scleroderma
  iv. Growth hormone
c. Cardiology
d. Counterterrorism
e. Dermatology
f. Fatty liver
g. Rheumatology
h. Somnolence
i. Traumatic brain injury
j. Ulcerative colitis
k. Vaccines

Target Health has expertise in preparation and publishing of electronic submissions and is an FDA approved vendor for electronic submissions through the Electronic Submissions Gateway (ESG).

Target e*CRF®: Target e*CRF (EDC) has now been used in over 250 clinical trials since 1999. Largest trial to date is over 7,000 patients.

Target eClinical Trial Record (Target e*CTR®): Target e*CTR allows the clinical study sites to perform direct data entry into any EDC system, and at the same time generates a read-only electronic document, which can be designated as the primary source data (eSource). These data, maintained in a secure, read-only trusted 3rd party environment, are available to the clinical study sites, monitors and regulatory agencies in a human readable format.

Target e*Studio®: Target e*studio allows users to build Target eCRF applications using a technology transfer business model.

Target Document®: Target Document is a user-friendly, inexpensive; highly sophisticated, Web-based, document management system that allows authorized users to view, download, and manage any document for their organization. – No More paper – Target Document can be used for the eTrial Master File (eTMF) and features include: 1) 21 CFR Part 11 compliance; 2) routing for electronic signatures; 3) email alerts; 5) communication tools.

Target Encoder®: Target Encoder is a user-friendly, inexpensive; highly sophisticated, Web-based, coding system that allows authorized users to automatically code MedDRA and WHO Drug and other types of dictionaries. Target Encoder is fully integrated with Target e*CRF.

Target e*CTMS®: Target e*CTMS is a user-friendly, inexpensive; highly sophisticated, Web-based, clinical trial management system. A new clinical trial starts with identification of the sponsor and project name. Investigators, IRBs and users are maintained within the CTMS and can be easily assigned to a project. All staff within a clinical site can be identified with their title and contact information, as well as shipping addresses which could be different from the head office. As the site commits to participate in the clinical trial, a site number can be assigned. Once IRB approval is obtained, and all regulatory documents have been identified as received, an alert can be sent out via email to allow for drug shipment. Target e*CTMS provides many additional features such as: 1) Decision Logs, 2) Meeting Logs with uploading of the meeting minutes, 3) Questions and Answers, 4) status of Regulatory Submissions and Deliverables, and 5) Monitor Site Visit Tracking with document upload.

Target Batch Edit Checks: With Target e*CRF®, batch edit checks are now integrated with the electronic query system within the study. Target e*CRF® runs the edits and displays the results of those edits through a discrepancy review screen integrated with the query system.

Target e*Pharmacovigilance®: Target e*CRF integrates EDC with a pharmacovigilance module by 1) allowing the principle investigators to enter a narrative, 2) allowing the medical monitor to enter a narrative and then have the EDC system generate an approved version of Form 3500A or CIOMS for regulatory submission with the ability to control the original and followup submissions.

EDC vendor for 2 NIH grants in Juvenile Rheumatoid Arthritis at the Cleveland Clinic and University of Washington. Collaboration with the Biotechnology Center at SUNY Stony Brook, Rutgers and UMDNJ (the Medical School of New Jersey).

Dr. Mitchel is a Course Director for Center for Biotechnology, Fundamentals of the Bioscience Industry, SUNY Stony Brook School of Medicine.

1. Mitchel, J, Kim, YJ, Choi, JH, et al. Evaluation of Data Entry Errors and Data Changes to an Electronic Data Capture (EDC) Clinical Trial Database. Drug Information Journal. 2011, 45:421-430.

2. Morrison, B, Cochran, C, Giangrande, J, et al. Monitoring the quality of conduct of clinical trials: a survey of current practices. Clinical Trials, 2011; 8:342–349.

3. Mitchel, J. and Schloss-Markowitz, J. Time for Change. International Journal of Clinical Trials, February 2011; 22-29.

4. Tantsyura, V, Grimes, I, Mitchel, J. et al. Cost-Effective Approach to Managing Laboratory Reference Ranges for Local Laboratories in Clinical Research, DIA Journal (2012; in Press).

5. Mitchel, J., Schloss-Markowitz, J., Yin, H. et al. Lessons Learned From a Direct Data Entry (DDE) Phase 2 Clinical Trial Under a US IND. Drug Information Journal (2012 accepted for publication)

Where Have All the Young Men Gone


This award winning photo was taken by Todd Heisler of The New York Times while he was a staff photographer at The Rocky Mountain News in 2005. The night before the burial of her husband’s body, Katherine Cathey, pregnant, refused to leave the coffin, asking to sleep next to his body for the last time. The Marines made a bed for her. Associated Press/Rocky Mountain News, Todd Heisler



The New York Times, Memorial Day Weekend, May 2012, by Lily Burana — In the run-up to every Memorial Day weekend, for the past several years, a certain photo takes top spot in those most circulated among my fellow military and veteran wives. On blogs, on social media sites, it is shared and “liked” over and over. Taken by the photographer Todd Heisler, from his 2005 award-winning series for the Rocky Mountain News, “Jim Comes Home,” which documents the return and burial of Marine Second Lt. Jim Cathey, who lost his life in Iraq, the photo shows his pregnant widow Katherine lying on an air mattress in front of his coffin. She’s staring at her laptop, listening to songs that remind her of Jim. Her expression is vacant, her grief almost palpable.


It is the one and only photo that makes me cry each time I see it. What brings the tears to my eyes is not just the bereaved young woman, but the Marine who stands behind her. In an earlier photo in the series, we see him building her a little nest of blankets on the air mattress. Sweet Lord, I cry just typing the words, the matter-of-fact tenderness is so overwhelming. So soldierly. But in this photo – the one that lives on and on online – he merely stands next to the coffin, watching over her. It is impossible to be unmoved by the juxtaposition of the eternal stone-faced warrior and the disheveled modern military wife-turned-widow, him rigid in his dress uniform, her on the floor in her blanket nest, wearing glasses and a baggy T-shirt, him nearly concealed by shadow while the pale blue light from the computer screen illuminates her like God’s own grace.


I believe this photo has had such a long viral life not just because it is so honest but also because it is so modern. During a spouse’s deployment, your laptop is your battle buddy. Your sense of connection and emotional well-being is sustained via e-mail, Facebook, Skype and Instagram. It appears, per Lieutenant Cathey’s widow, that the same is true even in a time of loss. This heartbreaking – and groundbreaking – photo showcases the intersection of technology and agony.


I’ll never forget trying to describe the photo to my friend Veronica, an Army wife. I was standing in her stately West Point living room, trying to detail what was so moving about the stalwart posture of the Marine, the listlessness of the grieving wife, my voice cracking, and before I was halfway through my description, tears started streaming down her face. It is testimonial to the image’s power that it even affects people who haven’t seen it.


The photo was later included in the book, “Final Salute,” which includes photographs by Mr. Heisler and is written by Jim Sheeler, a former Rocky Mountain News reporter. The book tells the story of United States Marines stationed in Colorado at Buckley Air Force Base whose duty was to notify families of deaths in Iraq and then escort the bodies home for burial. The book is based on a series that also won a Pulitzer Prize for Mr. Sheeler in 2006. Mr. Heisler, who now works for The New York Times, also won a separate Pulitzer for his photographs.


That photo has an equally poignant companion in the same series, a view from the civilian side, wherein Lieutenant Cathey’s coffin is being unloaded from the cargo hold of a commercial airplane in Reno as the passengers look on through the windows. You can practically read the thoughts on their solemn faces: “Who is that?” “What if that were my son or daughter?” “I can’t imagine what his family must be feeling.” “How sad” or “How noble.” I would bet you every penny I have that not one of them was thinking, “When the hell is this going to be over so we can get off this thing?” Two parents lost their son, a wife lost her husband, an unborn child lost his father, and a handful of average citizens saw just how seriously the military treats a fallen warrior’s final trip home.


Associated Press/Rocky Mountain News, Todd HeislerSecond Lt. James Cathey’s body arrived at the RenoAirport in 2005.



On one hand, you could view this as a perfect representation of how the majority of civilians are cosseted from the atrocities of war – they’re in the comfy, climate-controlled cabin, untouched by tragedy and free to move on, to gather their luggage, head on home, and forget about it. On the other hand, you could view it as I do: A stunning moment that makes clear our connectivity. They all took that journey together, and on that airport tarmac, the much-discussed gap between civilians and the military was closed, a bond forever fused by the passengers’ bearing witness to the final stage of a sacrifice that was both foreign to them and for them.


I believe that the civilian-military gap isn’t always born of indifference, but rather, at times, a sense of helplessness on the civilian side. What can I do? If you do nothing else, you can remember those who have given their lives for their country. Our country. Remembrance, which may seem a modest contribution in the moment, is a sacred act with long-term payoff – a singularly human gift that keeps on giving, year after, year after, war-fatigued year. I don’t need to remind you that America’s sons and daughters are still dying in combat. I don’t want to browbeat you into feeling guilty for not doing more. Instead, I want to tell you that as the wife of a veteran, it is tremendously meaningful to know that on this Memorial Day, civilians will be bearing witness and remembering in their own way – that those who are gone are not forgotten. I also want to say that as you remember them, we remember you.


Thank you.


Lily Burana is the author of “I Love a Man in Uniform: A Memoir of Love War and Other Battles” (Weinstein Books). Her husband, a former soldier, is a veteran of Operation Desert Storm and Operation Iraqi Freedom.


“Give Peace a Chance”

Where Have All the Flowers Gone?

Startup Makes ‘Wireless Router for the Brain’


Mind control: This optogenetics system makes it possible to control brain cells with light in freely moving animals. The prototype plugs in to an implant in an animal’s brain.               Source:  Kendall Research



Kendall Research’s devices could make optogenetics research much more practical.



MIT Technology Review, by Courtney Humphries  Optogenetics has been hailed as a breakthrough in biomedical science—it promises to use light to precisely control cells in the brain to manipulate behavior, model disease processes, or even someday to deliver treatments.

But so far, optogenetic studies have been hampered by physical constraints. The technology requires expensive, bulky lasers for light sources, and a fiber-optic cable attached to an animal—an encumbrance that makes it difficult to study how manipulating cells affects an animal’s normal behavior.

Now Kendall Research, a startup in Cambridge, Massachusetts, is trying to free optogenetics from these burdens. It has developed several prototype devices that are small and light and powered wirelessly. The devices would allow mice and other small animals to move freely. The company is also developing systems to control experiments automatically and remotely, making it possible to use the technique for high-throughput studies.

Christian Wentz, the company’s founder, began the work while a student in Ed Boyden’s lab at MIT. He was studying ways to make optogenetics more useful for research on how the brain affects behavior. Optogenetics relies on genetically altering certain cells to make them responsive to light, and then selectively stimulating them with a laser to either turn the cells on or off. Instead of a laser light source, Kendall Research uses creatively packaged LEDs and laser diodes, which are incorporated into a small head-borne device that plugs into an implant in the animal’s brain.

The device, which weighs only three grams, is powered wirelessly by supercapacitors stationed below the animal’s cage or testing area. Such supercapacitors are ideal for applications that need occasional bursts of power rather than a continuous source. The setup also includes a wirelessly connected controller that plugs into a computer through a USB. “It’s essentially a wireless router for the brain,” says Wentz.

The wireless capabilities allow researchers to control the optogenetics equipment remotely, or even schedule experiments in advance.

Casey Halpern, a neurosurgeon at the University of Pennsylvania and one of several researchers beta-testing the device, says the physical impediments of current optogenetics techniques are tremendous. “You almost can’t do any behavioral experiment in a meaningful way,” he says.


Halpern, for instance, studies feeding behavior, and would like to understand how activating or inhibiting specific groups of neurons change the way mice eat. The ability to test that question right in the animal’s cage without a human in the room makes it more likely the animal will behave normally.

Wentz says that while the cost of the initial setup is comparable to a single laser system, it can be scaled up far more cheaply. This, coupled with the ability to remotely control experiments, would make it easier to conduct optogenetics experiments in a high-throughput fashion.

Kendall Research plans to make it possible to collect data from the brain through the device. The data could then be wirelessly transmitted to a computer. Sanjay Magavi, a research scientist at Vertex Pharmaceuticals, says while “it isn’t yet clear how this will be used in industry,” there’s increasing interest in using optogenetics in animals to develop more sophisticated models of disease for preclinical drug testing.

Congratulations to Dr. Tibor Sipos as FDA Approves Pertzye!



FDA Approves Pertzye (pancrelipase) Delayed-Release Capsules for the Treatment of Pancreatic Insufficiency Due to Cystic Fibrosis or Other Conditions



Target Health congratulates our good friend and colleague for receiving FDA approval of Pertzye (pancrelipase) Delayed-Release Capsules. Pertzye is indicated for the treatment of exocrine pancreatic insufficiency due to cystic fibrosis or other conditions. Dr. Sipos had championed Pancrease development while at JnJ and subsequently developed this unique delayed release formulation while at Digestive Care Inc. (DCI).


Target Health has been working with DCI on this and other programs since 1999. In addition, Dr. Jules Mitchel and Dr. Tibor Sipos have been colleagues and friends for over 20 years, so this is a very special event both professionally and personally. We both want to thank Dr. Glen Park and his terrific regulatory team at Target Health for guiding this program through FDA.




Target Health is at BioMed Israel this coming week of May 20 – 17, 2012


Tel Aviv Sunset Over the Mediterranean



For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website at

Neuroscience and the Electronic Pavlov Dog


(Credit: ©TheSupe87 / Fotolia)



Hungry dogs naturally salivate at the sight of food. Pavlov rang a bell before feeding the dog. After repeated bell-food pairings, the bell also caused the dogs to salivate. Nanotechnology scientists and memory researchers at the Kiel University redesigned a mental learning process using electronic circuits. The bell rings and the dog starts 1) ___. Such a reaction was part of studies performed by Ivan Pavlov, a famous Russian psychologist and physiologist and winner of the Nobel Prize for Physiology and Medicine in 1904. His experiment, nowadays known as “Pavlov’s Dog,” is ever since considered as a milestone for implicit learning processes. By using specific electronic components scientists form the Technical Faculty and the Memory Research at the Kiel University together with the Forschungszentrum Julich were now able to mimic the behavior of Pavlov`s 2) ____.


The study is published in the current issue of Advanced Functional Materials.


Digital and biological information processing are based on fundamentally different principles. Modern computers are able to work on mathematical-logical problems at an extremely high pace. In fact, procedures in the computer’s central processing unit and in the storage media run serially. While digital computers have shown immense success throughout the years in certain fields, they reveal weaknesses when it comes to pattern 3) ___ and cognitive tasks. However, to imitate biological information processing systems recognition and cognitive tasks are essential. Mammal brains — and therefore also the brains of humans — decode information in complex neuronal networks of synapses with up to 1014 (100 Trillion) connections. However, the connectivity between neurons is not fixed. “Learning means that new connections between 4) ___ are created, or existing connections are reinforced or weakened,” says PD Dr. Thorsten Bartsch of the Clinic for Neurology. This is called neuronal plasticity.


Is it possible to design neural circuits with electronic devices to mimic learning? At this crossroad between neurobiology, material science and nanoelectronics, scientists from the University of Kiel are collaborating with their colleagues from the Research Center Julich. Now, they have succeeded in electronically recreating the classical “5) ___ Dog” experiment. “We used memristive devices in order to mimic the associative behavior of Pavlov’s dog in form of an electronic circuit,” explains Professor Hermann Kohlstedt, head of the working group Nanoelectronics at the University of Kiel.


Memristors are a class of electronic circuit elements which have only been available to scientists in an adequate quality for a few years. They exhibit a memory characteristic in form of hysteretic current-voltage curves consisting of high and low resistance branches. In dependence on the prior charge flow through the device these resistances can vary. Scientists try to use this memory effect in order to create networks that are similar to neuronal connections between 6) ___. “In the long term, our goal is to copy the synaptic plasticity onto electronic circuits. We might even be able to recreate cognitive skills electronically,” says Kohlstedt. The collaborating scientific working groups in Kiel and Jülich have taken a small step toward this goal.


The project set-up consisted of the following: two electrical impulses were linked via a memristive device to a comparator. The two pulses represent the food and the 7) ___ in Pavlov’s experiment. A comparator is a device that compares two voltages or currents and generates an output when a given level has been reached. In this case, it produces the output signal (representing saliva) when the threshold value is reached. In addition, the memristive element also has a threshold voltage that is defined by physical and chemical mechanisms in the nano-electronic device. Below this threshold value the memristive device behaves like any ordinary linear resistor. However, when the threshold value is exceeded, a hysteretic (changed) current-voltage characteristic will appear.


“During the experimental investigation, the food for the dog (electrical impulse One) resulted in an output signal of the comparator, which could be defined as salivation. Unlike impulse One, the ring of the bell (electrical impulse Two) was set in such a way that the compartor’s output stayed unaffected — meaning no salivation,” describes Dr. Martin Ziegler, scientist at the Kiel University and the first-author of the publication. After applying both impulses simultaneously to the memristive device, the threshold value was exceeded. The working group had activated the memristive memory function. Multiple repetitions led to an associative learning process within the circuit — similar to Pavlov’s dogs. “From this moment on, we had only to apply electrical impulse Two (bell) and the comparator generated an output signal, equivalent to salivation,” says Ziegler and is very pleased with these results. Electrical impulse One (feed) triggers the same reaction as it did before the learning. Hence, the electric circuit shows a behavior that is termed classical conditioning in the field of behavioral 8) ___. Beyond that, the scientists were able to prove that the electrical circuit is able to unlearn a particular behavior if both impulses were no longer applied simultaneously.


ANSWERS: 1) drooling (or salivating); 2) dog; 3) recognition; 4) neurons; 5) Pavlov’s; 6) synapses; 7) bell; 8) psychology

Lenin’s Stroke: Doctor Has a Theory (and a Suspect) (1870 – 1924)


The Soviet leader Vladimir Ilyich Lenin on his death bed, in an undated photo
Photo Credit: Associated Press



The patient founded a totalitarian state known for its “merciless terror,” Dr. Victoria Giffi told a rapt audience of doctors and medical students. He died suddenly at 6:50 p.m. on Jan. 21, 1924, a few months before his 54th birthday. The cause of death: a massive stroke.


The man’s cerebral arteries, Dr. Giffi added, were “so calcified that when tapped with tweezers they sounded like stone.”

The occasion was a Clinicopathological Conference, at the University of Maryland, where clinicopathological conferences focus on historical figures and have been an annual event for the past 19 years.

At these conferences, a mysterious medical case is presented to an audience of doctors and medical students. Attending doctors have reviewed the case records.  In the end, a pathologist solves the mystery with a diagnosis.

This May 2012, was a conference with a twist. The patient was long dead — he was, in fact, Vladimir Ilyich Lenin. The questions posed to the conference speakers: Why did he have a fatal stroke at such a young age? Was there something more to his death than history has acknowledged?

On Friday, two experts were called upon to solve the mystery of Lenin’s death: Dr. Harry Vinters, professor of neurology and neuropathology at the University of California, Los Angeles, and Lev Lurie, a Russian historian in St. Petersburg.

Dr. Vinters began by telling the audience some details of Lenin’s medical and family history.

As a baby, Lenin had a head so large that he often fell over. He used to bang his head on the floor, making his mother worry that he might be mentally disabled.

As an adult, Lenin suffered diseases that were common at the time: typhoid, toothaches, influenza and a painful skin infection called erysipelas. He was under intense stress, of course, which led to insomnia, migraines and abdominal pain.

At 38, he was shot twice in an assassination attempt. One bullet lodged in his collarbone after puncturing his lung. Another got caught in the base of his neck. Both bullets remained in place for the rest of his life.

Lenin’s father died early, too, at 54. The cause of death was said to be cerebral hemorrhage, but Lenin’s father had an illness at the time of his death that may have been typhoid fever.

Most of Lenin’s seven brothers and sisters died young, two in infancy. A brother was executed at age 21 for plotting to assassinate Emperor Alexander III, and another brother died of typhoid at 19. Of the three who survived past young adulthood, a sister died of a stroke at age 71, another sister died of a heart attack at 59, and a brother died at age 69 of “stenocardia,” an archaic medical term whose meaning is no longer clear.

In the two years before he died, Lenin had three debilitating strokes. Prominent European doctors were consulted and proposed a variety of diagnoses: nervous exhaustion, chronic lead intoxication from the two bullets lodged in his body, cerebral arteriosclerosis and “endarteritis luetica.”

Dr. Vinters speculates that the last term referred to meningovascular syphilis, inflammation of the walls of blood vessels mainly around the brain, resulting in a thickening of the interior of the vessel. But there was no evidence of this on autopsy, and Lenin’s syphilis test was said to have been negative. He had been treated anyway with injections of a solution containing arsenic, the prevailing syphilis remedy.

Then, in his last hours and days of his life, Lenin experienced severe seizures.

An autopsy revealed a near total obstruction of the arteries leading to the brain, some of which were narrowed to tiny slits. But Lenin did not have some of the traditional risk factors for strokes.

He did not have untreated high blood pressure — had that been his problem, the left side of his heart would have been enlarged. He did not smoke and would not tolerate smoking in his presence. He drank only occasionally and exercised regularly. He did not have symptoms of a brain infection, nor did he have a brain tumor.

So what brought on the stroke that killed Lenin?

The clues lie in Lenin’s family history, Dr. Vinters said. The three siblings who survived beyond their 20s had evidence of cardiovascular disease, and Lenin’s father died of a disease that was described as being very much like Lenin’s. Dr. Vinters said Lenin might have inherited a tendency to develop extremely high cholesterol, causing the severe blockage of his blood vessels that led to his stroke.

Compounding that was the stress Lenin experienced, which can precipitate a stroke in someone whose blood vessels are already blocked.

But Lenin’s seizures in the hours and days before he died are a puzzle and perhaps historically significant. Severe seizures, Dr. Vinters said in an interview before the conference, are “quite unusual in a stroke patient.”

But, he added, “almost any poison can cause seizures.”

Dr. Lurie concurred on Friday, telling the conference that poison was in his opinion the most likely immediate cause of Lenin’s death. The most likely perpetrator? Stalin, who saw Lenin as his main obstacle to taking over the Soviet Union and wanted to get rid of him.

Communist Russia in the early 1920s, Dr. Lurie told the conference, was a place of “Mafia-like intrigue.”

In 1921 Lenin started complaining that he was ill. From then until his death in 1924, Lenin “began to feel worse and worse,” Dr. Lurie said.

“He complained that he couldn’t sleep and that he had terrible headaches. He could not write, he did not want to work,” Dr. Lurie said. He wrote to Alexei Maximovich Gorky, “I am so tired, I do not want to do anything at all.”

But he nonetheless was planning a political attack on Stalin, Dr. Lurie said. And Stalin, well aware of Lenin’s intentions, sent a top-secret note to the Politburo in 1923 claiming that Lenin himself asked to be put out of his misery.

The note said: “On Saturday, March 17th in the strictest secrecy Comrade Krupskaya told me of ‘Vladimir Ilyich’s request to Stalin,’ namely that I, Stalin, should take the responsibility for finding and administering to Lenin a dose of potassium cyanide. I felt it impossible to refuse him, and declared: ‘I would like Vladimir Ilyich to be reassured and to believe that when it is necessary I will fulfill his demand without hesitation.’”

Stalin added that he just could not do it: “I do not have the strength to carry out Ilyich’s request and I have to decline this mission, however humane and necessary it might be, and I therefore report this to the members of the Politburo.”

Dr. Lurie said Stalin might have poisoned Lenin despite this assurance, as Stalin was “absolutely ruthless.”

Dr. Vinters believes that sky-high cholesterol leading to a stroke was the main cause of Lenin’s death. But he said there is one other puzzling aspect of the story. Although toxicology studies were done on others in Russia, there was an order that no toxicology be done on Lenin’s tissues.

So the mystery remains.

But if Lenin had lived today, or if today’s cholesterol-lowering drugs had been available 100 years ago, might he have been spared those strokes?

“Yes,” Dr. Vinters said. “Lenin could have gone on for another 20 or 25 years, assuming he wasn’t assassinated. History would have been totally different.”



Lev Lurie, Ph.D., is a teacher, journalist, and broadcaster based in St. Petersburg, Russia. His Ph.D., dissertation, earned at Leningrad State University in 1987, was entitled “Social- Demographic Characteristics of the Revolutionary Movement in Russia 1810-1880,” and he has been recognized as one of the leading scholars on the life of Vladimir Lenin. From 1978 to 1991, Lurie was a senior researcher at the State Museum of History of Leningrad, and in 1989 was a founder of the first classical gymnasium in Russia where he serves as vice director for academic affairs and teacher of history. He is author of more than one hundred scientific articles on Russian history and has been a columnist for several magazines and newspapers. In 2011, Lurie founded and continues to serve as creative director of the independent education and cultural center Lev Lurie’s Dom Kultury.


Harry Vinters, M.D., is professor of pathology and laboratory medicine in the department of neurology at the David Geffen School of Medicine at UCLA. He received his medical degree from the University of Toronto Faculty of Medicine in 1976, interned at the University of Alberta Hospital, and received residency training in neuropathology at the University of Western Ontario. Vinters followed with a fellowship in pediatric neuropathology at Vancouver General Hospital and became board certified in neuropathology by the American Board of Pathology in 1981. He pursued an additional fellowship in neuropathology at the University of Iowa Hospitals and Clinics in 1982. Vinters’ practice is located at the Ronald Reagan UCLA Medical Center, and he serves as chief of neuropathology and as a member of its Brain Research Institute.


Experts differ on the likely causes of the stroke that killed Lenin at 53.
Photo Credit: The New York Times


The body of Vladimir Lenin , the Soviet state founder lies in the Mausoleum of Lenin on Red Square. Doctors say , the founder of Russian communism, may have died because of stress, family medical history or of poison given to him by his political successor Joseph Stalin, opposing a popular theory that he died of sexually-transmitted disease syphilis.
Photo: Peter Andrews/Reuters

Source: The New York Times, May 2012, by Gina Kolata

Coffee Drinkers Have Lower Risk of Death



According to an article published in the New England Journal of Medicine (2012; 366:1891-1904), older adults who drank coffee – caffeinated or decaffeinated – had a lower risk of death overall than others who did not drink coffee. The coffee drinkers were also less likely to die from heart disease, respiratory disease, stroke, injuries and accidents, diabetes, and infections, although the association was not seen for cancer. These results from a large study of older adults were observed after adjustment for the effects of other risk factors on mortality, such as smoking and alcohol consumption. The authors caution, however, that they can’t be sure whether these associations mean that drinking coffee actually makes people live longer.


The study examined the association between coffee drinking and risk of death in 400,000 U.S. men and women ages 50 to 71 who participated in the NIH-AARP Diet and Health Study. Information about coffee intake was collected once by questionnaire at study entry in 1995-1996. The participants were followed until the date they died or Dec. 31, 2008, whichever came first. Results showed that the association between coffee and reduction in risk of death increased with the amount of coffee consumed. Relative to men and women who did not drink coffee, those who consumed three or more cups of coffee per day had approximately a 10% lower risk of death. Coffee drinking was not associated with cancer mortality among women, but there was a slight and only marginally statistically significant association of heavier coffee intake with increased risk of cancer death among men.


The investigators caution that coffee intake was assessed by self-report at a single time point and therefore might not reflect long-term patterns of intake. Also, information was not available on how the coffee was prepared (espresso, boiled, filtered, etc.). The authors considered it possible that preparation methods may affect the levels of any protective components in coffee.


According to the authors the mechanism by which coffee protects against risk of death – if indeed the finding reflects a causal relationship – is not clear, because coffee contains more than 1,000 compounds that might potentially affect health.

Paralyzed Individuals Use Thought-Controlled Robotic Arm to Reach and Grasp


In an ongoing clinical trial, a paralyzed woman was able to reach for and sip from a drink on her own – for the first time in nearly 15 years – by using her thoughts to direct a robotic arm. The trial, funded in part by the National Institutes of Health, is evaluating the safety and feasibility of an investigational device called the BrainGate neural interface system. This is a type of brain-computer interface (BCI) intended to put robotics and other assistive technology under the brain’s control. NIH has supported basic and applied research in this area for more than 30 years. In 2009 and 2010, an additional $3.8 million in NIH funding was made possible through the Recovery Act.


The report published in Nature (2012;485:372-375), describes how two individuals – both paralyzed by stroke – learned to use the BrainGate system to make reach-and-grasp movements with a robotic arm, as part of the BrainGate2 clinical trial. The report highlights the potential for long-term use and durability of the BrainGate system, part of which is implanted in the brain to capture the signals underlying intentional movement. It also describes the most complex functions to date that anyone has been able to perform using a BCI.


For the woman, it was the first time since her stroke that she was able to sip a drink without help from a caregiver.


The BrainGate neural interface system consists of a sensor to monitor brain signals and computer software and hardware that turns these signals into digital commands for external devices. The sensor is a baby aspirin-sized square of silicon containing 100 hair-thin electrodes, which can record the activity of small groups of brain cells. It is implanted into the motor cortex, a part of the brain that directs movement.


The latest analysis from the BrainGate2 trial focused on two participants – a 58-year-old woman and a 66-year-old man. Both individuals are unable to speak or move their limbs because of brainstem strokes they had years ago – the woman’s in 1996 and the man’s in 2006. In the trial, both participants learned to perform complex tasks with a robotic arm by imagining the movements of their own arms and hands. In one task, several foam targets were mounted on levers on a tabletop and programmed to pop up one at a time, at different positions and heights. The participants had less than 30 seconds to grasp each target using the DEKA Arm System (Generation 2), which is designed to work as a prosthetic limb for people with arm amputations. One participant was able to grasp the targets 62% of the time, and the other had a 46% success rate. In some sessions, the woman controlled a DLR Light-Weight Robot III arm, which is heavier than the DEKA arm and designed to be used as an external assistive device. She used this arm prior to the DEKA arm in the foam target task, and had a success rate of 21%. In other sessions with the DLR arm, her task was to reach for a bottled drink, bring it to her mouth and sip from a straw. She was able to complete four out of six attempts.


The authors noted the woman’s ability to use the BrainGate was especially encouraging because her stroke occurred nearly 15 years ago and her sensor was implanted more than five years ago. Some researchers have wondered whether neurons in the motor cortex might die or stop generating meaningful signals after years of disuse. Researchers in the field have also worried that years after implantation, the sensor might break down and become less effective at enabling complex motor functions.


As the trial continues, the BrainGate research team needs to test the technology in more individuals. They envision a system that would be stable for decades, wireless and fully automated. For now, the sensor – and therefore the user – must be connected via cables to the rest of the system. Prior to each session with the robotic arms, a technician had to perform a calibration procedure that lasted 31 minutes on average. Improvements are also needed to enhance the precision and speed of control. In the foam target task, for example, a successful reach-and-grasp motion typically took almost 10 seconds.


The ultimate goal for helping people with paralysis is to reconnect the brain directly to paralyzed limbs rather than robotic ones. In the future, the BrainGate system might be used to control a functional electrical stimulation (FES) device, which delivers electrical stimulation to paralyzed muscles. Such technology has shown promise in monkeys. The Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD) has long supported the clinical trial research for BrainGate, with the goal of enabling mental control of an FES system for limb movement. In previous reports from the BrainGate2 trial, a participant was able to use the BrainGate system to direct the movements of a virtual, computer-animated arm designed to simulate FES control of a real arm.


To support this research, NIH has worked closely with the Department of Veterans Affairs (VA) and the Defense Advanced Research Projects Agency (DARPA), the research arm of the Department of Defense. DARPA supports development of the DEKA arm. Development of the DLR arm is funded by the German aerospace agency DLR. NIH has supported the fundamental neuroscience and BCI development, and the clinical research in collaboration with the VA.


The BrainGate trial began in 2004 and was run by Cyberkinetics Inc., in collaboration with Brown University and MGH. NICHD began funding the trial in 2005. After Cyberkinetics withdrew from the research for financial reasons, funding continued through this NICHD contract, MGH became the clinical trial and administrative lead, and the trial was renamed BrainGate2. The trial is currently recruiting.

New Clues on How ApoE4 Affects Alzheimer’s Risk



Alzheimer’s disease is the most common cause of dementia in older adults, and affects more than 5 million Americans. A hallmark of the disease is a toxic protein fragment called beta-amyloid that accumulates in clumps, or plaques, within the brain. Gene variations that cause higher levels of beta-amyloid are associated with a rare type of Alzheimer’s that appears early in life, between age 30 and 60. However, it is the ApoE4 gene variant that is most strongly tied to the more common, late-onset type of Alzheimer’s disease. Inheriting a single copy of ApoE4 from a parent increases the risk of Alzheimer’s disease by about three-fold. Inheriting two copies, one from each parent, increases the risk by about 12-fold.


While common variants of the ApoE gene are strongly associated with the risk of developing late-onset Alzheimer’s disease, the gene’s role in the disease has been unclear. Now, according to an article published online in Nature (16 May 2012), it was discovered that mice having the most risky variant of ApoE damages the blood vessels that feed the brain. The study found that the high-risk variant, ApoE4, triggers an inflammatory reaction that weakens the blood-brain barrier, a network of cells and other components that lines brain’s brain vessels. Normally, this barrier allows nutrients into the brain and keeps harmful substances out.


The ApoE gene encodes a protein that helps regulate the levels and distribution of cholesterol and other lipids in the body. The gene exists in three varieties. ApoE2 is thought to play a protective role against both Alzheimer’s and heart disease, ApoE3 is believed to be neutral, and ApoE4 confers a higher risk for both conditions. Outside the brain, the ApoE4 protein appears to be less effective than other versions at clearing away cholesterol; however, inside the brain, exactly how ApoE4 contributes to Alzheimer’s disease has been a mystery.


The study evaluated several lines of genetically engineered mice, including one that lacks the ApoE gene and three other lines that produce only human ApoE2, ApoE3 or ApoE4. Mice normally have only a single version of ApoE. The authors found that mice whose bodies made only ApoE4, or made no ApoE at all, had a leaky blood-brain barrier. With the barrier compromised, harmful proteins in the blood made their way into the mice’s brains, and after several weeks, authors were able to detect loss of small blood vessels, changes in brain function, and a loss of connections between brain cells.


The study also found that ApoE2 and ApoE3 help control the levels of an inflammatory molecule called cyclophilin A (CypA), but ApoE4 does not. Levels of CypA were raised about five-fold in blood vessels of mice that produce only ApoE4. The excess CypA then activated an enzyme, called MMP-9, which destroys protein components of the blood-brain barrier. Treatment with the immunosuppressant drug cyclosporine A, which inhibits CypA, preserved the integrity of the blood-brain barrier and lessened damage to the brain. An inhibitor of the MMP-9 enzyme had similar beneficial effects. In prior studies, inhibitors of this enzyme have been shown to reduce brain damage after stroke in animal models.

Next Page →