UPDATE FROM TARGET HEALTH INC. – HIGHLIGHTS OF THE YEAR

 

 

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

REGULATORY AFFAIRS
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

ELECTRONIC SUBMISSIONS
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).

CLINICAL TRIAL SOFTWARE PACKAGES
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.

ACADEMIC COLLABORATIONS
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.

PUBLICATIONS
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 www.targethealth.com

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.

TARGET HEALTH excels in Regulatory Affairs. Each week we highlight new information in this challenging area.

 

 

FDA Approves Generic Versions of Blood Thinner Plavix

 

 

The FDA last week approved generic versions of the blood thinning drug Plavix (clopidogrel bisulfate), which helps reduce the risk of heart attack and stroke by making it less likely that platelets in the blood will clump and form clots in the arteries. Clopidogrel is FDA-approved to treat patients who have had a recent heart attack or a recent stroke, or have partial or total blockage of an artery (peripheral artery disease).

 

According to Keith Webber, Ph.D., deputy director of the Office of Pharmaceutical Science in the FDA’s Center for Drug Evaluation and Research, “for people who must manage chronic health conditions, having effective and affordable treatment options is important,” and that “the generic products approved today will expand those options for patients.”

 

Clopidogrel has a boxed warning to alert health care professionals and patients that the drug may not work well for those with certain genetic factors that affect how the body metabolizes the drug. Patients can be tested for these genetic factors to ensure that clopidogrel is the right choice for them. Also, certain medicines, such as proton pump inhibitors Prilosec (omeprazole) and Nexium (esomeprazole), reduce the effect of clopidogrel, leaving a person at greater risk for heart attack and stroke.

 

Clopidogrel may cause bleeding, which can be serious and sometimes lead to death. While taking the drug, people may bruise and bleed more easily, be more likely to have nose bleeds, and it may take longer for all bleeding to stop. Clopidogrel is dispensed with a patient Medication Guide that provides important instructions on its use and drug safety information.

 

Dr. Reddy’s Laboratories, Gate Pharmaceuticals, Mylan Pharmaceuticals, and Teva Pharmaceuticals have gained FDA approval for 300 milligram (mg) clopidogrel. Apotex Corporation, Aurobindo Pharma, Mylan Pharmaceuticals, Roxane Laboratories, Sun Pharma, Teva Pharmaceuticals, and Torrent Pharmaceuticals have received approval for 75 mg clopidogrel.

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