Science Weekly: The Book of Human Life – second edition

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The first map of human genetic variation; homeopathy on the NHS; the space shuttle; a ‘liberal gene’; plus, an eco-tour of Hampstead Heath

EDC in Korea

Target Health is pleased to announce Mr. Yong Joong Kim, Mr. Joonhyuk Choi and Dr. Mitchel will be in Korea the 2nd week of December to launch Target e*CRF® with our Korean partner, LSK. LSK led by Dr. Jack Lee, is our CRO partner in Korea. LSK is very strong in data management and statistics and has been pushing us to build a version of Target e*CRF which would allow them to build EDC applications for the Asian markets.

Last week, Dr. Jules Mitchel and Joyce Hays attended the week long TEDMED conference in San Diego, CA.

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. Target Health’s software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.

Breathing For Better Lung Health

While working to find novel ways to treat the life-threatening disease of cystic fibrosis, researchers at the University of North Carolina discovered that the rhythmic motion of the lungs during normal breathing is a critical regulator of the clearance of 1) ___ and other noxious materials. Their research, funded by the Cystic Fibrosis Foundation and the National Institute of Health, was published in The Journal of Physiology.

Their findings have important implications in the understanding and treatment of cystic fibrosis (CF), the most common fatal 2) ___ disease in the United States (30,000 sufferers) and the UK (7,500 sufferers). As a result of CF, the body produces abnormally thick, sticky 3) ___ that clogs the lungs, leading to difficulty in breathing and chronic, life-threatening lung infections.

Dr. Brian Button and colleagues at the University of North Carolina’s Cystic Fibrosis Research and Treatment Center found that the rhythmic motion of the lung during normal 4) ___ is important in establishing the rate of mucus clearance and can help the lung in responding to changes in lung environment, such as during a lung infection.

More importantly, in CF, they found that rhythmic 5) ___ of the lung can result in re-hydration of the airways and acceleration of mucus clearance, thus promoting lung health in CF patients. The researchers speculate that this may explain the preservation of mucus clearance in young CF patients prior to the onset of chronic infections.

The UNC researchers also suggest that these studies provide an understanding of the mechanism underlying the observed beneficial effects of physical and deep-breathing exercise in CF patients. “We believe that knowledge gained in these studies will be useful in developing novel therapeutic regimes to increase mucus 6) ___ in the lungs of CF patients”, said Dr. Button.

ANSWERS: 1) bacteria; 2) genetic; 3) mucus; 4) breathing; 5) motion; 6) clearance

Elliott P. Joslin MD (1869-1962)

Dr. Elliott P. Joslin (1899)                      “EPJ” (1961)

Dr. Joslin – most often referred to as “EPJ” – is considered a pioneer in diabetes. He was the first doctor in the U.S. to specialize in the disease, and this distinction is the first of many “firsts” associated with him. Everyone who works in the diabetes field at some point learns about EPJ. What makes him unique is both his early interest in a little known disease and his vision as to how to treat it.

Elliott Proctor Joslin was born in 1869 in Oxford, Mass. He attended Yale University and Harvard Medical School. In the late 19th century, diabetes was considered a very obscure disease and there was little treatment, but both personal and professional experiences led EPJ to becoming one of the few doctors to pursue this area of medicine.

EPJ’s Aunt Helen was diagnosed with diabetes while he was in college. He studied up on her disease and coincidentally was assigned to a student who had diabetes during his third year in medical school. He was challenged by the outcomes of these patients and began a listing of his patients in large accounting books, complete with all the facts, progress and outcomes. This was the beginning of the first diabetes registry in the world. He then compared his data with public statistics and the field of diabetes epidemiology was launched.

This enormous amount of data that Dr. Joslin collected from his patients was written in ledgers, referred to as the “black books.” He was ahead of anyone in terms of compiling diabetes statistics – so much so that the Metropolitan Life Insurance Company arranged to use Dr. Joslin’s statistics for their actuarial tables. This remains the largest collection of clinical data on diabetes in the world.

EPJ saw his first patient in 1898 at his parent’s townhouse on 517 Beacon St. He practiced at Beacon Street until late 1905 when he moved his office to 81 Bay State Road. His townhouse and building next door served his practice and staff for the next 50 years. In 1956 the office was moved to its current location at One Joslin Place. Joslin Clinic was the world’s first diabetes care facility.

Ironically EPJ’s mother was diagnosed one year after he began his practice. Her progress and the work of a German professor shaped EPJ’s theory about how diabetes should be managed and it reflects his future thinking on the matter: diagnose diabetes early, treat the condition vigorously, which included the use of carbohydrate-restricted diets and fasting, and get regular exercise. He assembled 1,000 of his own cases into the first diabetes textbook, The Treatment of Diabetes Mellitus, in which he outlined how he reduced the death rate of his patients by 20%. This was the beginning of EPJ’s theory that managing tight control of one’s blood glucose through diet, exercise and constant testing could extend one’s life and prevent complications.

Two years later he published the Diabetic Manual – for the Doctor and Patient. This was the first diabetes patient handbook, and it detailed how the patient could take control of the disease. The significance of this book can’t be overemphasized – educating patients about diabetes was the first step toward people feeling empowered instead of victimized by the disease. This became the Joslin approach and to this day, the goals of JoslinCare practiced in Joslin Clinic and by Joslin Affiliates are to live a healthy and happy life while managing a chronic disease.

In addition to putting the patient front and center, Dr. Joslin expanded the role of nurses after the discovery of insulin in 1923. The “wandering nurses” would go out into the community to instruct people with diabetes about insulin management, diet and exercise. Now we know these nurses as certified diabetes educators.

EPJ also was the first to name diabetes as a serious public health issue. Just after WWII he lamented to the Surgeon General of the U.S. Public Health Service that diabetes was an epidemic and challenged the government to do a study in the town of his birthplace, Oxford, Mass. The study was started in 1946 and carried out over the next 20 years. The results confirmed EPJ’s belief that diabetes was becoming an epidemic. As a result of this study it was the very first time diabetes was named a public health issue.

Dr. Joslin’s practice grew enormously after insulin was introduced. He worked with other diabetes specialists, such as Leo Krall, M.D., Howard Root, M.D., and Priscilla White, M.D., and they all followed the Joslin way of treating the patient using a team approach.

The Joslin practice reflected EPJ’s early writings and his theory of strict control of blood glucose, frequent testing and daily exercise to prevent diabetes complications. One distinctive characteristic of EPJ’s approach involves his belief in the “troika,” the Russian word meaning threesome. EPJ created a three-horse chariot to reflect his philosophy of living with diabetes – the three-horse motif symbolized insulin, diet and exercise, which are needed to achieve “victory” over diabetes. Five years later, in 1953, he incorporated the figure into the signage for the Diabetes Foundation, Inc. Horses were important to EPJ, and he drew upon them during his career.

This is part of The Diabetic Creed he included in the 4-8th editions of the Patient Manual and some explanation of the Troika:


Three horses draw the diabetic chariot and their names are diet, exercise and insulin. In fact, all of us in our life’s journey depend on the three, but seldom recognize the third although we often realize we are poor charioteers. Yet we fortunate ones have instinct to help us hold the reins, but the diabetic cannot trust his instincts as a guide, and in place of it must depend upon dieticians, nurses and doctors unless he understands his disease.

EPJ’s approach to diabetes management was debated for decades by other endocrinologists and scientists. But EPJ did not live to see his theory validated. He died in 1962, at the age of 92, at his home in Brookline, Mass. It wasn’t until 1993 that EPJ’s approach was supported by the 10-year study, “The Diabetes Control and Complications Trial Report,” published in the prestigious New England Journal of Medicine. The study demonstrated that the onset of diabetes complications was delayed by tight blood glucose control. To honor Dr. Joslin’s foresight, buttons were produced for Joslin Clinic patients and staff that read “I Told You So.”

Improving Mothers’ Literacy Skills May Be Best Way To Boost Children’s Achievement

A study funded by the National Institutes of Health (NIH) has concluded that programs to boost the academic achievement of children from low income neighborhoods might be more successful if they also provided adult literacy education to parents. The study based its conclusion on their finding that a mother’s reading skill is the greatest determinant of her children’s future academic success, outweighing other factors, such as neighborhood and family income. The analysis, performed by Narayan Sastry, Ph.D., of the University of Michigan, and Anne R. Pebley, Ph.D., of the University of California, Los Angeles, and published in Demography (2010;47:777-800), examined data on more than 3,000 families.

The analysis was based on data collected between April 2000 and December 2001 as part of the Los Angeles Family and Neighborhood Survey, an ongoing examination of families in 65 LA county communities. The information included the results of reading and math assessments of 2,350 children ages 3 to 17, their mothers’ education level, census records of neighborhood income, and family income and assets. The participants in the study were representative of the larger Los Angeles community. Results showed that neighborhood income had the largest impact on achievement for children ages 8 to 17, who are at the middle and higher end of the age range. This is consistent with the idea that the environment outside the home becomes more important as children grow older. According to the authors, the analysis gives a chance to isolate the different factors that affect children’s achievement and that policy measures to encourage mixed-income neighborhoods, improve early childhood education, and build mothers’ reading skills each could have positive effects on children’s achievement scores.

Severe Sepsis Associated With Later Cognitive, Physical Decline

In sepsis, immune system chemicals released into the blood to combat serious infection trigger widespread inflammation. This can lead to low blood pressure, heart weakness, and organ failure. Anyone can get sepsis, but infants, children, older people, and those with weakened immune systems are most vulnerable. People with sepsis often receive treatment in hospital intensive care units to combat the infection, support vital organs and prevent a drop in blood pressure.

According to an article published in the Journal of the American Medical Association (2010;304:1787-1794), older adults who survive hospitalization involving severe sepsis are at higher risk for cognitive impairment and physical limitations than older adults hospitalized for other reasons. The study found that an older person’s risk of cognitive decline increased almost threefold following hospitalization for severe sepsis. It was also found that severe sepsis was associated with greater risk for the development of at least one new limitation in performing daily activities following hospitalization.

For the study, data obtained from the NIA-supported Health and Retirement Study (HRS) were analyzed for the cognitive and physical function of older people before and after hospitalization for severe sepsis. The HRS is a long-term study that collects information on the health, economic and social factors influencing the health and well-being of a nationally representative sample of Americans over age 50. Study data on participants 65 and older are linked to Medicare claims data to enable detailed analysis of medical conditions and health status.

The study analyzed Medicare claims data from 516 people who survived 623 hospitalizations for severe sepsis between 1998 and 2005. The average age of participants was 77 at the time of hospitalization. Also examined were the individuals’ HRS data on cognitive function, measured through standard tests. Physical limitations were measured by the need for assistance in six activities of daily living basic self-care tasks (walking, dressing, bathing, eating, toileting and getting into and out of bed) and five instrumental activities of daily living (preparing a hot meal, shopping for groceries, making telephone calls, taking medicines and managing money), which are associated with the ability to live independently. For comparison, the study analyzed Medicare and HRS data on 4,517 survivors of 5,574 non-sepsis general hospitalizations during this time period.

Results showed that almost 60% of hospitalizations for severe sepsis were associated with worsened cognitive and/or physical function among survivors in the first survey following hospitalization. The risk of progression to moderate or severe cognitive impairment in sepsis survivors was 3.3 times higher than their risk before hospitalization. Severe sepsis was associated with the development of 1.6 new functional limitations among patients with no limitations before sepsis. In contrast, patients who did not develop sepsis and had no functional limitations before hospitalization developed an average of 0.5 new functional limitations. Non-sepsis hospital admissions were not associated with an increased risk for cognitive decline.

The HRS, now in its 18th year, follows more than 22,000 people over the age of 50, collecting data every two years, from pre-retirement to advanced age.


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Anaplastic Lymphoma Kinase Inhibition in Non–Small-Cell Lung Cancer

Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in a subgroup of non–small-cell lung cancers, representing 2 to 7% of such tumors. As a result, a study published in the New England Journal of Medicine (2010;363:1693-1703), was performed to explore the therapeutic efficacy of inhibiting ALK in such tumors in an early-phase clinical trial of crizotinib (PF-02341066), an orally available small-molecule inhibitor of the ALK tyrosine kinase.

The study screened tumor samples from approximately 1,500 patients with non–small-cell lung cancer for the presence of ALK rearrangements and identified 82 patients with advanced ALK-positive disease who were eligible for the clinical trial. Most of the patients had received previous treatment. These patients were enrolled in an expanded cohort study instituted after phase 1 dose escalation had established a recommended crizotinib dose of 250 mg twice daily in 28-day cycles. Patients were assessed for adverse events and response to therapy.

Results showed that patients with ALK rearrangements tended to be younger than those without the rearrangements, and most of the patients had little or no exposure to tobacco and had adenocarcinomas. At a mean treatment duration of 6.4 months, the overall response rate was 57% (47 of 82 patients, with 46 confirmed partial responses and 1 confirmed complete response); 27 patients (33%) had stable disease. A total of 63 of 82 patients (77%) were continuing to receive crizotinib at the time of data cutoff, and the estimated probability of 6-month progression-free survival was 72%, with no median for the study reached. The drug resulted in grade 1 or 2 (mild) gastrointestinal side effects.

According to the authors, the inhibition of ALK in lung tumors with the ALK rearrangement resulted in tumor shrinkage or stable disease in most patients.

TARGET HEALTH excels in Regulatory Affairs and Public Policy issues. Each week we highlight new information in these challenging areas.

FDA approves Latuda to Treat Schizophrenia In Adults

Schizophrenia affects about 1% of the U.S. population, ages 18 years and older, in a given year. The most prominent symptoms include hallucinations, delusions, disordered thinking and behavior, and suspiciousness. Hearing voices that other people don’t hear is the most common type of hallucination. These experiences can make people with the disorder fearful and withdrawn.

The FDA has approved Latuda (lurasidone HCl) tablets for the treatment of adults with schizophrenia. Latuda is included in the atypical antipsychotic class of drugs. All atypical antipsychotics contain a boxed warning alerting prescribers to an increased risk of death associated with off-label use of these drugs to treat behavioral problems in older people with dementia-related psychosis. No drug in this class is approved to treat patients with dementia-related psychosis.

Four six-week controlled studies of adults with schizophrenia demonstrated the effectiveness and safety of Latuda. In the trials, patients treated with Latuda had fewer symptoms of schizophrenia than those taking an inactive pill (placebo).

The most common adverse reactions reported by those in clinical trials were drowsiness, feelings of restlessness and the urge to move (akathisia), nausea, movement abnormalities such as tremors, slow movement, or muscle stiffness (Parkinsonism), and agitation.

Latuda is manufactured by Sunovion Pharmaceuticals Inc. of Fort Lee, N.J.

For more information about our expertise in Medical Affairs, contact Dr. Mark L. Horn. For Regulatory Affairs, please contact Dr. Jules T. Mitchel or Dr. Glen Park.