Marfan and Loeys-Dietz Syndromes – Antoine Marfan MD, Harry (Hal) C. Dietz MD, Bart Leo Loeys MD, PhD
Antoine Marfan; portrait by Henry Bataille
Antoine Bernard-Jean Marfan (June 23, 1858 – February 11, 1942) was a French pediatrician. He was born in Castelnaudary (d?partement Aude, Languedoc-Roussillon) to Antoine Prosper Marfan and Adelaide Thuries. He began his medical studies in Toulouse, where he stayed for two years before moving to Paris. He graduated in 1886, his education having been interrupted by a period of military service. In 1914 he became a professor of infantile hygiene in the pediatric clinic of the University of Paris. During the same year, he became a member of the Acad?mie de M?decine.
In 1896, Marfan described a hereditary disorder of connective tissue which became known as Marfan syndrome. The term Marfan’s syndrome was first used by Henricus Jacobus Marie Weve (1888-1962) of Utrecht in 1931. Today, it is thought that Marfan’s patient (a five year old girl named Gabrielle) was affected by a condition known as congenital contractural arachnodactyly (Beals syndrome), and not Marfan’s syndrome.
Further eponymous medical conditions named after Antoine Marfan include:
1. Dennie-Marfan syndrome
2. Marfan’s hypermobility syndrome
3. Marfan’s law
4. Marfan’s sign
5. Marfan’s symptom
6. Marfan-Madelung syndrome
Marfan also had interests in the pediatric aspects of tuberculosis, nutrition and diphtheria. With Jacques-Joseph Grancher (1843-1907) and Jules Comby (1853-1947), he was co-publisher of Trait? des maladies de l’enfance. From 1913 to 1922, he was publisher of the journal Le Nourrisson.
Harry (Hal) C. Dietz MD
Loeys-Dietz syndrome is a recently discovered autosomal dominant genetic syndrome which has many features similar to Marfan syndrome, but which is caused by mutations in the genes encoding transforming growth factor beta receptor 1 (TGFBR1) or 2 (TGFBR2). It was identified and characterized by American physician Harry C. Dietz and Belgian physician Bart L. Loeys, for whom it is named. There are currently two forms of Loeys-Dietz syndrome which are further subdivided into another two forms.
A de novo mutation in TGFB3, a ligand of the TGF beta pathway, was identified in an individual with a syndrome presenting partially overlapping symptoms with Marfan Syndrome and Loeys-Dietz Syndrome.
The main clinical characteristics include:
1. Widely spaced eyes (orbital hypertelorism)
2. Cleft palate orbifid uvula(a split in the tissue that hangs down in the back of the throat)
3. Aortic and arterial aneurysms/dissections with tortuosity (corkscrew structure) of the arteries.
Other findings can include:
1. Scoliosis or Kyphosis
2. Indented or protruding chest wall (pectus excavatum or pectus carinatum)
3. Contractures of fingers and toes (camptodactyly)
4. Long fingers and lax joints
5. Club foot
6. Premature fusion of the skull bones (craniosynostosis)
7. Joint hypermobility
8. Congenital heart problems including patent ductus arteriosus (connection between the aorta and the lung circulation) and atrial septal defect (connection between heart chambers)
9. Translucency of the skin with velvety texture
10. Abnormal junction of the brain and medulla (Arnold-Chiari malformation)
11. Bicuspid aortic valves
Many of the physical findings typical in Loeys-Dietz syndrome are also found in Marfan syndrome cases, including increased risk of ascending aortic aneurysm and aortic dissection, abnormally long limbs and fingers, and dural ectasia (a gradual stretching and weakening of the dura mater that can cause abdominal and leg pain). However, it also has some additional traits not typical of Marfan patients, including widely spaced eyes, a split uvula in the back of the throat, and skin findings such as easy bruising or abnormal scars.
As there is no known cure, Loeys-Dietz syndrome is a lifelong condition. Due to the high risk of death from aortic aneurysm rupture, patients should be followed closely to monitor aneurysm formation, which can then be corrected with vascular surgery. Previous research in laboratory mice has suggested that the angiotensin II receptor antagonist losartan, which appears to block TGF-beta activity, can slow or halt the formation of aortic aneurysms in Marfan syndrome. A large clinical trial sponsored by the NIH is currently underway to explore the use of losartan to prevent aneurysms in Marfan syndrome patients. Both Marfan syndrome and Loeys-Dietz syndrome are associated with increased TGF-beta signaling in the vessel wall.
Bart Loeys is a Professor in the Institute of Genetic Medicine and at the University of Ghent in Belgium. He was intimately involved in the recognition and characterization of the Loeys-Dietz syndrome. He continues to work on the genetic basis of aortic aneurysm conditions.
Risk Stratification at Diagnosis for Children with Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is a condition in which the heart muscle becomes thick. Often, only one part of the heart is thicker than the other parts. The thickening can make it harder for blood to leave the heart, forcing the heart to work harder to pump blood.
According to an article published in The Lancet (2013;382:1889-1897), treatment of children with hypertrophic cardiomyopathy might be improved if the risk of death or heart transplantation could be predicted by risk factors present at the time of diagnosis.
The study analyzed data from the Pediatric Cardiomyopathy Registry, which collected longitudinal data for 1085 children with HCM from 1990 to 2009. The goal of the study was to understand how patient factors measured at diagnosis predicted the subsequent risk of the primary outcome of death or heart transplantation. The Kaplan-Meier method was used to calculate time-to-event rates from time of diagnosis to the earlier of heart transplantation or death for children in each subgroup. Cox proportional-hazards regression was used to identify univariable and multivariable predictors of death or heart transplantation within each causal subgroup.
Results showed that at 2 years, the poorest outcomes were recorded for the 69 children with pure HCM with inborn errors of metabolism, for whom the estimated rate of death or heart transplantation was 57%. Children with mixed functional phenotypes also did poorly, with rates of death or heart transplantation of 45% for the 69 children with mixed hypertrophic and dilated cardiomyopathy and 38% for the 58 children with mixed hypertrophic and restrictive cardiomyopathy. For children diagnosed with hypertrophic cardiomyopathy at younger than 1 year, the rate of death or transplantation was 21%. For children diagnosed with HCM and a malformation syndrome, the rate of death or transplantation was 23%. Excellent outcomes were reported for the 407 children who were diagnosed with idiopathic HCM at age 1 year or older, with a rate of death or heart transplantation of 3%. The risk factors for poor outcomes varied according to HCM subgroup, but they generally included young age, low weight, presence of congestive heart failure, lower left ventricular fractional shortening, or higher left ventricular end-diastolic posterior wall thickness or end-diastolic ventricular septal thickness at the time of cardiomyopathy diagnosis. For all HCM subgroups, the risk of death or heart transplantation was significantly increased when two or more risk factors were present and also as the number of risk factors increased.
According to the authors, in children with HCM, the risk of death or heart transplantation was greatest for those who presented as infants or with inborn errors of metabolism or with mixed hypertrophic and dilated or restrictive cardiomyopathy. Risk stratification by subgroup of cardiomyopathy, by characteristics such as low weight, congestive heart failure, or abnormal echocardiographic findings, and by the presence of multiple risk factors allows for more informed clinical decision making and prognosis at the time of diagnosis.
Overweight Adolescents and Life Events in Childhood
According to an article published in Pediatrics (2013;132:1506-1512), a study was performed to 1) test the association of life events in childhood with overweight risk in adolescence; 2) examine the effects of chronicity, timing, intensity, valence, and type of life events; and 3) test potential moderators.
For the study, mothers of children enrolled in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Study of Early Child Care and Youth Development responded to the Life Experiences Survey at ages 4, 9, and 11 years. Using logistic regression analysis, the authors tested the association of experiencing many negative life events with being overweight at age 15 years, controlling for child gender, race/ethnicity, maternal education, and maternal obesity. Child gender, maternal education, maternal obesity, child’s ability to delay gratification for food, and maternal sensitivity were tested as moderators.
Results showed that among the 848 study children (82% non-Hispanic white), experiencing many negative life events was associated with a higher risk of overweight (odds ratio: 1.47). Greater chronicity and negative valence of the event were associated with greater overweight risk; timing of exposure and maternal reported impact of the event were not. The association was more robust for events related to family physical or mental health and among children of obese mothers and children who waited longer for food.
According to the authors, children who experience many negative life events are at higher risk of being overweight by age 15 years. The authors added that future work should investigate mechanisms involved in this association, particularly those connected to appetitive drive and self-regulation, and that these mechanisms may hold promise for obesity prevention strategies.
TARGET HEALTH excels in Regulatory Affairs. Each week we highlight new information in this challenging area.
FDA Approves Sovaldi for Chronic Hepatitis C
Hepatitis C is a viral disease that causes inflammation of the liver that can lead to diminished liver function or liver failure. Most people infected with HCV have no symptoms of the disease until liver damage becomes apparent, which may take several years. Some people with chronic HCV infection develop scarring and poor liver function (cirrhosis) over many years, which can lead to complications such as bleeding, jaundice (yellowish eyes or skin), fluid accumulation in the abdomen, infections or liver cancer. According to the Centers for Disease Control and Prevention, about 3.2 million Americans are infected with HCV.
The FDA has approved Sovaldi (sofosbuvir) to treat chronic hepatitis C virus (HCV) infection. Sovaldi is the first drug that has demonstrated safety and efficacy to treat certain types of HCV infection without the need for co-administration of interferon. Sovaldi is a nucleotide analog inhibitor that blocks a specific protein needed by the hepatitis C virus to replicate. Sovaldi is to be used as a component of a combination antiviral treatment regimen for chronic HCV infection. There are several different types of HCV infection. Depending on the type of HCV infection a patient has, the treatment regimen could include Sovaldi and ribavirin or Sovaldi, ribavirin and peginterferon-alfa. Ribavirin and peginterferon-alfa are two drugs also used to treat HCV infection.
Sovaldi’s effectiveness was evaluated in six clinical trials consisting of 1,947 participants who had not previously received treatment for their disease (treatment-naive) or had not responded to previous treatment (treatment-experienced), including participants co-infected with HCV and HIV. The trials were designed to measure whether the hepatitis C virus was no longer detected in the blood at least 12 weeks after finishing treatment (sustained virologic response), suggesting a participant’s HCV infection has been cured.
Results from all clinical trials showed a treatment regimen containing Sovaldi was effective in treating multiple types of the hepatitis C virus. Additionally, Sovaldi demonstrated efficacy in participants who could not tolerate or take an interferon-based treatment regimen and in participants with liver cancer awaiting liver transplantation, addressing unmet medical needs in these populations.
The most common side effects reported in clinical study participants treated with Sovaldi and ribavirin were fatigue and headache. In participants treated with Sovaldi, ribavirin and peginterferon-alfa, the most common side effects reported were fatigue, headache, nausea, insomnia and anemia.
Sovaldi is the third drug with breakthrough therapy designation to receive FDA approval. The FDA can designate a drug as a breakthrough therapy at the request of the sponsor if preliminary clinical evidence indicates the drug may demonstrate a substantial improvement over available therapies for patients with serious or life-threatening diseases. Sovaldi was reviewed under the FDA’s priority review program, which provides for an expedited review of drugs that treat serious conditions and, if approved, would provide significant improvement in safety or effectiveness.
Sovaldi is the second drug approved by the FDA in the past two weeks to treat chronic HCV infection. On November 22, the FDA approved Olysio (simeprevir).
Sovaldi is marketed by Gilead, based in Foster City, Calif. Olysio is marketed by Raritan, N.J.-based Janssen Pharmaceuticals.
Target e*CTR® (eClinical Trial Record), the eSource Solution for Clinical Trials, When Fully Integrated with EDC Systems, Eliminates Paper Source Records and Provides Significant Cost Savings
Target e*CTR® (eClinical Trial Record), the eSource solution for clinical trials:
1. enables clinical research sites to enter subject level data directly into EDC system at the time of the office visit, thus dramatically reducing the need for paper source records, and source document verification and review.
2. coupled with direct data-entry (DDE) and real-time, risk-based monitoring, can save pharmaceutical companies a minimum of $10,000 per site per year. For larger pharmaceutical companies, this one factor alone can translate to cost savings of $50,000,000 to $80,000,000 per year.
3. provides sites with a contemporaneous, independent, investigator copy (CIIC) of the trial data – no other EDC system provides this capability today.
4. has been implemented in 16 clinical trials under 10 INDs (drugs) and 1 IDE (devices).
Additional Advantages Include the Following:
1. Knowledge about issues in real time enables rapid fire corrective actions.
2. Improved quality of data with associated cost savings.
a. Lessons learned across sites achieve better overall quality at lower cost.
b. Reduces the number of protocol violations.
c. Reduces the number of queries.
3. Increased productivity savings accrued to the clinical study sites.
a. Once the subject leaves the clinic, the only activity is responding to queries.4. Improved site/sponsor relationships allows for a more focused level of cooperation.
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. Mitchelor Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website, and if you like the weekly newsletter, ON TARGET, you’ll love the Blog.
THANKSGIVING CALORIES, Plus Fat Alert Quiz (scroll down)
Do You Know the Calories in Thanksgiving Food?
Thanksgiving Weekend Fat Alert Quiz
Q:Weight loss occurs in the belly before anywhere else. ___________
Check One: A) True or B) False
Whether you’re an apple shape with excess belly fat or a pear with wide hips and thighs, when you lose weight, you’ll most likely lose proportionately more from the abdominal region than elsewhere. Belly fat is more metabolically active and easier to lose than subcutaneous fat under the skin, especially if you have plenty of it.
Q:Belly (abdominal) fat is also known as _______________ fat.
Check One: A) Brown; B) Visceral; C) Baby; D) Saturated or E) All of the above?
Belly is fat is also called visceral fat, which is found deep in the belly and around internal organs. There is no disputing the fact that visceral fat is the most dangerous for our health. Visceral fat is easy to lose and can be lost without any changes to your diet.
Q:Crunches (sit-ups) will flatten your belly. _____________
Check One: A) True or B) False
Hundreds of crunches each day won’t flatten your belly if you need to lose weight. If your abdominal muscles aren’t covered with excess fat, strengthening them can help you look tighter and thinner, but spot exercises won’t banish belly fat.
Q:Men have too much belly fat if their waists are more than 40 inches around. _______
Check One: A) True or B) False
Men with waists that measure more than 40 inches have too much belly fat and may be at risk for heart disease and other conditions. Men in this situation should lose weight.
Q:Eating a diet rich in ______________ helps to reduce fat.
Check One: A) Whole grains or B) Dairy?
Eating a diet rich in whole grains (which also tend to be higher in fiber) helps improve insulin sensitivity. This, in turn, helps the body more efficiently use blood glucose, lowers blood glucose levels, and reduces fat deposition.
Q:Which food is considered a whole grain? ____________
Check One: A) Popcorn; B) Broccoli; C) Peas; D) All of the above
A whole grain is a grain that still has its outer covering, which is nutritionally rich in vitamins, minerals, and fiber. Examples of whole grains include popcorn, whole grain corn, whole oats/oatmeal, brown rice, whole rye, whole grain barley, wild rice, buckwheat, triticale, bulgur (cracked wheat), millet, quinoa, sorghum, and 100% whole wheat flour. Please note that many commercially available microwave popcorns have additional ingredients which can add calories to these products.
Q:Belly fat acts like an organ in the body. _________________
Check One: A) True or B) False
Belly fat doesn’t just lay idle at your beltline. Researchers describe it as an active “organ” in your body — one that churns out hormones and inflammatory substances. Abdominal fat is thought to break down easily into fatty acids, which flow directly into the liver and into muscle. Fats and clots get into the bloodstream, and that sets the stage for diabetes, heart disease, and more.
Q:Can skinny people have hidden belly fat? __________
Check One: A) Yes or 2) No
Even skinny people can have unhealthy hidden belly fat. Research shows that fat may be folded deep inside the belly around the stomach organs, visible only by CT or MRI imaging. This fat puts skinny people at the same health risks as someone with more obvious big girth, researchers say.
Q:What is the golden path to belly fat loss? __________
Check One: A) Liposuction; B) Bariatric surgery; C) Walking; D) Tummy tuck
Exercise such as walking is the golden path to help lose belly fat. Cutting calories is part of it, but physical activity is really the answer. Liposuction can’t get rid of enough fat to eliminate the health risks. Bariatric (gastric bypass) surgery, though more effective, is not ideal.
Q:Who collects more belly fat? ______________
Check One: A) Men; B) Women; C) Both
Men tend to collect more belly fat than women, and it starts early in life. In adolescence and post-adolescence, men start collecting abdominal fat. It’s one of the reasons men have more coronary disease than women.
Government Healthcare in the 1700s 1800s 1900s and 2000s
Campus of the NIH in Bethesda, Maryland
Editor’s Note: Research for this article was done by the Editor in Chief of On Target, Joyce Hays, CEO of Target Health. The following article describes the involvement of the United States government in healthcare and medical research. Americans should be more aware of the extensive, completely bi-partisan, involvement of our federal government in these achievements. Up until about the 1980s and 90s our political parties operated, for the most part, in a cooperative way, when it came to healthcare and medical research. Time to get back to the basics.
Going forward, we will continue to inform you, from time to time, with historical summaries, of the deep commitment by our nation, to healthcare and medical research. There is every reason for American citizens to feel proud of our government’s accomplishments in these endeavors.
The city of New Orleans, Louisiana, deserves special mention for contributing two important hospitals in the early 1700s. The first was the Royal Hospital, which had humble beginnings when it was built in 1722 as a small military infirmary, but grew to importance when the Ursuline Sisters took over the management of it in 1727 and made it a major hospital for the public, with a new and larger building built in 1734. The other major New Orleans hospital was the Charity Hospital, which was staffed by many of the same people but was established in 1736 as a supplement to the Royal Hospital so that the poorer classes (who usually could not afford treatment at the Royal Hospital) had somewhere to go.
In most of the American colonies, medicine was rudimentary for the first few generations, as few upper-class British physicians emigrated to the colonies. The first medical society was organized in Boston in 1735. In the 18th century, 117 Americans from wealthy families had graduated in medicine in Edinburgh, Scotland, but most physicians learned as apprentices in the colonies. In Philadelphia in 1765, the Medical College of Philadelphia was founded, and became affiliated with the university in 1791. In New York, the medical department of King’s College was established in 1767, and in 1770, awarded the first American M.D. degree.
Smallpox inoculation was introduced 1716-1766, well before it was accepted in Europe. The first medical schools were established in Philadelphia in 1765 and New York in 1768. The first textbook appeared in 1775, though physicians had easy access to British textbooks. The first pharmacopoeia appeared in 1778. The number of physicians was small, and the national resources were stretched thin by the medical needs of the Revolutionary Army, where supplies and facilities were often inadequate.
State and city funded pest houses aimed at newly arrived infected sailors were established in port cities, notably Boston (1710), Philadelphia (1740) Charleston (1752) and New York (1757). The first general hospital was established in Philadelphia in 1752.
NIH’s (National Institutes of Health) roots extend back to a Marine Hospital Service in the late 1790s that provided medical relief to sick and disabled men in the U.S. Navy. By 1870, a network of marine hospitals had developed and was placed under the charge of a medical officer within the Bureau of the Treasury Department. In the late 1870s, Congress allocated funds to investigate the causes of epidemics like cholera and yellow fever, and it created the National Board of Health, making medical research an official government initiative.
In the American Civil War (1861-65), as was typical of the 19th century, more soldiers died of disease than in battle, and even larger numbers were temporarily incapacitated by wounds, disease and accidents. Conditions were poor in the Confederacy, where doctors and medical supplies were in short supply. The war had a dramatic long-term impact on American medicine, from surgical techniques to hospitals to nursing and to research facilities. The hygiene of the training and field camps was poor, especially at the beginning of the war when men who had seldom been far from home were brought together for training with thousands of strangers. First came epidemics of the childhood diseases of chicken pox, mumps, whooping cough, and, especially, measles. Operations in the South meant a dangerous and new disease environment, bringing diarrhea, dysentery, typhoid fever, and malaria. There were no antibiotics, so the surgeons prescribed coffee, whiskey, and quinine. Harsh weather, bad water, inadequate shelter in winter quarters, poor policing of camps, and dirty camp hospitals took their toll. This was a common scenario in wars from time immemorial, and conditions faced by the Confederate army were even worse. The Union responded by building army hospitals in every state. What was different in the Union was the emergence of skilled, well-funded medical organizers who took proactive action, especially in the much enlarged United States Army Medical Department, and the United States Sanitary Commission, a new private agency. Numerous other new agencies also targeted the medical and morale needs of soldiers, including the United States Christian Commission as well as smaller private agencies such as the Women’s Central Association of Relief for Sick and Wounded in the Army (WCAR) founded in 1861 by Henry Whitney Bellows, and Dorothea Dix. Systematic funding appeals raised public consciousness, as well as millions of dollars. Many thousands of volunteers worked in the hospitals and rest homes, most famously poet Walt Whitman. Frederick Law Olmstead, a famous landscape architect (designed Central Park in NYC), was the highly efficient executive director of the Sanitary Commission.
States could use their own tax money to support their troops as Ohio did. Following the unexpected carnage at the battle of Shiloh in April 1862, the Ohio state government sent 3 steamboats to the scene as floating hospitals with doctors, nurses and medical supplies. The state fleet expanded to eleven hospital ships. The state also set up 12 local offices in main transportation nodes to help Ohio soldiers moving back and forth. The U.S. Army learned many lessons and in 1886, it established the Hospital Corps. The Sanitary Commission collected enormous amounts of statistical data, and opened up the problems of storing information for fast access and mechanically searching for data patterns. The pioneer was John Shaw Billings (1838-1913). A senior surgeon in the war, Billings built the Library of the Surgeon General’s Office (now the National Library of Medicine, the centerpiece of modern medical information systems. Billings figured out how to mechanically analyze medical and demographic data by turning it into numbers and punching onto cardboard cards as developed by his assistant Herman Hollerith, the origin of the computer punch card system that dominated statistical data manipulation until the 1970s.
After 1870 the Nightingale model of professional training of nurses was widely copied. Linda Richards (1841-1930) studied in London and became the professionally trained American nurse. She established nursing training programs in the United States and Japan, and created the first system for keeping individual medical records for hospitalized patients. In 1887, an NIH laboratory for the study of bacteria, the Hygienic Laboratory, was established at the Marine Hospital in New York. In the early 1900s, Congress began appropriating funds for the Marine Hospital Service. In 1902, the: U.S. Public Health Service was created. In1922, this organization changed its name to Public Health Services and established a Special Cancer Investigations laboratory at Harvard Medical School. This marked the beginning of a partnership with universities.
In June 1906, Republican President Theodore Roosevelt signed into law the government agency, Food and Drug Act, also known as the Wiley Act after its chief advocate Dr. Harvey Washington Wiley who riveted the country’s and eventually congress’s attention with public hygiene demonstrations. This act was the basis for the modern USFDA, being originally given the name of the Food, Drug, and Insecticide organization. The name eventually was shortened to the Food and Drug Administration (FDA) a few years later.
In 1930, the Hygienic Laboratory was re-designated as the National Institutes of Health by the Ransdell Act and was given $750,000 to construct two NIH buildings. Over the next few decades, Congress would increase its funding tremendously to the NIH, and various institutes and centers within the NIH were created for specific research programs.
Republican President Warren G. Harding proposed a Department of Education and Welfare as early as 1923.
Under President Franklin D. Roosevelt, and Supreme Allied Commander in Europe, Dwight D. Eisenhower, and due to the tremendous WW2 war effort, in the first 5 months of 1943, 400 million units of penicillin were produced in the US. In the next 7 months, 20.5 billion units were produced, an increase of over 500 times. In 1945, 650 billion units of penicillin were distributed each month in the US and also in 1945, the first vaccine for influenza was produced.
Under Harry S. Truman, The Communicable Diseases Center was founded July 1, 1946 as the successor to the World War II Malaria Control in War Areas program of the Office of National Defense Malaria Control Activities. Preceding its founding, organizations with global influence in malaria control were the Malaria Commission of the League of Nations and the Rockefeller Foundation. The Rockefeller Foundation greatly supported malaria control, sought to have the governments take over some of its efforts, and collaborated with the agency.
CDC headquarters in Druid Hills, Georgia, as seen from Emory University
CDC’s Roybal campus in Atlanta, GA
The new agency was a branch of the U.S. Public Health Service and Atlanta was chosen as the location because malaria was endemic in the Southern United States.
Under President Lyndon B. Johnson, in 1965, Medicare and Medicaid were introduced to the U.S. healthcare system for, respectively, senior citizens and the poor. In 1967, the Division of Regional Medical Programs was created to administer government grants for research for heart disease, cancer, and strokes. That same year, the NIH director lobbied the White House for increased federal funding in order to increase research and the speed with which health benefits could be brought to the people. An advisory committee was formed to oversee further development of the NIH and its research programs.
By 1971, cancer research was in full force and President Nixon signed the National Cancer Act, initiating a National Cancer Program, President’s Cancer Panel, National Cancer Advisory Board, and 15 new research, training, and demonstration centers. In 1979, the Department of Health, Education, and Welfare was renamed the Department of Health and Human Services (HHS), when its education functions were transferred to the newly created United States Department of Education under the Department of Education Organization Act. HHS was left in charge of the Social Security Administration, agencies constituting the Public Health Service, and Family Support Administration.
By the 1990s, the focus of the NIH committee had shifted to DNA research, and the Human Genome Project was launched. In 2009, President Obama reinstated federally funded stem-cell research, revoking the ban imposed in 2001. From logistical restructuring, to funding increases, to research prioritization, to government expansion and political influence, the history of the National Institutes of Health is extensive and full of change. The NIH has grown to encompass nearly 1% of the federal government’s operating budget. The NIH now controls more than 50% of all funding for health research, and 85% of all funding for health studies in universities. In 1995, the Social Security Administration was removed from the Department of Health and Human Services, and established as an independent agency of the executive branch of the United States Government. In 2000, scientists with the International Human Genome Project release a rough draft of the human genome to the public. For the first time the world can read the complete set of human genetic information and begin to discover what our roughly 23,000 genes do.
In 2007, scientists discover how to use human skin cells to create embryonic stem cells.
In 2010, The Patient Protection and Affordable Care Act (PPACA), commonly called Obamacare or the Affordable Care Act (ACA), is signed into law by President Barack Obama, creating America’s first government health insurance program.
In May 2011, the state of Vermont became the first state to pass legislation establishing a Single-Payer health care system. The legislation, known as Act 48, establishes health care in the state as a human right and lays the responsibility on the state to provide a health care system which best meets the needs of the citizens of Vermont. The state is currently in the studying phase of how best to implement this system.
In 2012, The U.S. Supreme Court upheld the constitutionality of most of the ACA in the case National Federation of Independent Business v. Sebelius.
In 2013, for the first time in US history, American citizens were able to sign up for healthcare under the ACA federal law.
Sources: Medical Advances Timeline | Infoplease.com; Stanford.edu, The New York Times, Wikipedia, Scott Harrah inAcademics, U.S. Medical History, UMHS News;http://www.medpagetoday.
Effect of Thalidomide on Clinical Remission in Children and Adolescents With Refractory Crohn Disease
Pediatric-onset Crohn disease is more aggressive than adult-onset disease, has high rates of resistance to existing drugs, and can lead to permanent impairments. Few trials have evaluated new drugs for refractory Crohn disease in children. As a result, a study published in the Journal of the American Medical Association (2013;310:2164-2173) was performed to determine whether thalidomide is effective in inducing remission in refractory pediatric Crohn disease.
The investigation was a multicenter, double-blind, placebo-controlled, randomized clinical trial of 56 children with active Crohn disease despite immunosuppressive treatment. The study was conducted in 6 pediatric tertiary care centers in Italy.
For the study, thalidomide (1.5 to 2.5 mg/kg per day), or placebo was administered once daily for 8 weeks. Twenty-eight children were randomized to thalidomide and 26 to placebo. In an open-label extension, nonresponders to placebo received thalidomide for an additional 8 weeks. All responders continued to receive thalidomide for an additional minimum 52 weeks. The primary outcomes were clinical remission at week 8, measured by Pediatric Crohn Disease Activity Index (PCDAI) score and reduction in PCDAI by >25% or >75% at weeks 4 and 8. Primary outcomes during the open-label follow-up were clinical remission and 75% response.
Results showed that clinical remission was achieved by significantly more children treated with thalidomide (46.4% vs. 11.5%; P=0.01. In terms of the criterion of 75% response, responses were not different at 4 weeks, but greater improvement was observed at 8 weeks in the thalidomide group 75% response (46.4% vs. 11.5%; P=0.01; and 25% response (64.2% vs. 30.8%; P=0.01). Of the non-responders to placebo who began receiving thalidomide, 52.4% subsequently reached remission at week 8 (P=0.01). Overall, 63% of children treated with thalidomide achieved clinical remission, and 65.3% achieved 75% response. Mean duration of clinical remission in the thalidomide group was 181.1 weeks vs. 6.3 weeks in the placebo group (P <0.001). Peripheral neuropathy the most frequent severe adverse event.
According to the authors, in children and adolescents with refractory Crohn disease, thalidomide compared with placebo resulted in improved clinical remission at 8 weeks of treatment and longer-term maintenance of remission in an open-label follow-up, and that the findings require replication to definitively determine clinical utility of this treatment.
Gene Hastens Kidney Disease Progression in African-Americans
An estimated 20 million or more American adults have chronic kidney disease (CKD), and over 400,000 people in the United States and 2 million worldwide depend on dialysis to treat kidney failure. Although exceedingly rare in white people, the APOL1 gene variant is found in 13-15% of African-Americans. Some have speculated that it evolved to protect against one of the two forms of African sleeping sickness, a lethal parasitic disease transmitted by the tsetse fly.
Investigators from the Chronic Renal Insufficiency Cohort (CRIC) study and the African American Study of Kidney Disease and Hypertension (AASK) published joint results in the New England Journal of Medicine (12 November 2013). The authors noted that a gene variant common in African-Americans predicts that people with that gene who also have chronic kidney disease (CKD) are twice as likely to progress to kidney failure as African-Americans without the high-risk gene and white people with CKD. People with the high-risk gene also tend to lose kidney function at twice the rate of those without the gene.
The impact of the gene variant — known as APOL1 — on risk for and rate of CKD progression was consistent in both studies, regardless of whether patients maintained good blood pressure control or had diabetes. High blood pressure and diabetes are major risk factors for CKD and its progression to kidney failure.
The discovery builds on landmark 2008 research by NIH kidney specialist Dr. Jeffrey Kopp and others, led by Dr. Martin Pollak at The Laboratory of Inherited Kidney Disease at Beth Israel Deaconess Medical Center and Harvard Medical School in Boston, which found the APOL1 gene variant to be a risk factor for kidney disease that wasn’t associated with diabetes.
AASK is the largest and longest completed study of CKD in African-Americans. Beginning as a randomized clinical trial in 1995, the investigation was completed in 2007 as a cohort study. The CRIC study is one of the largest and longest ongoing studies of CKD epidemiology in the United States. CRIC recently embarked on an expansion to add more than 1,500 patients over the next five years, increasing the study’s total size to approximately 5,500.
TARGET HEALTH excels in Regulatory Affairs. Each week we highlight new information in this challenging area.
NIH to Retire Research Chimps
Will there be a time that we will not have to test new drugs on animals or at least fine-tune the rules and evaluate the benefit to risk for each proposed study based on previous knowledge.
The following is from Francis S. Collins, M.D., Ph.D., Director, National Institutes of Health.
With an immense sense of gratitude, I applaud today’s action by President Barack Obama that will enable the National Institutes of Health (NIH) to retire most of our research chimpanzees. Americans have benefitted greatly from chimpanzees’ service to biomedical research, but new scientific methods and technologies have rendered their use in research largely unnecessary [our emphasis). Consequently, it is now time to move most of the NIH-owned chimpanzees to the federal sanctuary system. Profound thanks are due to the bipartisan effort in both the House and Senate that made it possible for this legislation to be passed and sent to the White House. By signing into law Senate Bill 252 (S. 252), the President has provided us with the means to fund the care of all NIH-owned and supported chimpanzees — including those that are retired — over the next five years.
Specifically, S. 252 contains amendments approved by both the Senate and House that removes the spending cap set forth in The Chimpanzee Health Improvement, Maintenance, and Protection (CHIMP) Act. With the funding roadblock removed, NIH can move forward with our previously stated plans to transfer all but 50 of its 347 research chimpanzees into the federal sanctuary system, which currently consists only of Chimp Haven in Keithville, LA. The remaining animals will be maintained, but not bred, for possible future research that is consistent with the principles set forth by the Institute of Medicine’s 2011 report on the use of chimpanzees in biomedical research. Another 208 chimpanzees owned by NIH are already retired and are housed at Chimp Haven or scheduled to move there when new construction is completed early next year.