Science Weekly: Brian Cox’s Wonders of the Solar System

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Particle physicist Brian Cox discusses his new TV series. Plus: the Flat Earth Society; AAAS; and Lord Robert Winston

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As part of the Target Health Global Partnership, Target Health is pleased to announce that it is now collaborating “B to B“ with several CROs who are using the Target Health Suite of software products including:

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One of the advantages of working with Target Health is that we bring years of experience to the projects, and we understand the needs of CROs as well as the needs of Sponsors. The partnering CRO can also provide their expertise to projects generated by Target Health, especially for international programs.

For more information about Target Health and our software tools for paperless clinical trials, please contact Warren Pearlson (212-681-2100 ext 104) or Ms. Joyce Hays. Target Health’s software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health website at: www.targethealth.com

Why Symptoms of Schizophrenia Emerge in Young Adulthood

Numerous studies have suggested that schizophrenia results from abnormal connectivity. The fact that symptoms typically arise soon after adolescence, a time of massive reorganization of connections between nerve cells, supports this idea. In reports of two new studies, researchers led by Johns Hopkins say they have identified the mechanisms rooted in two anatomical 1) ___ abnormalities that may explain the onset of schizophrenia and the reason symptoms don’t develop until young adulthood. Both types of anatomical glitches are influenced by a gene known as DISC1, whose mutant form was first identified in a Scottish family with a strong history of schizophrenia and related mental disorders. In one of the studies, published in the March issue of Nature Neuroscience, DISC1’s role in forming connections between 2) ___ cells was studied. The study began by surveying rat nerve cells to see where DISC1 was most active. As expected, they found the highest DISC1 activity in 3) ___ between nerve cells. To determine what DISC1 was doing in this location, a technique called RNA interference was used to partially shut off DISC1 activity. Consequently, a transient increase and eventual reduction in size and number of dendritic spines were observed. Dendritic spikes on nerve cells are branch-like extensions that receive input from other nerve cells. To determine how DISC1 regulates 4) ___ spine formation, the study evaluated which brain proteins interact with the protein expressed by the DISC1 gene. One protein was identified, known as Kal-7, which in earlier studies was shown to be critical for proper dendritic spine formation. Further experiments suggested that the DISC1 5) ___ acts as temporary holding place for Kal-7, binding it until it can be released to trigger a molecular cascade that results in dendritic spine formation. Study leader Akira Sawa, M.D., Ph.D., professor of psychiatry and director of the program in molecular psychiatry at the Johns Hopkins University School of Medicine, says it is becoming clear that having a defective DISC1 gene might lead to an abnormally small number and size of dendritic spines, which could lead nerve cells to maintain weaker connections with unusually low numbers of neighboring 6) ___. Such abnormal connectivity has long been seen in autopsied brains from schizophrenia patients. Connections between neurons are constantly being made and broken throughout life, with a massive amount of broken connections, or “pruning,“ happening in adolescence. If this pruning doesn’t happen correctly, it may be one reason for the pathogenesis of schizophrenia. In the second study, published in the Feb. 25 issue of Neuron, a new animal model of schizophrenia was created by temporarily shutting off the DISC1 gene in mice in the 7) ___ cortex, a brain area known to differ in schizophrenic people. The new model works by injecting short pieces of the nucleic acid RNA engineered in the brain to shut off the DISC1 gene into cavities in the developing brains of mouse fetuses two weeks after conception. Tests showed that these snippets of 8) ___ migrated into cells in the prefrontal cortex. This shutoff was temporary, with the gene’s function fully restored within three weeks, or about a couple of weeks after birth. At various times after the gene was reactivated, the animals’ brains and behavior were examined, looking for differences from normal mice. It was found that in the DISC1 shutoff group, nerve cells in the prefrontal cortex that produce dopamine, one of the chemical signals that nerve cells use to communicate, were markedly immature as the animals entered 9) ___. Furthermore, the animals showed signs of a deficit of interneurons, nerve cells that connect other neurons in neural pathways. They also found several behavioral differences between these mice compared to normal mice as the animals entered adolescence. For example, those in the shutoff group reacted more strongly to stimulants, displaying more locomotion than normal mice. Interestingly, these effects were somewhat mitigated when the animals received clozapine, a drug used to treat 10) ___. Taken together, the results of both studies suggest that these anatomical differences, which seem to be influenced by the 11) ___ gene, cause problems that start before birth but surface only in young adulthood. If we can learn more about the cascade of events that lead to these anatomical differences, we may eventually be able to alter the course of schizophrenia and possibly intervene to prevent or lessen 12) ___ during adolescence.

 

ANSWERS: 1) brain; 2) nerve; 3) connections; 4) dendritic; 5) protein; 6) neurons; 7) prefrontal; 8) RNA; 9) adolescence; 10) schizophrenia; 11) DISC1; 12) symptoms

A Retrospective Diagnosis Says Lenin Had Syphilis

Whispers have circulated for decades that Vladimir Lenin, founder of the Bolshevik Party and the totalitarian Soviet state it ushered to power, was afflicted with syphilis throughout his career. In an article in The European Journal of Neurology (2004), three physicians sifted through historical references to build what they regard as a probable diagnosis that Lenin contracted the STD in Europe years before he led the October Revolution in 1917. Not long after the socialists’ victory, the illness strengthened its grip, leading to an agonizing decline and, in 1924, his death. This idea was not entirely new. Despite the former Soviet Union’s efforts to preserve a near theology around its central political figure, Lenin was long rumored to have suffered from the disease. The thesis is not so much a breakthrough as a historical rumor revived and reframed. To do so, the authors quoted the journals of doctors who treated Lenin in Europe and the Soviet Union and reviewed materials related to his medical condition and autopsy, which they suggested was a propaganda job. They ask a question of enduring importance to civic life. Do modern societies know enough about the health of their political leaders? In Lenin’s case, they strive to show, the answer is a resounding no. Some scholars of the early Soviet period are skeptical, saying the talk of syphilis circulated for decades, to little effect. The study’s authors propose a possible way to settle the question, further testing of Lenin’s brain material, which is stored in Moscow. Lenin was 53 when he died, after battling an erratic but progressively debilitating illness. His death has been variously attributed to cerebral hemorrhage, stroke, syphilis, exhaustion or cerebral arteriosclerosis, which had killed his father. The difficulty with a diagnosis of syphilis is that the symptoms are common to other ailments, so much so that it is called “the great imitator.“ The infection, caused by a bacterium called the Treponema spirochete, first appears as an ulcerous sore, from which it spreads throughout the body, including the brain. Fever, an extensive rash and malaise typically follow. After initial infection, a syphilitic can spend years alternating between bouts of illness and apparently fine health. When they occur, symptoms can be severe, including headaches, nervous disorders and gastrointestinal, muscle or joint pain. In late stages, often 20 or more years after infection, the victim can experience mood swings and bursts of creativity, as well as depression, lethargy and dementia. Cardiovascular damage can lead to paralysis, aneurysm or stroke. Until the advent of therapeutic penicillin in World War II, the disease was incurable. Lenin’s illness at least mimicked the progression of syphilis, afflicting him for months with occasional seizures and excruciating headaches, as well as bouts of nausea, sleeplessness and partial paralysis. As Stalin plotted for control of the Communist Party, Lenin was alternately lucid and incapacitated. Sometimes, he was unable to walk without assistance or to speak. The worst spells were horrific. According to “Lenin: A Biography,“ by Dr. Robert J. Service, professor of Russian history at St. Anthony’s College, Oxford, he twice asked for poison with which he might end his life. Communist Party orthodoxy required suppression of the deterioration, and many details were kept secret. But time has unlocked some of the confidences, and the authors combed the disparate evidence, some from archives available only after the collapse of Communism, to render their diagnosis. The authors found that Lenin was briefly treated with salvarsan, a drug that was used specifically to combat syphilis. Salvarsan had powerful side effects. Venereal disease was an acute problem under the tsars. After the revolution, the Soviet Health Ministry launched a campaign to treat syphilitics and ease the stigma of the disease. In light of that campaign, it would have been the height of irony if Lenin died of syphilis. Eight decades after his death, Lenin’s corpse still lies in state outside the Kremlin. Importantly, for those seeking an answer to the syphilis question, his brain tissue remains at the Moscow Institute of the Brain, where in early Soviet times it was sliced into wafers in an effort to find anatomical explanations for genius. The authors end their article by suggesting that an examination of the tissue might find the DNA of syphilis and yield a definitive answer. However, a representative of the Moscow Institute of the Brain, declined even to discuss syphilis Source: NYTimes, June 2004

OBITUARY

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Albert M. Kligman MD, PhD (1916-2010)

Dr. Albert M. Kligman, a dermatologist who invented the widely used acne medication Retin-A died at age 93 in Philadelphia. He was a professor emeritus at the University of Pennsylvania, and had been a member of the faculty for more than 50 years. Dr. Kligman authored of hundreds of scientific papers on everyday maladies like athlete’s foot and dandruff and emphasized the importance of the scientific study of disease. Dr. Kligman’s scientific contributions include descriptions of the human hair cycle and the step-by-step progression of acne. By feeding chocolate bars to teenagers with acne in a controlled study, Dr. Kligman debunked the myth that chocolate made acne worse. He is credited with coining the terms “photoaging,“ to describe the wrinkles and discoloration that result from a lifetime of overexposure to the sun, and “cosmeceuticals,“ to describe skin care products that are part cosmetic, part drug. Dr. Kligman’s discovery that tretinoin, the active ingredient in Retin-A, could improve acne and reduce facial wrinkles generated substantial royalties, which he used to donate millions of dollars to the University of Pennsylvania’s dermatology department. Albert Montgomery Kligman was born in Philadelphia on March 17, 1916, the son of Jewish immigrants. His father, born in Ukraine, was a newspaper distributor; his mother, born in England, was a sales clerk. His family was poor, but he made his way to college with financial help from Simon Greenberg, a prominent conservative rabbi whom Dr. Kligman had met through a high school friend. He received a bachelor’s degree from Pennsylvania State University in 1939 and a doctorate in botany from the University of Pennsylvania in 1942. He studied fungi and wrote a handbook about mushrooms. He received his medical degree from the University of Pennsylvania in 1947 and decided to become a dermatologist so that he could put his knowledge of fungi to use. Some of Dr. Kligmans’s earliest research involved the course and treatment of ringworm, a fungal infection. With a colleague, Dr. Kligman modified an existing laboratory test so it could be used to detect ringworm and other fungi, an innovation still used today. In the 1960s Dr. Kligman became interested in tretinoin, a pharmacologically active derivative of Vitamin A. European researchers had experimented with it but considered it too irritating for topical use. Finding the right dosage was a challenge. By 1967, Dr. Kligman and his colleagues had found the right formulation. The discovery was licensed to Johnson & Johnson, which introduced Retin-A in 1971. Nearly 40 years later, tretinoin remains a staple of acne treatment. Soon after Retin-A was approved, Dr. Kligman’s older acne patients began telling him that the prescription drug appeared to have other benefits: their skin was smoother, with fewer wrinkles. Dr. Kligman then performed some experiments that confirmed what his patients were saying. This discovery was licensed to Johnson & Johnson, which introduced the prescription antiwrinkle cream Renova in 1996. Dr. Kligman turned 80 that year, but he never became a user of his antiwrinkle invention. He had no need for it, his daughter said as “He had genetically great skin.“

Association Between Acute Care and Critical Illness Hospitalization and Cognitive Function in Older Adults

Studies suggest that many survivors of critical illness experience long-term cognitive impairment. However, these studies have not included premorbid measures of cognitive functioning and have not evaluated risk for dementia associated with critical illness. As a result, a study published in the Journal of the American Medical Association (2010;303:763-770), was performed to determine 1) whether decline in cognitive function was greater among older individuals who experienced acute care or critical illness hospitalizations relative to those not hospitalized and 2) whether the risk for incident dementia differed by these exposures. The study analyzed data from a prospective cohort study from 1994 through 2007 comprising 2,929 individuals 65 years old and older without dementia at baseline residing in the community in the Seattle area and belonging to the Group Health Cooperative. Participants with 2 or more study visits were included, and those who had a hospitalization for a diagnosis of primary brain injury were censored at the time of hospitalization. Individuals were screened with the Cognitive Abilities Screening Instrument (CASI) (score range, 0-100) every 2 years at follow-up visits, and those with a score less than 86 underwent a clinical examination for dementia. The main outcomes measures were 1) core on the CASI at follow-up study visits and 2) incident dementia diagnosed in study participants, adjusted for baseline cognitive scores, age, and other risk factors. Results showed that during a mean (SD) follow-up of 6.1 (3.2) years, 1,601 participants had no hospitalization, 1,287 had 1 or more noncritical illness hospitalizations, and 41 had 1 or more critical illness hospitalizations. The CASI score was assessed more than 45 days after discharge for 94.3% of participants. Adjusted CASI scores averaged 1.01 points lower for visits following acute care illness hospitalization compared with follow-up visits not following any hospitalization (P < .001) and 2.14 points lower on average for visits following critical illness hospitalization (P = .047). There were 146 cases of dementia among those not hospitalized, 228 cases of dementia among those with 1 or more noncritical illness hospitalizations, and 5 cases of dementia among those with 1 or more critical illness hospitalizations. The adjusted hazard ratio for incident dementia was 1.4 following a noncritical illness hospitalization (P = .001) and 2.3 following a critical illness hospitalization (P = .09). According to the authors, among a cohort of older adults without dementia at baseline, those who experienced acute care hospitalization and critical illness hospitalization had a greater likelihood of cognitive decline compared with those who had no hospitalization. Noncritical illness hospitalization was significantly associated with the development of dementia.

Mutations in the Lysosomal Enzyme – Targeting Pathway and Persistent Stuttering

Stuttering is a disorder in which speech fluency can be severely compromised. It is characterized by the involuntary repetition or prolongation of sounds, syllables, words, or phrases, as well as frequent pauses, impeding the rhythmic flow of speech. Onset is typically between 3 and 6 years of age, and approximately 5% of preschool children are affected. The majority of young children who stutter go on to make a full recovery. For a considerable number, however, the disorder continues unabated, resulting in a prevalence of about 1% among adults. Genetic factors have been implicated in this disorder, and previous studies of stuttering have identified linkage to markers on chromosome 12. As a result, a study published in the New England Journal of Medicine (2010;362:677-685), analyzed the chromosome 12q23.3 genomic region in consanguineous Pakistani families, some members of which had nonsyndromic (not associated with any disease) stuttering, and in unrelated case and control subjects from Pakistan and North America. The study identified a missense? mutation in the N-acetylglucosamine-1-phosphate transferase gene (GNPTAB), which encodes the alpha and beta catalytic subunits of GlcNAc-phosphotransferase (GNPT [EC 2.7.8.15 [EC] ]), that was associated with stuttering in a large, consanguineous Pakistani family. This mutation occurred in the affected members of approximately 10% of Pakistani families studied, but it occurred only once in 192 chromosomes from unaffected, unrelated Pakistani control subjects and was not observed in 552 chromosomes from unaffected, unrelated North American control subjects. This and three other mutations in GNPTAB occurred in unrelated subjects with stuttering but not in control subjects. The study also identified three mutations in the GNPTG gene, which encodes the gamma subunit of GNPT, in affected subjects of Asian and European descent but not in control subjects. Furthermore, three mutations were identified in the NAGPA gene, which encodes the so-called uncovering enzyme, in other affected subjects but not in control subjects. These genes encode enzymes that generate the mannose-6-phosphate signal, which directs a diverse group of hydrolases to the lysosome. Deficits in this system are associated with the mucolipidoses, rare lysosomal storage disorders that are most commonly associated with bone, connective tissue, and neurologic symptoms. According to the authors, susceptibility to nonsyndromic stuttering is associated with variations in genes governing lysosomal metabolism.

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FDA Approves Therapy to Treat Gaucher Disease

The FDA has approved velaglucerase alfa for injection (VPRIV) to treat children and adults with a form of the rare genetic disorder Gaucher disease. Gaucher disease occurs in people who do not produce enough of an enzyme called glucocerebrosidase. Without this enzyme, harmful amounts of a certain fatty substance (lipid) can build up in the liver, spleen, bones, bone marrow and nervous system, and can prevent cells and organs from working properly. About 1 in 50,000 to 1 in 100,000 people in the general population have Gaucher disease. VPRIV provides long-term enzyme replacement therapy for Type 1 Gaucher disease, the most common form of the genetic disorder. It is an alternative to Cerezyme (imiglucerase), another enzyme replacement therapy. Cerezyme is currently in short supply. “The approval of VPRIV will provide a safe and effective alternative treatment for patients with Gaucher disease,“ said Julie Beitz, M.D., director of the FDA’s Office of Drug Evaluation III. “Patients who previously received Cerezyme as an enzyme replacement therapy for their Type 1 Gaucher disease can be safely switched to VPRIV.“ The safety and effectiveness of VPRIV was assessed in three clinical studies involving 82 patients with Type 1 Gaucher disease ages 4 years and older. The studies included patients who switched to VPRIV after being treated with Cerezyme. The most common adverse reactions to VPRIV are allergic reactions. Other observed adverse reactions with VPRIV are headache, dizziness, abdominal pain, back pain, joint pain, nausea, fatigue/weakness, fever, and prolongation of activated partial thromboplastin time, a measure of clotting time. VPRIV is manufactured by Shire Human Genetic Therapies Inc. of Cambridge, Mass.

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