Jermaine Cunningham has become the latest Boston athlete to be suspended for violating a performance-enhancing drug policy. The defensive end reportedly tested positive for Adderall, a drug commonly prescribed for patients with attention disorders.
Cunningham joined a list of prominent athletes, many from Boston, who have been accused or convicted of using substances banned by their various leagues
The biology underlying excessive daytime sleepiness (hypersomnolence) is incompletely understood. After excluding known causes of sleepiness in 32 hypersomnolent patients, we showed that, in the presence of 10 μM γ-aminobutyric acid (GABA), cerebrospinal fluid (CSF) from these subjects stimulated GABAA receptor function in vitro by 84.0 ± 40.7% (SD) relative to the 35.8 ± 7.5% (SD) stimulation obtained with CSF from control subjects (Student’s t test, t = 6.47, P < 0.0001); CSF alone had no effect on GABAA signaling. The bioactive CSF component had a mass of 500 to 3000 daltons and was neutralized by trypsin. Enhancement was greater for α2 subunit– versus α1 subunit–containing GABAA receptors and negligible for α4 subunit–containing ones. CSF samples from hypersomnolent patients also modestly enhanced benzodiazepine (BZD)–insensitive GABAA receptors and did not competitively displace BZDs from human brain tissue. Flumazenil—a drug that is generally believed to antagonize the sedative-hypnotic actions of BZDs only at the classical BZD-binding domain in GABAA receptors and to lack intrinsic activity—nevertheless reversed enhancement of GABAA signaling by hypersomnolent CSF in vitro. Furthermore, flumazenil normalized vigilance in seven hypersomnolent patients. We conclude that a naturally occurring substance in CSF augments inhibitory GABA signaling, thus revealing a new pathophysiology associated with excessive daytime sleepiness.
Abstract: A genome-wide association study identified a strong correlation between body mass index and the presence of a 21-kb copy number variation upstream of the human GPRC5B gene; however, the functional role of GPRC5B in obesity remains unknown. We report that GPRC5B-deficient mice were protected from diet-induced obesity and insulin resistance because of reduced inflammation in their white adipose tissue. GPRC5B is a lipid raft–associated transmembrane protein that contains multiple phosphorylated residues in its carboxyl terminus. Phosphorylation of GPRC5B by the tyrosine kinase Fyn and the subsequent direct interaction with Fyn through the Fyn Src homology 2 (SH2) domain were critical for the initiation and progression of inflammatory signaling in adipose tissue. We demonstrated that a GPRC5B mutant lacking the direct binding site for Fyn failed to activate a positive feedback loop of nuclear factor B–inhibitor of B kinase signaling. These findings suggest that GPRC5B may be a major node in adipose signaling systems linking diet-induced obesity to type 2 diabetes and may open new avenues for therapeutic approaches to diabetic progression.
NEJM
Effect of Three Decades of Screening Mammography on Breast-Cancer Incidence
Benefit and Harm with Screening Mammography and Use of Aspirin over 10 Years. Use of Screening Mammography and Incidence of Stage-Specific Breast Cancer in the United States, 1976–2008.
RESULTS
The introduction of screening mammography in the United States has been associated with a doubling in the number of cases of early-stage breast cancer that are detected each year, from 112 to 234 cases per 100,000 women — an absolute increase of 122 cases per 100,000 women. Concomitantly, the rate at which women present with late-stage cancer has decreased by 8%, from 102 to 94 cases per 100,000 women — an absolute decrease of 8 cases per 100,000 women. With the assumption of a constant underlying disease burden, only 8 of the 122 additional early-stage cancers diagnosed were expected to progress to advanced disease. After excluding the transient excess incidence associated with hormone-replacement therapy and adjusting for trends in the incidence of breast cancer among women younger than 40 years of age, we estimated that breast cancer was overdiagnosed (i.e., tumors were detected on screening that would never have led to clinical symptoms) in 1.3 million U.S. women in the past 30 years. We estimated that in 2008, breast cancer was overdiagnosed in more than 70,000 women; this accounted for 31% of all breast cancers diagnosed.
Despite substantial increases in the number of cases of early-stage breast cancer detected, screening mammography has only marginally reduced the rate at which women present with advanced cancer. Although it is not certain which women have been affected, the imbalance suggests that there is substantial overdiagnosis, accounting for nearly a third of all newly diagnosed breast cancers, and that screening is having, at best, only a small effect on the rate of death from breast cancer.
FIGURE 1 Extended Kaplan–Meier Curves for Patients in the Swedish Patient Register with a Diagnosis of ADHD Who Were Born No Later Than 1990, According to Sex and Medication Status.
BACKGROUND
Attention deficit–hyperactivity disorder (ADHD) is a common disorder that has been associated with criminal behavior in some studies. Pharmacologic treatment is available for ADHD and may reduce the risk of criminality.
METHODS
Using Swedish national registers, we gathered information on 25,656 patients with a diagnosis of ADHD, their pharmacologic treatment, and subsequent criminal convictions in Sweden from 2006 through 2009. We used stratified Cox regression analyses to compare the rate of criminality while the patients were receiving ADHD medication, as compared with the rate for the same patients while not receiving medication.
RESULTS
As compared with nonmedication periods, among patients receiving ADHD medication, there was a significant reduction of 32% in the criminality rate for men (adjusted hazard ratio, 0.68; 95% confidence interval [CI], 0.63 to 0.73) and 41% for women (hazard ratio, 0.59; 95% CI, 0.50 to 0.70). The rate reduction remained between 17% and 46% in sensitivity analyses among men, with factors that included different types of drugs (e.g., stimulant vs. nonstimulant) and outcomes (e.g., type of crime).
CONCLUSIONS
Among patients with ADHD, rates of criminality were lower during periods when they were receiving ADHD medication. These findings raise the possibility that the use of medication reduces the risk of criminality among patients with ADHD. (Funded by the Swedish Research Council and others.)
Protein clumps called Lewy bodies (centre) found in Parkinson’s disease are caused as misfolded α-synuclein moves from cell to cell.
KELVIN LUK/UNIV. PENNSYLVANIA/SCIENCE AAAS
A team led by Virginia Lee, a neurobiologist at the University of Pennsylvania in Philadelphia, injected a misfolded synthetic version of the protein α-synuclein into the brains of normal mice and saw the key characteristics of Parkinson’s disease develop and progressively worsen. The study, published today in Science1, suggests that the disease is spread from one nerve cell to another by the malformed protein, rather than arising spontaneously in the cells.
The finding raises the possibility that an antibody that binds the misfolded α-synuclein could be used to intercept the protein as it passes between nerve cells. “It’s very hard to ask antibodies not only to get inside the brain, but to get inside cells,” says Lee. “But now you have the possibility of stopping the spreading. And if you stop the spreading, perhaps you can slow the progression of the disease.”
The idea that Parkinson’s might be spread from neuron to neuron by a rogue protein took off in 2008, when transplants of fetal nerve tissue given to patients with the disease developed the characteristic clumps associated with the condition2, 3. This indicated that the nearby diseased cells had somehow infected the transplanted tissue. Subsequent studies showed that misfolded α-synuclein can spread between neighbouring cells4 and can cause cell death5.
But the question remained as to whether the misfolded α-synuclein was responsible for the cascade of damage seen in Parkinson’s. Lee says that her team has now captured the full consequences of runaway α-synuclein in the brain.
“We knew this transfer from one cell to another can happen, but whether it could play a significant role in the disease was still open,” says Tim Greenamyre, director of the Pittsburgh Institute for Neurodegenerative Diseases in Pennsylvania, who was not involved in the latest work.
Insidious spread
Parkinson’s disease has two distinct features: clumps of protein called Lewy bodies and a dramatic loss of nerve cells that produce the chemical messenger dopamine. When Lee’s team injected the misfolded α-synuclein into a part of the mouse brain rich in dopamine-producing cells, Lewy bodies began to form. This was followed by the death of dopamine neurons. Nerve cells that linked to those near the injection site also developed Lewy bodies, a sign that cell-to-cell transmission was taking place, say the researchers.
Greenamyre says that that is possible, but hasn’t yet been proved. “All of the cells affected in this paper were those directly in contact with the injection site,” he says.
Nevertheless, within six months of the injection, coordination of movement, grip strength and balance had all deteriorated in the mice, echoing what happens in people with Parkinson’s disease.
“It’s really pretty extraordinary,” says Eliezer Masliah, a neuroscientist at the University of California, San Diego. “We have been trying that experiment for a long time in the lab and we have not seen such dramatic effects.” The study lends theoretical support to the handful of biotechnology companies that are sponsoring clinical trials of α-synuclein antibodies for Parksinson’s, Masliah says. It should also spur research on how the protein gets in and out of cells, he adds.
At least one mystery still remains: why do the Lewy bodies appear in the first place? “Parkinson’s disease is not a disorder in which somebody injects synuclein into your brain,” notes Ted Dawson, director of the Institute for Cell Engineering at Johns Hopkins University in Baltimore, Maryland. “So what sets it in motion?”
B–inhibitor of 
signaling. These findings suggest that GPRC5B may be a major node in adipose signaling systems linking diet-induced obesity to type 2 diabetes and may open new avenues for therapeutic approaches to diabetic progression.
