Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype

Inhibitory neurotransmission in the brain is largely mediated by GABA(A) receptors. Potentiation of GABA receptor activation through an allosteric benzodiazepine (BZ) site produces the sedative, anxiolytic, muscle relaxant, anticonvulsant and cognition-impairing effects of clinically used BZs such as diazepam. We created genetically modified mice (alpha1 H101R) with a diazepam-insensitive alpha1 subtype and a selective BZ site ligand, L-838,417, to explore GABA(A) receptor subtypes mediating specific physiological effects. These two complimentary approaches revealed that the alpha1 subtype mediated the sedative, but not the anxiolytic effects of benzodiazepines. This finding suggests ways to improve anxiolytics and to develop drugs for other neurological disorders based on their specificity for GABA(A) receptor subtypes in distinct neuronal circuits.     

Exercise as a treatment for hypertension in low-socioeconomic-status black children

Low-socioeconomic-status (SES) Black children have a higher mean blood pressure than most other groups. The antihypertensive effects of a 12-week aerobic exercise program were examined on 11 low-SES Black children, ages 8-12, who had blood pressure above the 95th percentile. A multiple baseline across three groups of children with baseline and exercise conditions was conducted. After the introduction of the exercise program, there were significant decreases in diastolic and systolic blood pressure. Cardiovascular fitness improved concurrently. The results suggest that vigorous exercise can decrease the blood pressure of low-SES hypertensive Black children.     

Development of an intracorporeal Thoratec ventricular assist device for univentricular or biventricular support

There is a need for a small, simple, and versatile intracorporeal ventricular assist device (IVAD) as an alternative to the large implantable electromechanical LVAD systems in current use. Because the basic design of the Thoratec paracorporeal VAD has been demonstrated in over 1,000 patients, weighing from 17 to 144 kg, and for durations up to 515 days including patient discharge (by using the portable driver), we are developing a new intracorporeal version of our VAD. This IVAD has a smooth contoured, polished titanium housing, and maintains the same blood flow path and Thoralon polyurethane blood pumping sac as the paracorporeal VAD. The IVAD is controlled with the Thoratec TLC-II Portable VAD Driver, which is a small briefcase sized, battery powered, pneumatic control unit. Intracorporeal LVADs and/or RVADs are implanted in a preperitoneal position, with a single small (9 mm OD) percutaneous pneumatic driveline for each VAD. The major advantages of the new IVAD design are size and simplicity. The IVAD weight (339 g) and implanted volume (252 ml) are substantially smaller than current implantable electromechanical LVAD systems. Only the small blood pump is implanted, leaving the more complex control unit external, where it can be serviced and replaced. The versatile design is intended for left and/or right heart support in large or small patients. The IVAD in combination with the TLC-II portable driver will be a viable and attractive alternative to large, implanted electromechanical systems.     

Preferential coassembly of alpha4 and delta subunits of the gamma-aminobutyric acidA receptor in rat thalamus.

Pharmacological study of rat thalamic gamma-aminobutyric acidA (GABAA) receptors revealed the presence of two distinct populations, namely, diazepam-sensitive and diazepam-insensitive [3H]Ro15-4513 binding sites accounting for 94 +/- 2% (1339 +/- 253 fmol/mg protein) and 6 +/- 2% (90 +/- 44 fmol/mg protein) of total sites, respectively. Thalamic diazepam-insensitive sites exhibited a pharmacology that was distinct from diazepam-sensitive sites but comparable to that of the alpha4beta3gamma2 subtype of the GABAA receptor stably expressed in L(tk-) cells. Immunoprecipitation experiments with a specific anti-alpha4-antiserum immunoprecipitated 20 and 7% of total thalamic [3H]muscimol and [3H]Ro15-4513 sites, respectively. Combinatorial immunoprecipitation using antisera against the alpha4, gamma2, and delta subunit revealed that alpha4delta- and alpha4gamma2-containing receptors account for 13 +/- 2 and 8 +/- 3% of [3H]muscimol sites from thalamus, respectively. It also indicated that all delta subunits coexist with an alpha4 subunit in this brain region. In conclusion, our results show that in rat thalamus both alpha4betagamma2 and alpha4betadelta subtypes are expressed but alpha4betadelta is the major alpha4-containing GABAA receptor population.     

Patient-oriented outcomes from low back surgery: a community-based study

STUDY DESIGN: This study used a prospective cohort design. OBJECTIVE: To examine factors associated with favorable self-reported patient outcomes 1 year after elective surgery for degenerative back problems. SUMMARY OF BACKGROUND DATA: Many previous studies addressing the results of low back surgery have been conducted in academic institutions or by single surgeons. As part of a quality improvement effort, surgeons in private practice led a community-based outcomes management project in Washington State. METHODS: Patients ages 18 and older with the following diagnoses were eligible for the study: degenerative changes, herniated disc, instability, and spinal stenosis. Nine orthopedists and neurosurgeons enrolled a total of 281 patients. Participants were asked to complete baseline and 1-year follow-up surveys. Data concerning diagnoses, clinical signs, and operative procedures were provided by the surgeons. The researchers examined sociodemographic characteristics, self-reported symptoms before surgery, preoperative clinical signs, diagnoses, and operative procedures associated with three primary outcomes: better functioning, improved quality of life, and overall treatment satisfaction. RESULTS: Follow-up surveys were completed by 236 (84%) of the enrolled patients. Approximately two thirds of the study participants reported much better functioning (65%), a great quality of life improvement (64%), and a very positive perspective about their treatment outcome (68%). The following variables were associated with worse patient outcomes: older age, previous low back surgery, workers' compensation coverage, and consultation with an attorney before surgery. Patients undergoing a fusion procedure were more likely to report good outcomes. CONCLUSIONS: The authors' experience indicates that community-based outcomes data collection efforts are feasible and can be incorporated into usual clinical practice. The study results indicate that compensation payments and litigation are two important predictors of poor outcomes after low back surgery in community practice.Because of small numbers, varied diagnoses, and possible selection bias, the findings with respect to fusion should be interpreted cautiously.     

Complications of tibial shaft soccer fractures

A retrospective study of AO type 42 tibial diaphyseal fractures that presented to a teaching hospital over a 54 month period was made to identify the proportion sustained whilst playing soccer, determine their characteristics and report treatment and outcome. Sport accounts for 73/329 (22.1%) of these fractures and soccer 58/73 (79. 5%) of these. All patients were male with mean age of 24.3 years (range 8-48). Fifty-four fractures were closed and 93.1% (54/58) were situated in the middle third or at the junction of the middle and distal thirds of the diaphysis. Fifty-six (96.6%) had simple or wedge patterns and 45 (77.6%) were right sided. Forty-four (76.2%) were treated non-operatively in plaster, 12 (20.3%) by intramedullary nails and two (3.4%) with external fixators. Two patients were lost to follow-up and the remaining 56 fractures united at a mean of 6.5 months. There were 21 complications in 19/56 (33.9%) patients which included 8/56 (14.3%) delayed/non-unions requiring surgery. There was a significantly higher complication rate for operated fractures (p<0.005) but no significant link to AO fracture type. Thus we cannot assume that treatment of these common fractures is without risk, especially if they are treated operatively.     

The toxicology of perfluorooctanoate

PFOA is a peroxisome proliferator (PPAR agonist) and exerts morphological and biochemical effects characteristic of PPAR agonists. These effects include increased beta-oxidation of fatty acids, increases in several cytochrome P-450 (CYP450)-mediated reactions, and inhibition of the secretion of very low-density lipoproteins and cholesterol from the liver. These effects on lipid metabolism and transport result in a reduction of cholesterol and triglycerides in serum and an accumulation of lipids in the liver. The triad of tumors observed (liver, Leydig cell, and pancreatic acinar-cell) is typical of many PPAR agonists and is believed to involve nongenotoxic mechanisms. The hepatocellular tumors observed in rats are likely to have been the result of the activation of the peroxisome proliferator activated receptor alpha (PPARalpha). The tumors observed in the testis (Leydig-cell) have been hypothesized to be associated with an increased level of serum estradiol in concert with testicular growth factors. The mechanism responsible for the acinar-cell tumors of the pancreas in rats remains the subject of active investigation. The mechanism resulting in the hepatocellular tumors in rats (PPARalpha activation) is not likely to be relevant to humans. Similarly, the proposed mechanism for Leydig-cell tumor formation is of questionable relevance to humans. Acinar tumors of the pancreas are rare in humans, and the relevance of the these tumors, as found in rats, to humans is uncertain. Epidemiological investigations and medical surveillance of occupationally exposed workers have not found consistent associations between PFOA exposure and adverse health effects.     

Endemic Norovirus Infections in Children,Ho Chi Minh City,Vietnam, 2009–2010

We performed a case–control investigation to identify risk factors for norovirus infections among children in Vietnam. Of samples from 1,419 children who had diarrhea and 609 who were asymptomatic, 20.6% and 2.8%, respectively, were norovirus positive. Risk factors included residential crowding and symptomatic contacts, indicating person-to-person transmission of norovirus.