To develop a benchmark measure of US physicians' level of knowledge and extent of use of pharmacogenomic testing, we conducted an anonymous, cross‐sectional, fax‐based, national survey. Of 397,832 ...physicians receiving the survey questionnaire, 10,303 (3%) completed and returned it; the respondents were representative of the overall US physician population. The factors associated with the decision to test were evaluated using χ2 and multivariate logistic regression. Overall, 97.6% of responding physicians agreed that genetic variations may influence drug response, but only 10.3% felt adequately informed about pharmacogenomic testing. Only 12.9% of physicians had ordered a test in the previous 6 months, and 26.4% anticipated ordering a test in the next 6 months. Early and future adopters of testing were more likely to have received training in pharmacogenomics, but only 29.0% of physicians overall had received any education in the field. Our findings highlight the need for more effective physician education on the clinical value, availability, and interpretation of pharmacogenomic tests.
Clinical Pharmacology & Therapeutics (2012); 91 3, 450–458. doi:10.1038/clpt.2011.306
To reach the pressures and densities required for ignition, it may be necessary to develop an approach to design that makes it easier for simulations to guide experiments. Here, we report on a new ...short-pulse inertial confinement fusion platform that is specifically designed to be more predictable. The platform has demonstrated 99%+0.5% laser coupling into the hohlraum, high implosion velocity (411 km/s), high hotspot pressure (220+60 Gbar), and high cold fuel areal density compression ratio (>400), while maintaining controlled implosion symmetry, providing a promising new physics platform to study ignition physics.
Poor sleep has increasingly gained attention as a potential contributor to the recent obesity epidemic. The increased prevalence of obesity in Western nations over the past half-century has been ...paralleled by a severe reduction in sleep duration. Physiological studies suggest reduced sleep may impact hormonal regulation of appetite. Prospective studies suggest reduced habitual sleep duration as assessed by self-report is an independent risk factor for an increased rate of weight gain and incident obesity. Cross-sectional studies have demonstrated that the association between reduced sleep and obesity persists when sleep habits are measured objectively, that the association is as a result of elevations in fat and not muscle mass and that this association is not related to sleep apnoea. Thus, reduced sleep appears to represent a novel, independent risk factor for increased weight gain. Further research is needed to determine whether interventions aimed at increasing sleep may be useful in combating obesity.
A series of pyrazolo(dihydro)pyridines was synthesized and evaluated for antileishmanial efficacy against experimental visceral leishmaniasis (VL). Among all compounds, 6d and 6j exhibited better ...activity than miltefosine against intracellular amastigotes. Compound 6j (50 mg/kg/day) was further studied against Leishmania donovani/BALB/c mice via the intraperitoneal route for 5 days and displayed >91 and >93% clearance of splenic and liver parasitic burden, respectively. Combination treatment of 6j with a subcurative dose of miltefosine (5 mg/kg) in BALB/c mice almost completely ameliorated the disease (>97% inhibition) by augmenting nitric oxide generation and shifting the immune response toward Th1. Furthermore, investigating the effect of 6j on Leishmania promastigotes revealed that it induced molecular events, such as a loss in mitochondrial membrane potential, externalization of phosphatidylserine, and DNA fragmentation, that ultimately resulted in the programmed cell death of the parasite. These results along with pharmacokinetic studies suggest that 6j could be a promising lead for treating VL as an adjunct therapy with miltefosine.
We report the discovery and initial follow-up of a double neutron star (DNS) system, PSR J1946+2052, with the Arecibo L-Band Feed Array pulsar (PALFA) survey. PSR J1946+2052 is a 17 ms pulsar in a ...1.88 hr, eccentric (e = 0.06) orbit with a 1.2 M companion. We have used the Jansky Very Large Array to localize PSR J1946+2052 to a precision of 0 09 using a new phase binning mode. We have searched multiwavelength catalogs for coincident sources but did not find any counterparts. The improved position enabled a measurement of the spin period derivative of the pulsar ( P ˙ = 9 2 × 10 − 19 ); the small inferred magnetic field strength at the surface (BS = 4 × 109 G) indicates that this pulsar has been recycled. This and the orbital eccentricity lead to the conclusion that PSR J1946+2052 is in a DNS system. Among all known radio pulsars in DNS systems, PSR J1946+2052 has the shortest orbital period and the shortest estimated merger timescale, 46 Myr; at that time it will display the largest spin effects on gravitational-wave waveforms of any such system discovered to date. We have measured the advance of periastron passage for this system, ˙ = 25.6 0.3 deg yr − 1 , implying a total system mass of only 2.50 0.04 M , so it is among the lowest-mass DNS systems. This total mass measurement combined with the minimum companion mass constrains the pulsar mass to 1.3 M .
Objective: Although obese children are at increased risk for coronary heart disease in later life, it is not clear if the association results from the persistence of childhood obesity into adulthood. ...We examined the relation of both childhood and adult levels of body mass index (BMI, kg m- 2) to carotid intima-media thickness (IMT) measured at the (mean) age of 36 years. Design and Subjects: Prior to the determination of adult IMT, the 1142 participants had been examined 7 (mean) times in the Bogalusa Heart Study. Measurements: In addition to BMI, levels of lipids, lipoproteins and blood pressure were measured at each examination. Cumulative levels of each risk factor were based on the areas under the individual growth curves calculated using multilevel models for repeated (BMI) measurements. We then examined the relation of these cumulative levels to adult IMT. Results: Carotid IMT was associated with cumulative levels of BMI in both childhood and adulthood (P<0.001 for each association). Furthermore, the association between childhood BMI and adult IMT persisted, but was reduced, after controlling for adult BMI. Although childhood levels of lipids, lipoproteins and blood pressure were also associated with adult IMT, these associations were not independent of adult levels of these risk factors. Conclusions: These results emphasize the adverse effects of elevated childhood BMI levels. In addition to the strong tracking of BMI levels from childhood to adulthood, there appears to be a modest, independent effect of childhood BMI on adult IMT. The prevention of childhood obesity should be emphasized.
Diabetes mellitus is a chronic disease that leads to complications including heart disease, stroke, kidney failure, blindness and nerve damage. Type 2 diabetes, characterized by target-tissue ...resistance to insulin, is epidemic in industrialized societies and is strongly associated with obesity; however, the mechanism by which increased adiposity causes insulin resistance is unclear. Here we show that adipocytes secrete a unique signalling molecule, which we have named resistin (for resistance to insulin). Circulating resistin levels are decreased by the anti-diabetic drug rosiglitazone, and increased in diet-induced and genetic forms of obesity. Administration of anti-resistin antibody improves blood sugar and insulin action in mice with diet-induced obesity. Moreover, treatment of normal mice with recombinant resistin impairs glucose tolerance and insulin action. Insulin-stimulated glucose uptake by adipocytes is enhanced by neutralization of resistin and is reduced by resistin treatment. Resistin is thus a hormone that potentially links obesity to diabetes.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Platelets are formed and released into the bloodstream by precursor cells called megakaryocytes that reside within the bone marrow. The production of platelets by megakaryocytes requires an intricate ...series of remodeling events that result in the release of thousands of platelets from a single megakaryocyte. Abnormalities in this process can result in clinically significant disorders. Thrombocytopenia (platelet counts less than 150,000/microl) can lead to inadequate clot formation and increased risk of bleeding, while thrombocythemia (platelet counts greater than 600,000/microl) can heighten the risk for thrombotic events, including stroke, peripheral ischemia, and myocardial infarction. This Review will describe the process of platelet assembly in detail and discuss several disorders that affect platelet production.
Cyclin-dependent kinase 4/6 (CDK4/6)-specific inhibitors, such as palbociclib, have shown clinical efficacy, but primary or secondary resistance has emerged as a problem. To develop more effective ...therapeutic approaches, investigation is needed into the mechanisms of resistance or adaption. Here, it is demonstrated that CDK2 compensates for loss of CDK4 activity to rescue palbociclib-arrested breast cancer cells, suggesting that inhibition of both kinases is required to achieve durable response. In addition, a novel strategy is described to inhibit tyrosine phosphorylation of p27Kip1 (CDKN1B) and simultaneously inhibit both CDK2 and CDK4. p27Kip1 is a required assembly factor for cyclin-CDK4 complexes, but it must be phosphorylated on residue Y88 to open or activate the complex. The Brk-SH3 peptide, ALT, blocks p27 Y88 phosphorylation, inhibiting CDK4. Nonphosphorylated p27 is no longer a target for ubiquitin-mediated degradation and this stabilized p27 now also inhibits CDK2 activity. Thus, ALT induction inhibits both the kinase that drives proliferation (CDK4) and the kinase that mediates resistance (CDK2), causing a potent and long-lasting cell-cycle arrest. ALT arrests growth of all breast cancer subgroups and synergizes with palbociclib to increase cellular senescence and to cause tumor regression in breast cancer xenograft models. The use of ALT demonstrates that both CDK4 and CDK2 need to be inhibited if long-term efficacy is to be achieved and represents a novel modality to inhibit breast cancer cells.
Modulating tyrosine phosphorylation of p27 impacts both proliferative (CDK4) and resistance (CDK2) mechanisms in breast cancer and suggests that phospho-p27 status may serve as a biomarker for patients that are responsive to CDK4/6 inhibition.
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