Race and the Georgia Courts: Implications of the Georgia Public Trust and Confidence Survey for Batson v. Kentucky and its Progeny

Put simply, there is a perception among many Georgians that the court system treats minorities worse than whites. This Essay considers implications of the Georgia findings for a line of United States Supreme Court decisions designed to prevent racial discrimination by trial lawyers in the selection of trial juries

Effect of ramipril on renal function in patients with intermittent claudication

Simon D Hobbs1, Martin W Claridge1, Antonius BM Wilmink1, Donald J Adam1, Mark E Thomas2, Andrew W Bradbury11University Department of Vascular Surgery and 2Department of Nephrology, Heart of England NHS Trust (Teaching), Birmingham, UKBackground: The Heart Outcomes Prevention Study (HOPE) demonstrated that ramipril resulted in a blood-pressure-independent 25% reduction in cardiovascular events in patients with peripheral arterial disease (PAD). Despite this, general practitioners and vascular surgeons remain reluctant to prescribe ACE inhibitors in this group of patients because of concerns about renal artery stenosis (RAS). We aimed to define the effect of ramipril on renal function in patients with intermittent claudication (IC).Methods and Results: Of 132 unselected patients with IC entering the study 78 (59%) were excluded due to: current ACE inhibitor use (38%), renal impairment (serum creatinine above normal range) (15%), known severe RAS (1%) or unwillingness to participate (5%). The remaining 54 patients were titrated to 10 mg ramipril and renal function was monitored at 1, 5, and 12 weeks. Treatment was discontinued during titration in 5 patients due to symptoms (3) or lack of compliance (2). In the remainder, median [IQR] serum creatinine increased (94 [85.8–103.3] to 98 [88.0–106.5] µmol/L, p ≤ 0.001) and median [IQR] GFR decreased (71.5 [64.6–82.3] to 68.7 [59.8–74.7] mL/min per 1.73 m2, p ≤ 0.001) between baseline and 5 weeks. These changes were not considered clinically significant. By 12 weeks these values had returned almost to baseline (Cr 95.5 [88.0–103.25] µmol/L, GFR 71.8 [65.3–77.4] mL/min). No patient had a serum creatinine rise >30%.Conclusion: Most of patients with IC and a normal serum creatinine can be safely commenced on ramipril provided they are screened, titrated and monitored as described above. Studies in patients with borderline renal impairment (serum creatinine up to 30% above baseline) are on-going.Keywords: peripheral arterial disease, ramipril, renal function, intermittent claudicatio

MUSCLE : automated multi-objective evolutionary optimization of targeted LC-MS/MS analysis:Automated multi-objective evolutionary optimization of targeted LC-MS/MS analysis

Summary: Developing liquid chromatography tandem mass spectrometry (LC-MS/MS) analyses of (bio)chemicals is both time consuming and challenging, largely because of the large number of LC and MS instrument parameters that need to be optimized. This bottleneck significantly impedes our ability to establish new (bio)analytical methods in fields such as pharmacology, metabolomics and pesticide research. We report the development of a multi-platform, user-friendly software tool MUSCLE (multi-platform unbiased optimization of spectrometry via closed-loop experimentation) for the robust and fully automated multi-objective optimization of targeted LC-MS/MS analysis. MUSCLE shortened the analysis times and increased the analytical sensitivities of targeted metabolite analysis, which was demonstrated on two different manufacturer’s LC-MS/MS instruments. Availability and implementation: Available at http://www.muscleproject.org. Contact: [email protected] Supplementary information: Supplementary data are available at Bioinformatics online

Randomised controlled feasibility trial of a web-based weight management intervention with nurse support for obese patients in primary care

<b>Background</b><p></p> There is a need for cost-effective weight management interventions that primary care can deliver to reduce the morbidity caused by obesity. Automated web-based interventions might provide a solution, but evidence suggests that they may be ineffective without additional human support. The main aim of this study was to carry out a feasibility trial of a web-based weight management intervention in primary care, comparing different levels of nurse support, to determine the optimal combination of web-based and personal support to be tested in a full trial.<p></p> <b>Methods</b><p></p> This was an individually randomised four arm parallel non-blinded trial, recruiting obese patients in primary care. Following online registration, patients were randomly allocated by the automated intervention to either usual care, the web-based intervention only, or the web-based intervention with either basic nurse support (3 sessions in 3 months) or regular nurse support (7 sessions in 6 months). The main outcome measure (intended as the primary outcome for the main trial) was weight loss in kg at 12 months. As this was a feasibility trial no statistical analyses were carried out, but we present means, confidence intervals and effect sizes for weight loss in each group, uptake and retention, and completion of intervention components and outcome measures.<p></p> <b>Results</b><p></p> All randomised patients were included in the weight loss analyses (using Last Observation Carried Forward). At 12 months mean weight loss was: usual care group (n = 43) 2.44 kg; web-based only group (n = 45) 2.30 kg; basic nurse support group (n = 44) 4.31 kg; regular nurse support group (n = 47) 2.50 kg. Intervention effect sizes compared with usual care were: d = 0.01 web-based; d = 0.34 basic nurse support; d = 0.02 regular nurse support. Two practices deviated from protocol by providing considerable weight management support to their usual care patients.<p></p> <b>Conclusions</b><p></p> This study demonstrated the feasibility of delivering a web-based weight management intervention supported by practice nurses in primary care, and suggests that the combination of the web-based intervention with basic nurse support could provide an effective solution to weight management support in a primary care context

Indirect effects of pesticides on breeding yellowhammer (Emberiza citrinella

Abstract Intensification of agriculture is believed to have caused declines in farmland bird populations. One of the key elements of recent agricultural intensification is the increased use of pesticides. However, studies elucidating relationships between individual management practices and responses in bird populations remain rare. Here, evidence is presented of indirect effects of pesticides on behaviour and nestling condition of yellowhammers (Emberiza citrinella L.). Insecticide use was associated with reduced abundance of invertebrate food at the field scale resulting, early in the season (when nestlings were fed exclusively on invertebrates), in a negative correlation with yellowhammer foraging intensity. There was also a negative relationship between insecticide use and nestling body condition. While cumulative effects of repeated spraying can have impacts, the occurrence of any insecticide spraying in the breeding season may be more detrimental than multiple sprays at other times. Minimising applications of persistent broad-spectrum insecticides during March-June, the provision of alternative unsprayed foraging habitat and advice on mitigating indirect effects of pesticides to advisers and users are likely to benefit nesting yellowhammers.

Endogenous production of IL-1B by breast cancer cells drives metastasis and colonisation of the bone microenvironment

Background: Breast cancer bone metastases are incurable highlighting the need for new therapeutic targets. After colonizing bone, breast cancer cells remain dormant, until signals from the microenvironment stimulate outgrowth into overt metastases. Here we show that endogenous production of IL-1B by tumor cells drives metastasis and growth in bone. Methods: Tumor/stromal IL-B and IL-1R1 expression was assessed in patient samples and effects of the IL-1R antagonist, Anakinra or the IL-1B antibody Canakinumab on tumor growth and spontaneous metastasis were measured in a humanized mouse model of breast cancer bone metastasis. Effects of tumor cell-derived IL-1B on bone colonisation and parameters associated with metastasis were measured in MDA-MB-231, MCF7 and T47D cells transfected with IL-1B/control. Results: In tissue samples from >1300 patients with stage II/III breast cancer, IL-1B in tumor cells correlated with relapse in bone (hazard ratio 1.85; 95% CI 1.05-3.26; P=0.02) and other sites (hazard ratio 2.09; 95% CI 1.26-3.48; P=0.0016). In a humanized model of spontaneous breast cancer metastasis to bone, Anakinra or Canakinumab reduced metastasis and reduced the number of tumor cells shed into the circulation. Production of IL-1B by tumor cells promoted EMT (altered E-Cadherin, N-Cadherin and G-Catenin), invasion, migration and bone colonisation. Contact between tumor and osteoblasts or bone marrow cells increased IL-1B secretion from all three cell types. IL-1B alone did not stimulate tumor cell proliferation. Instead, IL-1B caused expansion of the bone metastatic niche leading to tumor proliferation. Conclusion: Pharmacological inhibition of IL-1B has potential as a novel treatment for breast cancer metastasis

The Epoxygenases CYP2J2 Activates the Nuclear Receptor PPARα In Vitro and In Vivo

Peroxisome proliferator-activated receptors (PPARs) are a family of three (PPARalpha, -beta/delta, and -gamma) nuclear receptors. In particular, PPARalpha is involved in regulation of fatty acid metabolism, cell growth and inflammation. PPARalpha mediates the cardiac fasting response, increasing fatty acid metabolism, decreasing glucose utilisation, and is the target for the fibrate lipid-lowering class of drugs. However, little is known regarding the endogenous generation of PPAR ligands. CYP2J2 is a lipid metabolising cytochrome P450, which produces anti-inflammatory mediators, and is considered the major epoxygenase in the human heart.Expression of CYP2J2 in vitro results in an activation of PPAR responses with a particular preference for PPARalpha. The CYP2J2 products 8,9- and 11-12-EET also activate PPARalpha. In vitro, PPARalpha activation by its selective ligand induces the PPARalpha target gene pyruvate dehydrogenase kinase (PDK)4 in cardiac tissue. In vivo, in cardiac-specific CYP2J2 transgenic mice, fasting selectively augments the expression of PDK4.Our results establish that CYP2J2 produces PPARalpha ligands in vitro and in vivo, and suggests that lipid metabolising CYPs are prime candidates for the integration of global lipid changes to transcriptional signalling events

A Search for Pulsed TeV γ\gamma Ray Emission from the Crab Pulsar

We present the results of a search for pulsed TeV emission from the Crab pulsar using the Whipple Observatory's 10m gamma-ray telescope. The direction of the Crab pulsar was observed for a total of 73.4 hours between 1994 November and 1997 March. Spectral analysis techniques were applied to search for the presence of a gamma-ray signal from the Crab pulsar over the energy band 250GeV to 4TeV. At these energies we do not see any evidence of the 33ms pulsations present at lower energies from the Crab pulsar. The 99.9% confidence level upper limit for pulsed emission above 250GeV is derived to be 4.8 10^-12 cm^-2 s^-1 or <3% of the steady flux from the Crab Nebula. These results imply a sharp cut-off of the power-law spectrum seen by the EGRET instrument on the Compton Gamma-Ray Observatory. If the cut-off is exponential, it must begin at 60GeV or lower to accommodate these upper limits

Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers

Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 x 10(53)). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 x 10(-20)). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management