Synthesis, Characterization and Antibacterial Activity of Some New 5,5'-diphenyl-4,4',5,5'-tetrahydro-1H,1'H-3,3'-bipyrazole Derivatives

An efficient and practical synthesis of five compounds of pyrazoline derivatives structures was achieved through cyclization of hydrazine hydrate with 1,6-diphenylhexa-1,5-diene-3,4-dione using glacial acetic acid as catalyst under thermal conditions. These compounds have been characterized by FT-IR, elemental analysis (C.H.N.) and 1H NMR spectroscopy. Keywords:pyrazoline, chalcone, heterocycli

The South Asian genome

Genetics of disease Microarrays Variant genotypes Population genetics Sequence alignment AllelesThe genetic sequence variation of people from the Indian subcontinent who comprise one-quarter of the world's population, is not well described. We carried out whole genome sequencing of 168 South Asians, along with whole-exome sequencing of 147 South Asians to provide deeper characterisation of coding regions. We identify 12,962,155 autosomal sequence variants, including 2,946,861 new SNPs and 312,738 novel indels. This catalogue of SNPs and indels amongst South Asians provides the first comprehensive map of genetic variation in this major human population, and reveals evidence for selective pressures on genes involved in skin biology, metabolism, infection and immunity. Our results will accelerate the search for the genetic variants underlying susceptibility to disorders such as type-2 diabetes and cardiovascular disease which are highly prevalent amongst South Asians.Whole genome sequencing to discover genetic variants underlying type-2 diabetes, coronary heart disease and related phenotypes amongst Indian Asians. Imperial College Healthcare NHS Trust cBRC 2011-13 (JS Kooner [PI], JC Chambers)

Ellagitannins of the fruit rind of pomegranate (Punica granatum) antagonize in vitro the host inflammatory response mechanisms involved in the onset of malaria

<p>Abstract</p> <p>Background</p> <p>The sun-dried rind of the immature fruit of pomegranate (<it>Punica granatum</it>) is presently used as a herbal formulation (OMARIA, Orissa Malaria Research Indigenous Attempt) in Orissa, India, for the therapy and prophylaxis of malaria. The pathogenesis of cerebral malaria, a complication of the infection by <it>Plasmodium falciparum</it>, is an inflammatory cytokine-driven disease associated to an up-regulation and activity of metalloproteinase-9 and to the increase of TNF production. The <it>in vitro </it>anti-plasmodial activity of <it>Punica granatum (Pg) </it>was recently described. The aim of the present study was to explore whether the anti-malarial effect of OMARIA could also be sustained via other mechanisms among those associated to the host immune response.</p> <p>Methods</p> <p>From the methanolic extract of the fruit rind, a fraction enriched in tannins (<it>Pg</it>-FET) was prepared. MMP-9 secretion and expression were evaluated in THP-1 cells stimulated with haemozoin or TNF. The assays were conducted in the presence of the <it>Pg</it>-FET and its chemical constituents ellagic acid and punicalagin. The effect of urolithins, the ellagitannin metabolites formed by human intestinal microflora, was also investigated.</p> <p>Results</p> <p><it>Pg</it>-FET and its constituents inhibited the secretion of MMP-9 induced by haemozoin or TNF. The effect occurred at transcriptional level since MMP-9 mRNA levels were lower in the presence of the tested compounds. Urolithins as well inhibited MMP-9 secretion and expression. <it>Pg</it>-FET and pure compounds also inhibited MMP-9 promoter activity and NF-kB-driven transcription.</p> <p>Conclusions</p> <p>The beneficial effect of the fruit rind of <it>Punica granatum </it>for the treatment of malarial disease may be attributed to the anti-parasitic activity and the inhibition of the pro-inflammatory mechanisms involved in the onset of cerebral malaria.</p

Arthroplasty Versus Internal Fixation for the Treatment of Undisplaced Femoral Neck Fractures: A Retrospective Cohort Study

OBJECTIVE: To compare the 24-month risk of mortality between arthroplasty and internal fixation for undisplaced femoral neck fractures (FNFs). DESIGN: Retrospective cohort study. SETTING: Secondary data analysis of 2 multinational randomized controlled trials. PARTICIPANTS: Patients aged 50 years or older with a FNF. INTERVENTION: Arthroplasty (n = 1441), including total hip arthroplasty and hemiarthroplasty, performed for a displaced FNF versus internal fixation (n = 734), including sliding hip screw or multiple cancellous screws, performed for an undisplaced FNF. MAIN OUTCOME MEASUREMENT: The primary outcome was mortality within 24 months of injury. Secondary outcomes included reoperation and health-related quality of life. RESULTS: The 24-month mortality rate was 15.0% (n = 327). Arthroplasty was associated with a significant reduction in the odds of mortality [adjusted odds ratio (aOR): 0.56, 95% confidence interval (CI): 0.44-0.72, P < 0.01] compared with treatment with internal fixation. 11.4% (n = 248) of the study patients required reoperation within 24 months of injury. The odds of reoperation were 59% lower with arthroplasty treatment than with internal fixation (aOR: 0.41, 95% CI: 0.32-0.55, P < 0.01). The 24-month SF-12 physical component scores were 2.7 points higher in arthroplasty patients compared with internal fixation patients (95% CI: 1.6-3.8, P < 0.01). CONCLUSIONS: Our findings suggest arthroplasty for a FNF may reduce the risk of mortality and reoperation compared with internal fixation of undisplaced fractures. This finding is counter to many current surgical practices but consistent with a mounting body of evidence. Before widespread adoption of arthroplasty for undisplaced fractures, these results should be confirmed in a definitive comparative trial. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence

Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P &lt; 2.2 × 10-7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition

Effect of 18F-fluciclovine positron emission tomography on the management of patients with recurrence of prostate cancer: Results from the FALCON Trial

Purpose: Early and accurate localization of lesions in patients with biochemical recurrence (BCR) of prostate cancer may guide salvage therapy decisions. The present study, 18F-Fluciclovine PET/CT in biochemicAL reCurrence Of Prostate caNcer (FALCON; NCT02578940), aimed to evaluate the effect of 18F-fluciclovine on management of men with BCR of prostate cancer. Methods and Materials: Men with a first episode of BCR after curative-intent primary therapy were enrolled at 6 UK sites. Patients underwent 18F-fluciclovine positron emission tomography/computed tomography (PET/CT) according to standardized procedures. Clinicians documented management plans before and after scanning, recording changes to treatment modality as major and changes within a modality as other. The primary outcome measure was record of a revised management plan postscan. Secondary endpoints were evaluation of optimal prostate specific antigen (PSA) threshold for detection, salvage treatment outcome assessment based on 18F-fluciclovine-involvement, and safety. Results: 18F-Fluciclovine was well tolerated in the 104 scanned patients (median PSA = 0.79 ng/mL). Lesions were detected in 58 out of 104 (56%) patients. Detection was broadly proportional to PSA level; ≤1 ng/mL, 1 out of 3 of scans were positive, and 93% scans were positive at PSA &gt;2.0 ng/mL. Sixty-six (64%) patients had a postscan management change (80% after a positive result). Major changes (43 out of 66; 65%) were salvage or systemic therapy to watchful waiting (16 out of 66; 24%); salvage therapy to systemic therapy (16 out of 66; 24%); and alternative changes to treatment modality (11 out of 66, 17%). The remaining 23 out of 66 (35%) management changes were modifications of the prescan plan: most (22 out of 66; 33%) were adjustments to planned brachytherapy/radiation therapy to include a 18F-fluciclovine-guided boost. Where 18F-fluciclovine guided salvage therapy, the PSA response rate was higher than when 18F-fluciclovine was not involved (15 out of 17 [88%] vs 28 out of 39 [72%]). Conclusions: 18F-Fluciclovine PET/CT located recurrence in the majority of men with BCR, frequently resulting in major management plan changes. Incorporating 18F-fluciclovine PET/CT into treatment planning may optimize targeting of recurrence sites and avoid futile salvage therapy

Comparison of PET/MRI With PET/CT in the Evaluation of Disease Status in Lymphoma

PURPOSE: The primary aim was to compare the diagnostic performance of PET/MRI (performed with basic anatomical MRI sequences) in detecting sites of disease in adult patients with lymphoma compared with the current standard of care, PET/CT. Secondary aims were to assess the additional value of diffusion-weighted imaging to PET/MRI in disease detection and to evaluate the relationship between the standardized uptake value on PET/MR and the apparent diffusion coefficient on diffusion-weighted imaging. METHODS: Sixty-eight studies in 66 consecutive patients with histologically proven Hodgkin or non-Hodgkin lymphoma were prospectively evaluated. Each patient had whole body PET/CT, followed by whole body PET/MR. Two experienced readers independently evaluated the PET/MRI studies, and two other experienced readers independently evaluated PET/CT. Site of lymphoma involvement and SUVmax at all nodal sites more avid than background liver were recorded. Readers provided stage (in baseline cases) and disease status (remission vs active disease). The apparent diffusion coefficient mean value corresponding to the most avid PET site of disease was recorded. RESULTS: Ninety-five nodal and 8 extranodal sites were identified on both PET/CT and PET/MRI. In addition, 3 nodal and 1 extranodal sites were identified on PET/MRI. For positive lesion detection, reader agreement in PET/MR was perfect between the 2 readers and almost perfect between PET/CT and PET/MR (k > 0.978). Intermodality agreement between PET/CT and PET/MRI was also near perfect to perfect for staging/disease status k = (0.979–1.000). SUVmax from PET/CT and PET/MRI correlated significantly (Spearman rho correlation coefficient, 0.842; P < 0.001). Diffusion-weighted imaging did not alter lesion detection or staging in any case. A negative correlation was demonstrated between ADC mean and SUVmax (Spearman rho correlation coefficient r, -0.642; P < 0.001). CONCLUSIONS: PET/MRI is a reliable alternative to PET/CT in the evaluation of patients with lymphoma. Diffusion-weighted imaging did not alter diagnostic accuracy. With comparable accuracy in detection of disease sites and added benefit of radiation dose reduction, PET/MRI has a potential to become part of routine lymphoma imaging

Areas of normal pulmonary parenchyma on HRCT exhibit increased FDG PET signal in IPF patients

Purpose: Patients with idiopathic pulmonary fibrosis (IPF) show increased PET signal at sites of morphological abnormality on high-resolution computed tomography (HRCT). The purpose of this investigation was to investigate the PET signal at sites of normal-appearing lung on HRCT in IPF. Methods: Consecutive IPF patients (22 men, 3 women) were prospectively recruited. The patients underwent 18F-FDG PET/HRCT. The pulmonary imaging findings in the IPF patients were compared to the findings in a control population. Pulmonary uptake of 18F-FDG (mean SUV) was quantified at sites of morphologically normal parenchyma on HRCT. SUVs were also corrected for tissue fraction (TF). The mean SUV in IPF patients was compared with that in 25 controls (patients with lymphoma in remission or suspected paraneoplastic syndrome with normal PET/CT appearances). Results: The pulmonary SUV (mean ± SD) uncorrected for TF in the controls was 0.48 ± 0.14 and 0.78 ± 0.24 taken from normal lung regions in IPF patients (p < 0.001). The TF-corrected mean SUV in the controls was 2.24 ± 0.29 and 3.24 ± 0.84 in IPF patients (p < 0.001). Conclusion: IPF patients have increased pulmonary uptake of 18F-FDG on PET in areas of lung with a normal morphological appearance on HRCT. This may have implications for determining disease mechanisms and treatment monitoring. © 2013 The Author(s)

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns