216 Engle St Suite 204
Englewood NJ 07631
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Tribbles-1 regulates hepatic lipogenesis through posttranscriptional regulation of C/EBPÎ±. - The Journal of clinical investigation
Variants near the gene TRIB1 are significantly associated with several plasma lipid traits, circulating liver enzymes, and the development of coronary artery disease in humans; however, it is not clear how its protein product tribbles-1 regulates lipid metabolism. Here, we evaluated mice harboring a liver-specific deletion of Trib1 (Trib1_LSKO) to elucidate the role of tribbles-1 in mammalian hepatic lipid metabolism. These mice exhibited increased hepatic triglyceride (TG) content, lipogenic gene transcription, and de novo lipogenesis. Microarray analysis revealed altered transcription of genes that are downstream of the transcription factor C/EBPÎ±, and Trib1_LSKO mice had increased hepatic C/EBPÎ± protein. Hepatic overexpression of C/EBPÎ± in WT mice phenocopied Trib1_LSKO livers, and hepatic knockout of Cebpa in Trib1_LSKO mice revealed that C/EBPÎ± is required for the increased lipogenesis. Using ChIP-Seq, we found that Trib1_LSKO mice had increased DNA-bound C/EBPÎ± near lipogenic genes and the Trib1 gene, which itself was transcriptionally upregulated by C/EBPÎ± overexpression. Together, our results reveal that tribbles-1 regulates hepatic lipogenesis through posttranscriptional regulation of C/EBPÎ±, which in turn transcriptionally upregulates Trib1. These data suggest an important role for C/EBPÎ± in mediating the lipogenic effects of hepatic Trib1 deletion and provide insight into the association between TRIB1 and plasma lipids, and liver traits in humans.
Is Prebiopsy MRI Good Enough to Avoid Prostate Biopsy? A Cohort Study Over a 1-Year Period. - Clinical genitourinary cancer
Prebiopsy multiparametric magnetic resonance imaging (MRI) is increasingly used in clinical practice to detect clinically significant prostate cancer, although its role is controversial. We audited the accuracy of prebiopsy MRI for men clinically suspected to have prostate cancer who underwent initial transrectal ultrasound (TRUS) biopsy at our institution.All patients who had a prebiopsy prostate MRI and initial TRUS prostate biopsy from January 1, 2013 to December 31, 2013 were included in the study. Prostate MRI was performed using a 1.5-T machine with T2 and diffusion weighted imaging axial phase. TRUS prostate biopsy was performed using a monoplane ultrasound machine. Systematic 12-core prostate biopsies were taken with a Tru-Cut biopsy needle from the apex, middle, and base of the left and right lobe.One hundred seventy-three patients met the inclusion criteria; 128 (74.4%) patients had a lesion detected on MRI and 114 (66.3%) patients had a positive biopsy. The sensitivity of MRI for significant prostate cancer on TRUS biopsy of the prostate was 83.5%, specificity was 35.2%, positive predictive value was 55%, and negative predictive value was 68.9%. A positive MRI scan was significantly associated with significant prostate cancer diagnosis, and higher National Comprehensive Cancer Network (NCCN) risk classification (PÂ â‰¤ .001). MRI detected 62 of 63 NCCN high-risk and 18 of 18 Gleason score 8 to 10 cases.The sensitivity and specificity of MRI appears insufficient to avoid TRUS biopsy in all men clinically suspected to have prostate cancer. Standardized MRI reporting and robust prospective studies are needed to define the role of prebiopsy MRI in this setting. For patients at risk of complications from biopsy, a negative MRI scan might be used to exclude high-risk disease.Copyright Â© 2015 Elsevier Inc. All rights reserved.
An Umpolung Approach for the Chemoselective Arylation of Selenocysteine in Unprotected Peptides. - Journal of the American Chemical Society
Herein we report an umpolung strategy for the bioconjugation of selenocysteine in unprotected peptides. This mild and operationally simple approach takes advantage of the electrophilic character of an oxidized selenocysteine (Se-S bond) to react with a nucleophilic arylboronic acid to provide the arylated selenocysteine within hours. This reaction is amenable to a wide range of boronic acids with different biorelevant functional groups and is unique to selenocysteine. Experimental evidence indicates that under oxidative conditions the arylated derivatives are more stable than the corresponding alkylated selenocysteine.
Using a Multimedia Presentation to Enhance Informed Consent in a Pediatric Emergency Department. - Pediatric emergency care
Informed consent is an ethical process for ensuring patient autonomy. Multimedia presentations (MMPs) often aid the informed consent process for research studies. Thus, it follows that MMPs would improve informed consent in clinical settings.The aim of this study was to determine if an MMP for the informed consent process for ketamine sedation improves parental satisfaction and comprehension as compared with standard practice.This 2-phase study compared 2 methods of informed consent for ketamine sedation of pediatric patients. Phase 1 was a randomized, prospective study that compared the standard verbal consent to an MMP. Phase 2 implemented the MMP into daily work flow to validate the previous year's results. Parents completed a survey evaluating their satisfaction of the informed consent process and assessing their knowledge of ketamine sedation. Primary outcome measures were parental overall satisfaction with the informed consent process and knowledge of ketamine sedation.One hundred eighty-four families from a free-standing, urban, tertiary pediatric emergency department with over 85,000 annual visits were enrolled. Different demographics were not associated with a preference for the MMP or improved scores on the content quiz. Intervention families were more likely "to feel involved in the decision to use ketamine" and to understand that "they had the right to refuse the ketamine" as compared with control families. The intervention group scored significantly higher overall on the content section than the control group. Implementation and intervention families responded similarly to all survey sections.Multimedia presentation improves parental understanding of ketamine sedation, whereas parental satisfaction with the informed consent process remains unchanged. Use of MMP in the emergency department for informed consent shows potential for both patients and providers.
ATF4 licenses C/EBPÎ² activity in human mesenchymal stem cells primed for adipogenesis. - eLife
A well-established cascade of transcription factor (TF) activity orchestrates adipogenesis in response to chemical cues, yet how cell-intrinsic determinants of differentiation such as cell shape and/or seeding density inform this transcriptional program remain enigmatic. Here, we uncover a novel mechanism licensing transcription in human mesenchymal stem cells (hMSCs) adipogenically primed by confluence. Prior to adipogenesis, confluency promotes heterodimer recruitment of the bZip TFs C/EBPÎ² and ATF4 to a non-canonical C/EBP DNA sequence. ATF4 depletion decreases both cell-density-dependent transcription and adipocyte differentiation. Global profiling in hMSCs and a novel cell-free assay reveals that ATF4 requires C/EBPÎ² for genomic binding at a motif distinct from that bound by the C/EBPÎ² homodimer. Our observations demonstrate that C/EBPÎ² bridges the transcriptional programs in naÃ¯ve, confluent cells and early differentiating pre-adipocytes. Moreover, they suggest that homo- and heterodimer formation poise C/EBPÎ² to execute diverse and stage-specific transcriptional programs by exploiting an expanded motif repertoire.
Resistance Analysis of Baseline and Treatment-Emergent Variants in Hepatitis C Virus Genotype 1 in the AVIATOR Study with Paritaprevir-Ritonavir, Ombitasvir, and Dasabuvir. - Antimicrobial agents and chemotherapy
AVIATOR, a phase 2 clinical trial, evaluated ritonavir-boosted paritaprevir (a protease inhibitor), ombitasvir (an NS5A inhibitor), and dasabuvir (a nonnucleoside polymerase inhibitor) (the three-drug [3D] regimen) with or without ribavirin (RBV) for 8, 12, or 24 weeks in 406 HCV genotype 1 (GT1)-infected patients. The rate of sustained virologic response 24 weeks after treatment ranged from 88% to 100% across the arms of the 3D regimen with or without RBV; 20 GT1a-infected patients and 1 GT1b-infected patient experienced virologic failure (5.2%). Baseline resistance-conferring variants in NS3 were rare. M28V in GT1a and Y93H in GT1b were the most prevalent preexisting variants in NS5A, and C316N in GT1b and S556G in both GT1a and GT1b were the most prevalent variants in NS5B. Interestingly, all the GT1a sequences encoding M28V in NS5A were from the United States, while GT1b sequences encoding C316N and S556G in NS5B were predominant in the European Union. Variants preexisting at baseline had no significant impact on treatment outcome. The most prevalent treatment-emergent resistance-associated variants (RAVs) in GT1a were R155K and D168V in NS3, M28T and Q30R in NS5A, and S556G in NS5B. The single GT1b-infected patient experiencing virologic failure had no RAVs in any target. A paritaprevir-ritonavir dose of 150/100 mg was more efficacious in suppressing R155K in NS3 than a 100/100-mg dose. In patients who failed after receiving 12 or more weeks of treatment, RAVs were selected in all 3 targets, while most patients who relapsed after 8 weeks of treatment did so without any detectable RAVs. Results from this study guided the selection of the optimal treatment regimen, treatment duration, and paritaprevir dose for further development of the 3D regimen. (This study has been registered at ClinicalTrials.gov under registration number NCT01464827.).Copyright Â© 2015, Krishnan et al.
A meta-analysis of randomized double-blind clinical trials in CMT1A to assess the change from baseline in CMTNS and ONLS scales after one year of treatment. - Orphanet journal of rare diseases
CMT1A is the most common inherited peripheral neuropathy. There is currently no approved treatment. We performed a meta-analysis including four randomized, double-blind, Placebo-controlled clinical trials to assess the disease progression after one year under Placebo, Ascorbic Acid (AA) or PXT3003, a combination of three repurposed drugs. We observed a weak deterioration in patients under Placebo, well below the reported natural disease progression. Patients treated with AA were stable after one year but not significantly different from Placebo. Patients undergoing PXT3003 treatment showed an improvement in CMTNS and ONLS, statistically significant versus Placebo and potentially precursory of a meaningful change in the disease course.
A review of the effect of omega-3 polyunsaturated fatty acids on blood triacylglycerol levels in normolipidemic and borderline hyperlipidemic individuals. - Lipids in health and disease
Circulating levels of triacylglycerol (TG) is a recognized risk factor for developing cardiovascular disease, a leading cause of death worldwide. The Institute of Medicine and the American Heart Association both recommend the consumption of n-3 polyunsaturated fatty acids (PUFA), specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), to reduce serum TG in hyperlipidemic individuals. Additionally, a number of systematic reviews have shown that individuals with any degree of dyslipidemia, elevated serum TG and/or cholesterol, may benefit from a 20-30% reduction in serum TG after consuming n-3 PUFA derived from marine sources. Given that individuals with serum lipid levels ranging from healthy to borderline dyslipidemic constitute a large portion of the population, the focus of this review was to assess the potential for n-3 PUFA consumption to reduce serum TG in such individuals. A total of 1341 studies were retrieved and 38 clinical intervention studies, assessing 2270 individuals, were identified for inclusion in the current review. In summary, a 9-26% reduction in circulating TG was demonstrated in studies where â‰¥ 4 g/day of n-3 PUFA were consumed from either marine or EPA/DHA-enriched food sources, while a 4-51% reduction was found in studies where 1-5 g/day of EPA and/or DHA was consumed through supplements. Overall, this review summarizes the current evidence with regards to the beneficial effect of n-3 PUFA on circulating TG levels in normolipidemic to borderline hyperlipidemic, otherwise healthy, individuals. Thus demonstrating that n-3 PUFA may play an important role in the maintenance of cardiovascular health and disease prevention.
Multicenter Clinical Evaluation of the Novel Alere i Strep A Isothermal Nucleic Acid Amplification Test. - Journal of clinical microbiology
Rapid detection of group A beta-hemolytic streptococcus (GAS) is used routinely to help diagnose and treat pharyngitis. However, available rapid antigen detection tests for GAS have relatively low sensitivity, and backup testing is recommended in children. Newer assays are more sensitive yet require excessive time for practical point-of-care use as well as laboratory personnel. The Alere i strep A test is an isothermal nucleic acid amplification test designed to offer highly sensitive results at the point of care within 8 min when performed by nonlaboratory personnel. The performance of the Alere i strep A test was evaluated in a multicenter prospective trial in a Clinical Laboratory Improvement Amendments (CLIA)-waived setting in comparison to bacterial culture in 481 children and adults. Compared to culture, the Aleri i strep A test had 96.0% sensitivity and 94.6% specificity. Discrepant results were adjudicated by PCR and found the Alere i strep A test to have 98.7% sensitivity and 98.5% specificity. Overall, the Alere i strep A test could provide a one-step, rapid, point-of-care testing method for GAS pharyngitis and obviate backup testing on negative results.Copyright Â© 2015, American Society for Microbiology. All Rights Reserved.
Six weeks of core stability training improves landing kinetics among female capoeira athletes: a pilot study. - Journal of human kinetics
Core stability training (CST) has increased in popularity among athletes and the general fitness population despite limited evidence CST programmes alone lead to improved athletic performance. In female athletes, neuromuscular training combining balance training and trunk and hip/pelvis dominant CST is suggested to reduce injury risk, and specifically peak vertical ground reaction forces (vGRF) in a drop jump landing task. However, the isolated effect of trunk dominant core stability training on vGRF during landing in female athletes had not been evaluated. Therefore, the objective of this study was to evaluate landing kinetics during a drop jump test following a CST intervention in female capoeira athletes. After giving their informed written consent, sixteen female capoeira athletes (mean Â± SD age, stature, and body mass of 27.3 Â± 3.7 years, 165.0 Â± 4.0 cm, and 59.7 Â± 6.3 kg, respectively) volunteered to participate in the training program which consisted of static and dynamic CST sessions, three times per week for six weeks. The repeated measures T-test revealed participants significantly reduced relative vGRF from pre- to post-intervention for the first (3.40 Â± 0.78 vs. 2.85 Â± 0.52 NÂ·NBW-1, respectively [p<0.05, effect size = 0.60]), and second landing phase (5.09 Â± 1.17 vs. 3.02 Â± 0.41 NÂ·NBW-1, respectively [p<0.001, effect size = 0.87]). The average loading rate was reduced from pre- to post-intervention during the second landing phase (30.96 Â± 18.84 vs. 12.06 Â± 9.83 NÂ·NBWÂ·s-1, respectively [p<0.01, effect size = 0.68]). The peak loading rate was reduced from pre- to post-intervention during the first (220.26 Â± 111.51 vs. 120.27 Â± 64.57 NÂ·NBWÂ·s-1 respectively [p<0.01, effect size = 0.64]), and second (99.52 Â± 54.98 vs. 44.71 Â± 30.34 NÂ·NBWÂ·s-1 respectively [p<0.01, effect size = 0.70]) landing phase. Body weight, average loading rate during the first landing phase, and jump height were not significantly different between week 0 and week 6 (p=0.528, p=0.261, and p=0.877, respectively). This study provides evidence that trunk dominant core stability training improves landing kinetics without improving jump height, and may reduce lower extremity injury risk in female athletes.
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216 Engle St Suite 204 Englewood, NJ 07631
401 S Van Brunt St Ste 405
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350 Engle St Englewood Hospital