Preiss D.,University of Glasgow |
Tikkanen M.J.,University of Helsinki |
Welsh P.,University of Glasgow |
Ford I.,University of Glasgow |
And 14 more authors.
JAMA - Journal of the American Medical Association | Year: 2012
Context: Statin therapy has been associated with pancreatitis in observational studies. Although lipid guidelines recommend fibrate therapy to reduce pancreatitis risk in persons with hypertriglyceridemia, fibrates may lead to the development of gallstones, a risk factor for pancreatitis. Objective: To investigate associations between statin or fibrate therapy and incident pancreatitis in large randomized trials. Data Sources: Relevant trials were identified in literature searches of MEDLINE, EMBASE, and Web of Science (January 1, 1994, for statin trials and January 1, 1972, for fibrate trials, through June 9, 2012). Published pancreatitis data were tabulated where available (6 trials). Unpublished data were obtained from investigators (22 trials). Study Selection: We included randomized controlled cardiovascular end-point trials investigating effects of statin therapy or fibrate therapy. Studies with more than 1000 participants followed up for more than 1 year were included. Data Extraction: Trial-specific data described numbers of participants developing pancreatitis and change in triglyceride levels at 1 year. Trial-specific risk ratios (RRs) were calculated and combined using random-effects model meta-analysis. Betweenstudy heterogeneity was assessed using the I 2 statistic. Results: In 16 placebo- and standard care-controlled statin trials with 113 800 participants conducted over a weighted mean follow-up of 4.1 (SD, 1.5) years, 309 participants developed pancreatitis (134 assigned to statin, 175 assigned to control) (RR, 0.77 [95% CI, 0.62-0.97; P=.03; I 2=0%]). In 5 dose-comparison statin trials with 39 614 participants conducted over 4.8 (SD, 1.7) years, 156 participants developed pancreatitis (70 assigned to intensive dose, 86 assigned to moderate dose) (RR, 0.82 [95% CI, 0.59-1.12; P=.21; I 2=0%]). Combined results for all 21 statin trials provided RR 0.79 (95% CI, 0.65-0.95; P=.01; I 2=0%). In 7 fibrate trials with 40 162 participants conducted over 5.3 (SD, 0.5) years, 144 participants developed pancreatitis (84 assigned to fibrate therapy, 60 assigned to placebo) (RR, 1.39 [95% CI, 1.00-1.95; P=.053; I 2=0%]). Conclusion: In a pooled analysis of randomized trial data, use of statin therapy was associated with a lower risk of pancreatitis in patients with normal or mildly elevated triglyceride levels. ©2012 American Medical Association. All rights reserved.
DeFronzo R.A.,University of Texas Health Science Center at San Antonio |
Tripathy D.,University of Texas Health Science Center at San Antonio |
Schwenke D.C.,Phoenix Veterans Affairs VA Health Care System |
Schwenke D.C.,Arizona State University |
And 14 more authors.
New England Journal of Medicine | Year: 2011
BACKGROUND: Impaired glucose tolerance is associated with increased rates of cardiovascular disease and conversion to type 2 diabetes mellitus. Interventions that may prevent or delay such occurrences are of great clinical importance. METHODS: We conducted a randomized, double-blind, placebo-controlled study to examine whether pioglitazone can reduce the risk of type 2 diabetes mellitus in adults with impaired glucose tolerance. A total of 602 patients were randomly assigned to receive pioglitazone or placebo. The median follow-up period was 2.4 years. Fasting glucose was measured quarterly, and oral glucose tolerance tests were performed annually. Conversion to diabetes was confirmed on the basis of the results of repeat testing. RESULTS: Annual incidence rates for type 2 diabetes mellitus were 2.1% in the pioglitazone group and 7.6% in the placebo group, and the hazard ratio for conversion to diabetes in the pioglitazone group was 0.28 (95% confidence interval, 0.16 to 0.49; P<0.001). Conversion to normal glucose tolerance occurred in 48% of the patients in the pioglitazone group and 28% of those in the placebo group (P<0.001). Treatment with pioglitazone as compared with placebo was associated with significantly reduced levels of fasting glucose (a decrease of 11.7 mg per deciliter vs. 8.1 mg per deciliter [0.7 mmol per liter vs. 0.5 mmol per liter], P<0.001), 2-hour glucose (a decrease of 30.5 mg per deciliter vs. 15.6 mg per deciliter [1.6 mmol per liter vs. 0.9 mmol per liter], P<0.001), and HbA1c (a decrease of 0.04 percentage points vs. an increase of 0.20 percentage points, P<0.001). Pioglitazone therapy was also associated with a decrease in diastolic blood pressure (by 2.0 mm Hg vs. 0.0 mm Hg, P = 0.03), a reduced rate of carotid intima-media thickening (31.5%, P = 0.047), and a greater increase in the level of high-density lipoprotein cholesterol (by 7.35 mg per deciliter vs. 4.5 mg per deciliter [0.4 mmol per liter vs. 0.3 mmol per liter], P = 0.008). Weight gain was greater with pioglitazone than with placebo (3.9 kg vs. 0.77 kg, P<0.001), and edema was more frequent (12.9% vs. 6.4%, P = 0.007). CONCLUSIONS: As compared with placebo, pioglitazone reduced the risk of conversion of impaired glucose tolerance to type 2 diabetes mellitus by 72% but was associated with significant weight gain and edema. Copyright © 2011 Massachusetts Medical Society.
Defronzo R.A.,University of Texas at San Antonio |
Banerji M.A.,Health Science Center at Brooklyn |
Bray G.A.,Louisiana State University |
Buchanan T.A.,University of Southern California |
And 10 more authors.
Diabetologia | Year: 2010
Aims/hypothesis: The aim of the study was to examine the determinants of oral glucose tolerance in 602 persons with impaired glucose tolerance (IGT) who participated in the Actos Now for Prevention of Diabetes (ACT NOW) study. Methods: In addition to the 602 IGT participants, 115 persons with normal glucose tolerance (NGT) and 50 with impaired fasting glucose (IFG) were identified during screening and included in this analysis. Insulin secretion and insulin sensitivity indices were derived from plasma glucose and insulin during an OGTT. The acute insulin response (AIR) (0-10 min) and insulin sensitivity (SI) were measured with the frequently sampled intravenous glucose tolerance test (FSIVGTT) in a subset of participants. Results: At baseline, fasting plasma glucose, 2 h postprandial glucose (OGTT) and HbA1c were 5.8 ± 0.02 mmol/l, 10.5 ± 0.05 mmol/l and 5.5 ± 0.04%, respectively, in participants with IGT. Participants with IGT were characterised by defects in early (ΔI 0-30/ΔG 0-30 × Matsuda index, where ΔI is change in insulin in the first 30 min and ΔG is change in glucose in the first 30 min) and total (ΔI0-120/ΔG0-120 × Matsuda index) insulin secretion and in insulin sensitivity (Matsuda index and SI). Participants with IGT in whom 2 h plasma glucose was 7.8-8.3 mmol/l had a 63% decrease in the insulin secretion/insulin resistance (disposition) index vs participants with NGT and this defect worsened progressively as 2 h plasma glucose rose to 8.9-9.94 mmol/l (by 73%) and 10.0-11.05 mmol/l (by 80%). The Matsuda insulin sensitivity index was reduced by 40% in IGT compared with NGT (p < 0.005). In multivariate analysis, beta cell function was the primary determinant of glucose AUC during OGTT, explaining 62% of the variance. Conclusion: Our results strongly suggest that progressive beta cell failure is the main determinant of progression of NGT to IGT. © 2009 Springer-Verlag.
PubMed | Health science Center at Brooklyn, H. Lee Moffitt Cancer Center and Research Institute and Rutgers University
Type: Journal Article | Journal: Cancer chemotherapy and pharmacology | Year: 2016
Vitamin E delta-tocotrienol (VEDT) has demonstrated chemopreventive and antineoplastic activity in preclinical models. The aim of our study was to determine the safety and pharmacokinetics of VEDT and its metabolites after single- and multiple-dose administrations in healthy subjects.Thirty-six subjects received from 100 to 1600mg of oral VEDT as a single dose or twice daily for 14 consecutive days. A 3+3 dose escalation design was utilized. Pharmacokinetic data were derived from high-performance liquid chromatography (HPLC) assays. Serial blood and urine samples were collected before and during VEDT administration, with serum and urine metabolites assessed using HPLC.No drug-related adverse events were observed. Pharmacokinetic parameters for single and multiple doses were, respectively, as follows (shown as range): time to maximum concentration of 4-9.3 and 4.7-7.3h, maximum concentration of 795.6-3742.6 and 493.3-3746ng/mL, half-life of 1.7-5.9 and 2.3-6.9h, and 0-12h area under the curve of 4518.7-20,781.4 and 1987.7-22,171.2ngh/mL. Plasma tocotrienols were significantly increased after VEDT administration, indicating oral bioavailability of VEDT in humans. Plasma and urine levels of metabolites, -carboxyethyl hydroxychroman, and -carboxymethylbutyl hydroxychroman were elevated after VEDT administration in a dose-dependent manner and were 30-60 times significantly higher than -tocotrienol levels. VEDT can be safely administered at doses up to 1600mg twice daily. Plasma VEDT concentrations were comparable to those obtained in VEDT-treated mice in which tumor growth was delayed.Our results suggest that VEDT can be safely consumed by healthy subjects and achieve bioactive levels, supporting the investigation of VEDT for chemoprevention.
Biro D.,Health Science Center at Brooklyn
Culture, Medicine and Psychiatry | Year: 2010
Medicine regards pain as a signal of physical injury to the body despite evidence contradicting the linkage and despite the exclusion of vast numbers of sufferers who experience psychological pain. By broadening our concept of pain and making it more inclusive, we would not only better accommodate the basic science of pain but also would recognize what is already appreciated by the layperson-that pain from diverse sources, physical and psychological, share an underlying felt structure. © 2010 The Author(s).
Levinger L.,York College |
Serjanov D.,York College |
Serjanov D.,Health Science Center at Brooklyn
RNA Biology | Year: 2012
Numerous mutations in the mitochondrial genome are associated with maternally transmitted diseases and syndromes that affect muscle and other high energy-demand tissues. The mitochondrial genome encodes 13 polypeptides, 2 rRNAs and 22 interspersed tRNAs via long bidirectional polycistronic primary transcripts, requiring precise excision of the tRNAs. Despite making up only ∼10% of the mitochondrial genome, tRNA genes harbor most of the pathogenesis-related mutations. tRNase Z endonucleolytically removes the pre-tRNA 3′ trailer. The flexible arm of tRNase Z recognizes and binds the elbow (including the T-loop) of pre-tRNA. Pathogenesis-related T-loop mutations in mitochondrial tRNAs could thus affect tRNA structure, reduce tRNase Z binding and 3′ processing, and consequently slow mitochondrial protein synthesis. Here we inspect the effects of pathogenesis-related mutations in the T-loops of mitochondrial tRNAs on pretRNA structure and tRNase Z processing. Increases in KM arising from 59A > G substitutions in mitochondrial tRNAGly and tRNAIle accompany changes in T-loop structure, suggesting impaired substrate binding to enzyme. © 2012 Landes Bioscience.
John M.,Feinstein Institute for Medical Research |
John M.,The Zucker Hillside Hospital |
John M.,Hofstra University |
Ikuta T.,University of Mississippi |
Ferbinteanu J.,Health Science Center at Brooklyn
Brain Structure and Function | Year: 2016
Changes in brain connectivity in patients with early Alzheimer’s disease (AD) have been investigated using graph analysis. However, these studies were based on small data sets, explored a limited range of network parameters, and did not focus on more restricted sub-networks, where neurodegenerative processes may introduce more prominent alterations. In this study, we constructed structural brain networks out of 87 regions using data from 135 healthy elders and 100 early AD patients selected from the Open Access Series of Imaging Studies (OASIS) database. We evaluated the graph properties of these networks by investigating metrics of network efficiency, small world properties, segregation, product measures of complexity, and entropy. Because degenerative processes take place at different rates in different brain areas, analysis restricted to sub-networks may reveal changes otherwise undetected. Therefore, we first analyzed the graph properties of a network encompassing all brain areas considered together, and then repeated the analysis after dividing the brain areas into two sub-networks constructed by applying a clustering algorithm. At the level of large scale network, the analysis did not reveal differences between AD patients and controls. In contrast, the same analysis performed on the two sub-networks revealed that small worldness diminished with AD only in the sub-network containing the areas of medial temporal lobe known to be heaviest and earliest affected. The second sub-network, which did not present significant AD-induced modifications of ‘classical’ small world parameters, nonetheless showed a trend towards an increase in small world propensity, a novel metric that unbiasedly quantifies small world structure. Beyond small world properties, complexity and entropy measures indicated that the intricacy of connection patterns and structural diversity decreased in both sub-networks. These results show that neurodegenerative processes impact volumetric networks in a non-global fashion. Our findings provide new quantitative insights into topological principles of structural brain networks and their modifications during early stages of Alzheimer’s disease. © 2016 Springer-Verlag Berlin Heidelberg
Qureshi N.,Health Science Center at Brooklyn
Skinmed | Year: 2011
Although studies have yet to prove definitively a causal relationship between diet and acne, the lay public has traditionally held that such causality exists. The authors' study aims to determine which nutritional elements are thought to be related to acne, both positively and negatively. YouTube, a popular video-sharing Web site, was used to survey the views of the lay public. The keywords "acne," "acne diet," and "acne food" were searched in YouTube in July and August of 2009, and 87 videos were included in the study. More than 85% of videos suggest at least a moderate correlation between diet and acne. Dairy products and oily and greasy foods were viewed as aggravating factors, while fruits, vegetables, and supplements were regarded as alleviating factors. Generally regarded "truths" can affect patient compliance with treatment regimens, and a knowledgeable physician is better able to address these issues with his or her patients.
Miller B.E.,NC Associates |
Blessing J.A.,Roswell Park Cancer Institute |
Stehman F.B.,Indiana University |
Shahin M.S.,Abington Memorial Hospital |
And 6 more authors.
Gynecologic Oncology | Year: 2010
Background. The objective of this study was to estimate antitumor activity and toxicity of weekly docetaxel and gemcitabine as second-line chemotherapy for patients with recurrent uterine carcinosarcoma. Methods. Patients with recurrent carcinosarcoma of the uterus who had failed one regimen of chemotherapy, had a Gynecologic Oncology Group (GOG) performance status of 0-2 and had measurable disease were included. Treatment consisted of gemcitabine 600 mg/m2 and docetaxel 35 mg/m2 intravenously on days 1, 8 and 15 of a 28-day cycle until disease progression or intolerable adverse effects. This study employed an optimal but flexible two-stage design with an early stopping rule. If more than 3 out of 22-24 or more than 4 out of 25-29 patients responded, accrual to the second stage was to be initiated. Results. Twenty-eight patients were enlisted. Three patients were not eligible after pathology review. One patient was never treated. Twenty-four patients were evaluable. Nine patients had previous radiation therapy. There were no complete responses. Partial responses were seen in two patients (8.3%), stable disease in eight (33.3%) and progressive disease in 12 patients (50%). Two patients were not evaluable (8.3%). The median progression-free survival was 1.8 months. The median survival was 4.9 months. The treatment caused myelosuppression, mainly neutropenia, but also thrombocytopenia and anemia. Dose modifications became necessary in the majority of patients. In five patients, treatment was discontinued due to toxicity. Conclusions. This regimen of docetaxel and gemcitabine is not active in patients with recurrent carcinosarcoma of the uterus as second-line chemotherapy. © 2010 Published by Elsevier Inc.
PubMed | Health science Center at Brooklyn, H. Lee Moffitt Cancer Center and Research Institute and University of Tennessee Health Science Center
Type: Journal Article | Journal: Oncotarget | Year: 2016
Early detection of colorectal cancer (CRC) is crucial for effective treatment. Among CRC screening techniques, optical colonoscopy is widely considered the gold standard. However, it is a costly and invasive procedure with a low rate of compliance. Our long-term goal is to develop molecular imaging agents for the non-invasive detection of CRC by molecular imaging-based colonoscopy using CT, MRI or fluorescence. To achieve this, cell surface targets must be identified and validated. Here, we report the discovery of cell-surface markers that distinguish CRC from surrounding tissues that could be used as molecular imaging targets. Profiling of mRNA expression microarray data from patient tissues including adenoma, adenocarcinoma, and normal gastrointestinal tissues was used to identify potential CRC specific cell-surface markers. Of the identified markers, six were selected for further validation (CLDN1, GPR56, GRM8, LY6G6D/F, SLCO1B3 and TLR4). Protein expression was confirmed by immunohistochemistry of patient tissues. Except for SLCO1B3, diffuse and low expression was observed for each marker in normal colon tissues. The three markers with the greatest protein overexpression were CLDN1, LY6G6D/F and TLR4, where at least one of these markers was overexpressed in 97% of the CRC samples. GPR56, LY6G6D/F and SLCO1B3 protein expression was significantly correlated with the proximal tumor location and with expression of mismatch repair genes. Marker expression was further validated in CRC cell lines. Hence, three cell-surface markers were discovered that distinguish CRC from surrounding normal tissues. These markers can be used to develop imaging or therapeutic agents targeted to the luminal surface of CRC.