The authors conducted a nested case-control study of serum steroid concentrations and risk of benign prostatic hyperplasia (BPH), using data from the placebo arm of the Prostate Cancer Prevention ...Trial (1993–2003). Incident BPH over 7 years (n = 708) was defined as receipt of treatment, a report of 2 International Prostate Symptom Score (IPSS) values greater than 14, or 2 increases of 5 or more from baseline IPSS values with at least 1 value greater than or equal to 12. Controls (n = 709) were selected from men who reported no BPH treatment or any IPSS greater than 7. Baseline serum was analyzed for testosterone, estradiol, estrone, 5α-androstane-3α, 17β-diol-glucuronide, and sex hormone-binding globulin. Covariate-adjusted odds ratios contrasting the highest quartiles with the lowest quartiles of testosterone, estradiol, and testosterone:17β-diol-glucuronide ratio were 0.64 (95% confidence interval (CI): 0.43, 0.95; Ptrend = 0.04), 0.72 (95% CI: 0.53, 0.98; Ptrend = 0.09), and 0.64 (95% CI: 0.46, 0.89; Ptrend = 0.004), respectively. Findings did not differ by age, body mass index, time to BPH endpoint, or type of BPH endpoint. High testosterone levels, estradiol levels, and testosterone:17β-diol-glucuronide ratio are associated with reduced BPH risk, which may reflect decreased activity of 5-α-reductase. Genetic or environmental factors that affect the activity of 5-α-reductase may be important in the development of symptomatic BPH.
Accelerated arteriosclerosis is now the major long-term complication of heart transplantation. Defining the risk factors associated with the development of accelerated arteriosclerosis will provide ...not only a means of identifying patients at risk for this complication but also clues to the etiology of accelerated arteriosclerosis. The purpose of this study was to examine the relationship between peritransplant myocardial ischemic injury and the development of accelerated arteriosclerosis. In a case-control study we examined the first three endomyocardial biopsies from 50 heart transplant recipients and graded the degree of ischemic injury present in these biopsies. The histologic changes graded in the biopsies included contraction band necrosis, coagulative necrosis, and macrophagic removal of ischemically injured myocytes. Of the 50 recipients included in the study, 25 had angiographic evidence of accelerated arteriosclerosis and 25 did not. In multivariate analysis, which included the number of class I major histocompatibility (MHC) antigen mismatches between the donor and the recipient, the recipient's post-transplant cytomegalovirus status, the donor's age, and the number of rejection episodes, the histologic degree of ischemic injury present in the biopsies emerged as the strongest predictor of the development of accelerated arteriosclerosis (RR 2.6, 95% CI 1.2-5.8, p = 0.02). These results suggest that ischemic injury to the heart during the peritransplant period significantly contributes to the development of accelerated arteriosclerosis in heart transplant recipients and that histologic changes in early posttransplant biopsies can be used to identify recipients at risk of developing accelerated arteriosclerosis.
Summary
Glutaric acidaemia type I (GA I) is an inborn error of metabolism caused by a deficiency of glutaryl‐CoA dehydrogenase (GCDH) and is characterized clinically by striatal degeneration that ...almost always occurs in early childhood. A murine knockout model of GA I has the organic aciduria seen in the human disorder, but this model does not develop striatal degeneration spontaneously. 3‐Nitropropionic acid (3NP), a succinic dehydrogenase inhibitor with specificity for the striatum, was investigated as a potential initiator of striatal degeneration in GCDH‐deficient mice. This study shows that GCDH‐deficient mouse pups are more susceptible to 3NP than their wild‐type littermates, and that all mouse pups are more sensitive to 3NP as infants than as adolescents and adults. Increased sensitivity to 3NP early in life may model the developmental window for the striatal damage observed in human GA I.
The oscillation results published by the Double Chooz Collaboration in 2011 and 2012 rely on background models substantiated by reactor-on data. In this analysis, we present a ...background-model-independent measurement of the mixing angle θ13 by including 7.53 days of reactor-off data. A global fit of the observed antineutrino rates for different reactor power conditions is performed, yielding a measurement of both θ13 and the total background rate. The results on the mixing angle are improved significantly by including the reactor-off data in the fit, as it provides a direct measurement of the total background rate. This reactor rate modulation analysis considers antineutrino candidates with neutron captures on both Gd and H, whose combination yields sin2(2θ13)=0.102±0.028(stat.)±0.033(syst.). The results presented in this study are fully consistent with the ones already published by Double Chooz, achieving a competitive precision. They provide, for the first time, a determination of θ13 that does not depend on a background model.
Infrared reflection absorption spectroscopy (IRAS) at low temperatures (ca. 40 K) has been used to study the interaction of NO with highly ordered MgO(100) thin films. Dimer formation has been ...observed in the multilayer regime at (<60 K) and in the monolayer regime at 60−70 K. Using 15NO, it is shown that dimeric NO, (NO)2, is the key intermediate in the formation of N2O above 70 K.
Although many regional multiple sclerosis (MS) databases existed in the United States and Canada, there was no single clinician-derived registry that examined this disease as a group across the North ...American continent. This distinction is important because information that results from such a database can potentially give perspectives about MS that cannot be derived from any single regional registry. A partnership was forged between the pharmaceutical industry and the Consortium of Multiple Sclerosis Centers (CMSC) to create a registry of patients with MS from Canada and the United States, including Puerto Rico. Case report forms were created to collect physician-derived information, and the Patient-Reported Outcomes Measurement Information System (PROMIS) was selected to capture patient-reported outcomes. As of November 2021, 754 of 1000 patients have been enrolled. Completion of recruitment is expected by the end of 2021. Twenty-five centers are participating, with an expected total of 30, including five centers from Canada. Clinical status, health economic outcomes, magnetic resonance images, and, soon, biomarkers relevant to understanding relapses and progression are collected. The short-term goal is to understand and better treat MS disease progression, and the long-term goal is its prevention. The North American Registry for Care and Research in Multiple Sclerosis (NARCRMS) is one of few clinician/patient-generated registries that examines MS across North America, including Puerto Rico. Information derived from the natural history studies should help physicians, the pharmaceutical industry, and regulatory bodies understand MS better and improve quality of life for patients with MS worldwide.
Blepharophimosis, ptosis, epicanthus inversus syndrome type I (BPES; OMIM 110100) is an autosomal dominant disorder affecting craniofacial development and ovarian function. We have identified a ...patient with BPES who carried a de novo reciprocal translocation 46,XX,t(3;21)(q23;q22.1). Fluorescence in situ hybridization analysis at band 3q23 using probes derived from BAC 175G20 (Research Genetics), PACs 108L15 and 169C10 (RPCI1), and cosmids AC174D4, AC68D3, AC44F5, and AC125C5 (Lawrence Livermore National Laboratory) was performed. The patient's breakpoint was found to lie within the overlapping region of the BAC and PACs but centromeric to all the cosmids. However, a 10.5-kb BamHI-digested fragment, common to the BAC and PAC clones, was shown to cross the breakpoint. The results have placed our patient's breakpoint proximal to that of the previously reported patient 46,XY,t(3;4)(q23;p15.2) and within a 10.5-kb interval. This is the second patient in which a breakpoint was refined by molecular cytogenetics. Our findings emphasize the significance of this region for BPES.
A large-scale optimisation of density functional theory (DFT) conditions for computational NMR structure elucidation has been conducted by systematically screening the DFT functionals and statistical ...models. The extended PyDP4 workflow was tested on a diverse and challenging set of 42 biologically active and stereochemically rich compounds, including highly flexible molecules. MMFF/mPW1PW91/M06-2X in combination with a 2 Gaussian, 1 region statistical model was capable of identifying the correct diastereomer among up to an upper limit of 32 potential diastereomers. Overall a 2-fold reduction in structural uncertainty and a 7-fold reduction in model overconfidence have been achieved. Tools for rapid set-up and analysis of computational and experimental results, as well as for the statistical model generation, have been developed and are provided. All of this should facilitate rapid and reliable computational NMR structure elucidation, which has become a valuable tool to natural product chemists and synthetic chemists alike.
Improvements to the DP4 computational structure elucidation method have led to a 2-fold reduction in structural uncertainty and 7-fold improvement of statistical confidence.
The ability to use archival tissue to test externally valid hypotheses of carcinogenesis is dependent on the availability of population-based samples of cancer tissue. Tissue microarrays (TMAs) ...provide an efficient format for developing population-based samples of tissue. A TMA was constructed consisting of archival tissue from patients diagnosed with invasive colorectal cancer in the state of Hawaii in 1995. The population representativeness of the TMA was evaluated by comparing patient and clinical characteristics of TMA cases to that of all cases of colorectal carcinoma diagnosed statewide in 1995. Cytokeratin 20 (CK20) and cytokeratin 7 (CK7) immunohistochemistry was used to validate the utility of the TMA, and the expression of these proteins was correlated with patient and tumor characteristics. The TMA comprised tissue specimens from 286 patients representing 47% of all invasive cases diagnosed statewide in 1995. TMA cases were comparable to all invasive colorectal cases statewide with respect to age, sex, race/ethnicity, anatomic site, and survival. There were some differences between TMA cases and all cases with respect to tumor stage, histological classification, and treatment. There were significant differences in the relative expression of CK20 and CK7 proteins between malignant and normal tissues and by tumor stage. Advanced cancers were more likely to have CK20+/cytokeratin 7+ (CK7+) profiles than early-stage cancers, which were predominantly CK20+/cytokeratin 7− (CK7−). CK7+ expression was not correlated with anatomic location of carcinomas. This well-characterized TMA offers a powerful tool for testing hypotheses regarding colorectal carcinogenesis, including the identification of potential markers of neoplastic development and progression.
5,6-Dihydrothymid-5-yl (4) is generated via Norrish type I cleavage of isopropyl ketone 7. Ketone 7 was site specifically incorporated into chemically synthesized polythymidylates and an ...oligonucleotide containing all four native deoxyribonucleotides. No damage is induced in oligonucleotides containing 7 upon photolysis under anaerobic conditions. In the presence of O2, strand breaks and alkaline labile lesions are formed at the original site of 7, and at nucleotides adjacent to the 5‘-phosphate of 7. Kinetic isotope effect experiments reveal that direct strand scission at the thymidine adjacent to the 5‘-phosphate of 4 arises from C1‘ hydrogen atom abstraction. The observed KIE (∼3.9) is attributed to hydrogen atom abstraction from C1‘ by the peroxyl radical 35 derived from 4. Enzymatic end group analysis and measurement of free base release are consistent with a process involving C1‘ hydrogen atom abstraction. Cleavage experiments carried out in the presence of t-BuOH (1.05 M) and NaN3 (10 mM) indicate that damage does not result from hydroxyl radical, but that 1O2 is responsible for a significant amount of the observed strand damage.
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