Urinary Tract Stones and Osteoporosis: Findings From the Women's Health Initiative

Kidney and bladder stones (urinary tract stones) and osteoporosis are prevalent, serious conditions for postmenopausal women. Men with kidney stones are at increased risk of osteoporosis; however, the relationship of urinary tract stones to osteoporosis in postmenopausal women has not been established. The purpose of this study was to determine whether urinary tract stones are an independent risk factor for changes in bone mineral density (BMD) and incident fractures in women in the Women's Health Initiative (WHI). Data were obtained from 150,689 women in the Observational Study and Clinical Trials of the WHI with information on urinary tract stones status: 9856 of these women reported urinary tract stones at baseline and/or incident urinary tract stones during follow‐up. Cox regression models were used to determine the association of urinary tract stones with incident fractures and linear mixed models were used to investigate the relationship of urinary tract stones with changes in BMD that occurred during WHI. Follow‐up was over an average of 8 years. Models were adjusted for demographic and clinical factors, medication use, and dietary histories. In unadjusted models there was a significant association of urinary tract stones with incident total fractures (HR 1.10; 95% CI, 1.04 to 1.17). However, in covariate adjusted analyses, urinary tract stones were not significantly related to changes in BMD at any skeletal site or to incident fractures. In conclusion, urinary tract stones in postmenopausal women are not an independent risk factor for osteoporosis. © 2015 American Society for Bone and Mineral Research.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/115895/1/jbmr2553.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/115895/2/jbmr2553_am.pd

Utility of a Work Process Classification System for characterizing non-fatal injuries in the Alaskan commercial fishing industry

Background. The US commercial fishing industry is hazardous, as measured by mortality data. However, research on non-fatal injuries is limited. Non-fatal injuries constitute the majority of occupational injuries and can result in workers' lowered productivity and wages, lost quality of life, and disability. In the United States, a Work Process Classification System (WPCS) has previously been applied in Alaskan freezer-trawl and freezer-longline fleets to identify causes of injuries and specific hazards, but not to other fishing fleets. Objectives. This descriptive epidemiologic study aimed to explore the application and modification of the WPCS in multiple Alaskan fleets, characterize non-fatal occupational injuries in these fleets, and identify work processes that could be targeted for further investigation and future injury prevention efforts. Design. Traumatic, non-fatal injuries on-board Alaskan commercial fishing vessels were identified through United States Coast Guard investigative reports. Characteristics of injuries, as well as worker characteristics, were analysed. Injuries were coded using the WPCS. Results. We successfully utilized the WPCS to code non-fatal injury cases (n = 136). The most frequent main work processes associated with non-fatal injuries included: on-board trawlers, handling frozen fish and processing the catch; on-board vessels using pot/trap gear, handling the gear and shooting/setting the gear; on-board longliners, traffic on board and hauling the gear; and on-board processor vessels, processing the catch, other work with the catch, and handling frozen fish. Conclusions. The study confirmed that a WPCS can be applied to multiple Alaskan fleets to identify hazardous tasks. Hazards were unique for each vessel gear type. Future injury prevention efforts should target work processes associated with the most frequent and most severe injuries. Future studies should establish time estimates for work processes in order to determine risk estimates. Efforts to improve non-fatal injury reporting, especially on smaller commercial fishing vessels, should be undertaken.To access the supplementary material for this article, please see Supplementary files under ‘Article Tools’ at: http://www.circumpolarhealthjournal.net/index.php/ijch/article/view/30070 This is the publisher’s final pdf. The published article is copyrighted by the author(s) and published by Co-Action Publishing for Circumpolar Health Research Network. The published article can be found at: http://www.circumpolarhealthjournal.net/index.php/ijchKeywords: Alaska, commercial fishing, occupational safety, work process, non-fatal injurie

MYC Overexpression Induces Prostatic Intraepithelial Neoplasia and Loss of Nkx3.1 in Mouse Luminal Epithelial Cells

Lo-MYC and Hi-MYC mice develop prostatic intraepithelial neoplasia (PIN) and prostatic adenocarcinoma as a result of MYC overexpression in the mouse prostate[1]. However, prior studies have not determined precisely when, and in which cell types, MYC is induced. Using immunohistochemistry (IHC) to localize MYC expression in Lo-MYC transgenic mice, we show that morphological and molecular alterations characteristic of high grade PIN arise in luminal epithelial cells as soon as MYC overexpression is detected. These changes include increased nuclear and nucleolar size and large scale chromatin remodeling. Mouse PIN cells retained a columnar architecture and abundant cytoplasm and appeared as either a single layer of neoplastic cells or as pseudo-stratified/multilayered structures with open glandular lumina—features highly analogous to human high grade PIN. Also using IHC, we show that the onset of MYC overexpression and PIN development coincided precisely with decreased expression of the homeodomain transcription factor and tumor suppressor, Nkx3.1. Virtually all normal appearing prostate luminal cells expressed high levels of Nkx3.1, but all cells expressing MYC in PIN lesions showed marked reductions in Nkx3.1, implicating MYC as a key factor that represses Nkx3.1 in PIN lesions. To determine the effects of less pronounced overexpression of MYC we generated a new line of mice expressing MYC in the prostate under the transcriptional control of the mouse Nkx3.1 control region. These “Super-Lo-MYC” mice also developed PIN, albeit a less aggressive form. We also identified a histologically defined intermediate step in the progression of mouse PIN into invasive adenocarcinoma. These lesions are characterized by a loss of cell polarity, multi-layering, and cribriform formation, and by a “paradoxical” increase in Nkx3.1 protein. Similar histopathological changes occurred in Hi-MYC mice, albeit with accelerated kinetics. Our results using IHC provide novel insights that support the contention that MYC overexpression is sufficient to transform prostate luminal epithelial cells into PIN cells in vivo. We also identified a novel histopathologically identifiable intermediate step prior to invasion that should facilitate studies of molecular pathway alterations occurring during early progression of prostatic adenocarcinomas

Boronic Acid Transition State Inhibitors as Potent Inactivators of KPC and CTX-M β-Lactamases: Biochemical and Structural Analyses

Design of novel beta-lactamase inhibitors (BLIs) is one of the currently accepted strategies to combat the threat of cephalosporin and carbapenem resistance in Gram-negative bacteria. Boronic acid transition state inhibitors (BATSIs) are competitive, reversible BLIs that offer promise as novel therapeutic agents. In this study, the activities of two alpha-amido-beta-triazolylethaneboronic acid transition state inhibitors (S02030 and MB_076) targeting representative KPC (KPC-2) and CTX-M (CTX-M-96, a CTX-M-15-type extended-spectrum beta-lactamase [ESBL]) beta-lactamases were evaluated. The 50% inhibitory concentrations (IC(50)s) for both inhibitors were measured in the nanomolar range (2 to 135 nM). For S02030, the k(2)/K for CTX-M-96 (24,000 M-1 s(-1)) was twice the reported value for KPC-2 (12,000 M-1 s(-1)); for MB_076, the k(2)/K values ranged from 1,200 M-1 s(-1) (KPC-2) to 3,900 M-1 s(-1) (CTX-M-96). Crystal structures of KPC-2 with MB_076 (1.38-& ANGS; resolution) and S02030 and the in silico models of CTX-M-96 with these two BATSIs show that interaction in the CTX-M-96-S02030 and CTX-M-96-MB_076 complexes were overall equivalent to that observed for the crystallographic structure of KPC-2-S02030 and KPC-2-MB_076. The tetrahedral interaction surrounding the boron atom from S02030 and MB_076 creates a favorable hydrogen bonding network with S70, S130, N132, N170, and S237. However, the changes from W105 in KPC-2 to Y105 in CTX-M-96 and the missing residue R220 in CTX-M-96 alter the arrangement of the inhibitors in the active site of CTX-M-96, partially explaining the difference in kinetic parameters. The novel BATSI scaffolds studied here advance our understanding of structure-activity relationships (SARs) and illustrate the importance of new approaches to beta-lactamase inhibitor design

Broad Spectrum Antiviral Activity of Favipiravir (T-705): Protection from Highly Lethal Inhalational Rift Valley Fever

Background:Development of antiviral drugs that have broad-spectrum activity against a number of viral infections would be of significant benefit. Due to the evolution of resistance to currently licensed antiviral drugs, development of novel anti-influenza drugs is in progress, including Favipiravir (T-705), which is currently in human clinical trials. T-705 displays broad-spectrum in vitro activity against a number of viruses, including Rift Valley Fever virus (RVFV). RVF is an important neglected tropical disease that causes human, agricultural, and economic losses in endemic regions. RVF has the capacity to emerge in new locations and also presents a potential bioterrorism threat. In the current study, the in vivo efficacy of T-705 was evaluated in Wistar-Furth rats infected with the virulent ZH501 strain of RVFV by the aerosol route.Methodology/Principal Findings:Wistar-Furth rats are highly susceptible to a rapidly lethal disease after parenteral or inhalational exposure to the pathogenic ZH501 strain of RVFV. In the current study, two experiments were performed: a dose-determination study and a delayed-treatment study. In both experiments, all untreated control rats succumbed to disease. Out of 72 total rats infected with RVFV and treated with T-705, only 6 succumbed to disease. The remaining 66 rats (92%) survived lethal infection with no significant weight loss or fever. The 6 treated rats that succumbed survived significantly longer before succumbing to encephalitic disease.Conclusions/Significance:Currently, there are no licensed antiviral drugs for treating RVF. Here, T-705 showed remarkable efficacy in a highly lethal rat model of Rift Valley Fever, even when given up to 48 hours post-infection. This is the first study to show protection of rats infected with the pathogenic ZH501 strain of RVFV. Our data suggest that T-705 has potential to be a broad-spectrum antiviral drug. © 2014 Caroline et al

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Design of a dust collection system and disposal of waste from the shot blasting process for the company SERVIMET SAS

Servimet SAS es una empresa líder en el sector metalmecánico. Para cumplir con el objetivo de preparación y limpieza de elementos metálicos la empresa cuenta con el sistema de Sandblasting, en el cual la arena no puede ser reutilizada, esto genera costos adicionales, pues cada vez que ocurre este fenómeno, se debe renovar el material abrasivo. Por esta razón, la empresa ha optado por un sistema ShotBlasting que cumple con las mismas funciones de limpieza superficial del anterior, pero de manera más eficiente. La empresa propone como proyecto general realizar el diseño de una línea de granallado donde se contará con una cabina de granallado, un elevador de cangilones, una grúa transportadora y un colector de polvos con disposición de desechos. Este proyecto se enfoca en el último módulo. El colector de polvos debe tomar los desechos producidos por las partículas contaminantes y limpiar el aire próximo a expulsar al medio ambiente. Se propone el uso de un ventilador para el flujo de aire. Se plantea además el uso de filtros de mangas, con el sistema de limpieza de aire comprimido Jet-pulse y el sistema de recolección de partículas por gravedad en la tolva, transportándose hacia tanques donde finalmente se retiran del colector. La nueva tecnología no está planeada para trabajar en continuo sino en un máximo de 8 horas al día y no es necesario que el sistema de colección tenga una capacidad de succión de limpieza rápida o inmediata. Al finalizar el diseño del equipo, se encontraron los parámetros adecuados de diseño y satisfacción ambiental y económica. Las características y especificaciones más destacadas del diseño son: Potencia del equipo de 0.5HP, dimensiones de 45 cm x 45 cm x 240 cm, 4 filtros de mangas, una caída de presión de tan sólo 5,93 inH2O y un flujo de partículas de 133 cfm. Logrando un diseño versátil, competitivo, económico ($15.600.000 aprox.) y satisfaciendo todas las necesidades del cliente y las normativas ambientales.Servimet SAS is a leading company in the metalworking sector. To meet the objective of preparation and cleaning of metallic elements, the company has a Sandblasting system, in which the sand cannot be reused, this generates additional costs, because each time this phenomenon occurs, the abrasive material must be renewed. . For this reason, the company has opted for a ShotBlasting system that fulfills the same surface cleaning functions as the previous one, but more efficiently. The company proposes as a general project the design of a blasting line where there will be a blasting cabin, a bucket elevator, a conveyor crane and a dust collector with waste disposal. This project focuses on the last module. The dust collector must take the debris produced by the polluting particles and clean the air next to expel to the environment. The use of a fan for air flow is proposed. The use of bag filters is also proposed, with the Jet-pulse compressed air cleaning system and the particle collection system by gravity in the hopper, transporting them to tanks where they are finally removed from the collector. The new technology is not planned to work continuously but for a maximum of 8 hours a day and it is not necessary for the collection system to have a quick or immediate cleaning suction capacity. At the end of the equipment design, the appropriate design parameters and environmental and economic satisfaction were found. The most outstanding design features and specifications are: 0.5HP equipment power, 45cm x 45cm x 240cm dimensions, 4 bag filters, a pressure drop of only 5.93 inH2O and a particle flow of 133 cfm. Achieving a versatile, competitive, economical design ($ 15,600,000 approx.) And satisfying all customer needs and environmental regulations

Association of Plasma SDF-1 with Bone Mineral Density, Body Composition, and Hip Fractures in Older Adults: The Cardiovascular Health Study

Aging is associated with an increase in circulating inflammatory factors. One, the cytokine stromal cell-derived factor 1 (SDF-1 or CXCL12), is critical to stem cell mobilization, migration, and homing as well as to bone marrow stem cell (BMSC), osteoblast, and osteoclast function. SDF-1 has pleiotropic roles in bone formation and BMSC differentiation into osteoblasts/osteocytes, and in osteoprogenitor cell survival. The objective of this study was to examine the association of plasma SDF-1 in participants in the cardiovascular health study (CHS) with bone mineral density (BMD), body composition, and incident hip fractures. In 1536 CHS participants, SDF-1 plasma levels were significantly associated with increasing age (p < 0.01) and male gender (p = 0.04), but not with race (p = 0.63). In multivariable-adjusted models, higher SDF-1 levels were associated with lower total hip BMD (p = 0.02). However, there was no significant association of SDF-1 with hip fractures (p = 0.53). In summary, circulating plasma levels of SDF-1 are associated with increasing age and independently associated with lower total hip BMD in both men and women. These findings suggest that SDF-1 levels are linked to bone homeostasis