Essentials
Mitochondrial hyperpolarization enhances the conversion of platelets to a procoagulant phenotype.
Mitochondrial calcium uniporter (MCU) function is essential in procoagulant platelet ...formation.
Mitochondrial calcium uniporter deletion does not impact other aspects of platelet activation.
Ablation of MCU results in the emergence of a permeability transition pore‐independent pathway.
Summary
Background
Procoagulant platelets comprise a phenotypically distinct subpopulation of activated platelets with high‐level phosphatidylserine externalization. When initiated by co‐stimulation with thrombin and a glycoprotein VI (GPVI) agonist, the transition to the procoagulant phenotype is mediated by extracellular calcium entry and mitochondrial permeability transition pore (mPTP) formation.
Objectives
The intracellular mechanisms coordinating these distinct cytoplasmic and mitochondrial processes remain unclear. The mitochondrial calcium uniporter (MCU) protein is a central component of the transmembrane ion channel that allows the passage of Ca2+ from the cytosol into the mitochondrial matrix. Here we investigate the role of the MCU in the regulation of procoagulant platelet formation.
Results
Procoagulant platelet formation was directly correlated with pre‐stimulatory mitochondrial transmembrane potential, a key determinant of calcium flux from the cytoplasm to the mitochondria. The role of MCU in the regulation of procoagulant platelet formation was investigated using MCU null platelets. Procoagulant platelet formation in MCU null platelets was significantly decreased coincident with decreased mPTP formation. In contrast, neither granule release nor initial integrin activation was altered in response to stimulation. In the genomic absence of MCU, developmental induction of an alternative intracellular pathway partially rescued procoagulant platelet formation.
Conclusion
These results identify a key role for the mitochondrial calcium uptake channel in the regulation of mPTP‐mediated procoagulant platelet formation and suggest a novel pharmacologic target for procoagulant‐platelet‐related pathologies.
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FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Men seek mental health treatment less often than women. The present study sought to elucidate identities and individual difference characteristics that are associated with enhanced or decreased ...mental health help-seeking in a large national sample of U.S. men. Using data from 4,825 U.S. men aged 20 to 59 years, main effects of race/ethnicity, sexual orientation, age, income–poverty ratio, relationship status, depression symptoms, and body mass index were explored within the sample of men as well as intersections of these predictors with racial/ethnic group identity. While the results of main effects testing generally supported prior research (i.e., greater mental health care help-seeking among White men, nonheterosexual men, men not in relationships, older men, and more depressed men), when examined associations across racial/ethnic groups, the direction and strength of these associations showed notable variation—variation unaccounted for in prior research. These findings highlight the need for future theory building and research that accounts for this variation at the intersection of race/ethnicity and these specific predictors of help-seeking behavior among men.
Volumetric laser endomicroscopy (VLE) uses optical coherence tomography (OCT) for real-time, microscopic cross-sectional imaging. A US-based multi-center registry was constructed to prospectively ...collect data on patients undergoing upper endoscopy during which a VLE scan was performed. The objective of this registry was to determine usage patterns of VLE in clinical practice and to estimate quantitative and qualitative performance metrics as they are applied to Barrett's esophagus (BE) management. All procedures utilized the NvisionVLE Imaging System (NinePoint Medical, Bedford, MA) which was used by investigators to identify the tissue types present, along with focal areas of concern. Following the VLE procedure, investigators were asked to answer six key questions regarding how VLE impacted each case. Statistical analyses including neoplasia diagnostic yield improvement using VLE was performed. One thousand patients were enrolled across 18 US trial sites from August 2014 through April 2016. In patients with previously diagnosed or suspected BE (894/1000), investigators used VLE and identified areas of concern not seen on white light endoscopy (WLE) in 59% of the procedures. VLE imaging also guided tissue acquisition and treatment in 71% and 54% of procedures, respectively. VLE as an adjunct modality improved the neoplasia diagnostic yield by 55% beyond the standard of care practice. In patients with no prior history of therapy, and without visual findings from other technologies, VLE-guided tissue acquisition increased neoplasia detection over random biopsies by 700%. Registry investigators reported that VLE improved the BE management process when used as an adjunct tissue acquisition and treatment guidance tool. The ability of VLE to image large segments of the esophagus with microscopic cross-sectional detail may provide additional benefits including higher yield biopsies and more efficient tissue acquisition. Clinicaltrials.gov NCT02215291.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Background Endoscopic screening for esophageal neoplasia can identify patients eligible for early intervention for precancerous lesions. Unsedated transnasal esophagoscopy may provide an efficient ...and accurate endoscopic assessment with fewer risks and less cost, compared with conventional upper endoscopy. Objective To assess the feasibility, safety, acceptability, and yield of unsedated transnasal esophagoscopy in a primary care population. Design Multicenter, prospective, cross-sectional study. Setting Two outpatient tertiary-care centers. Patients This study involved a general medical clinic population aged between 40 and 85 years. Intervention Unsedated, office-based transnasal esophagoscopy. Main Outcome Measurements Procedure yield; completeness of examination; procedure length; adverse events and complications; choking, gagging, pain, or anxiety during the examination; and overall tolerability. Results A total of 426 participants (mean ± standard deviation age 55.8 ± 9.5 years; 43% male) enrolled in the study, and 422 (99%) completed the examination. Mean (± standard deviation) examination time was 3.7 ± 1.8 minutes. There were no serious adverse events, and 12 participants (2.8%) reported minor complications. Participants reported minimal choking, gagging, pain, or anxiety. The examination was well-tolerated by most participants. Overall, 38% of participants had an esophageal finding that changed management (34% erosive esophagitis, 4% Barrett's esophagus). Limitations Nonrandomized study, tertiary-care centers only, self-selected population with a large proportion reporting esophageal symptoms. Conclusion Unsedated transnasal esophagoscopy is a feasible, safe, and well-tolerated method to screen for esophageal disease in a primary care population. Endoscopic findings are common in this patient population.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract We describe a three-step approach to develop and evaluate a novel coronary artery disease (CAD) self-management educational workbook. First, we conducted interviews using grounded theory ...methods with a diverse CAD cohort ( n = 61) to identify needs and perceptions. Second, we developed the workbook, incorporating themes that emerged from the qualitative interviews. Finally, 225 people with CAD used the workbook in a longitudinal study and we evaluated their use of and experience with the workbook at 12 months. 12-month evaluation data revealed that the workbook: provided practical health information; enhanced behavior-specific self-efficacy; and reinforced that healthy behaviors decrease risk. Participants who read the workbook had greater within-patient increases in physical activity at 12-months compared with non-readers ( p = 0.093) and among Black/Hispanic participants, workbook readers' increases were significant (592 vs. −645 kilocalories per week, p = 0.035). A self-management educational workbook developed using qualitative methods can provide relevant, disease-specific health information for patients with CAD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Surfactant protein D (SP-D) is a 43-kDa member of the collectin family of collagenous lectin domain-containing proteins that is expressed in epithelial cells of the lung. The SP-D gene was targeted ...by homologous recombination in embryonic stem cells that were used to produce SP-D (±) and SP-D (−/−) mice. Both SP-D (−/−) and SP-D (±) mice survived normally in the perinatal and postnatal periods. Whereas no abnormalities were observed in SP-D (±) mice, alveolar and tissue phosphatidylcholine pool sizes were markedly increased in SP-D (−/−) mice. Increased numbers of large foamy alveolar macrophages and enlarged alveoli were also observed in SP-D (−/−) mice. Phospholipid composition was unaltered in SP-D (−/−) mice, but surfactant morphology was abnormal, consisting of dense phospholipid membranous arrays with decreased tubular myelin. The pulmonary lipoidosis in the SP-D (−/−) mice was not associated with accumulation of surfactant proteins B or C, or their mRNAs, distinguishing the disorder from alveolar proteinosis syndromes. Surfactant protein A mRNA was reduced and, SP-A protein appeared to be reduced in SP-D (−/−) compared with wild type mice. Targeting of the mouse SP-D gene caused accumulation of surfactant lipid and altered phospholipid structures, demonstrating a previously unsuspected role for SP-D in surfactant lipid homeostasis in vivo.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Marked alterations in the expression of specific genes occur during the development of cardiac hypertrophy in vivo. Little is known, however, about the cis-acting elements that mediate these changes ...in response to clinically relevant hypertrophic stimuli, such as hemodynamic overload, in intact adult animals.
The left ventricular expression of a directly injected reporter gene driven by 3542 bp of rat beta-myosin heavy chain (beta-MHC) promoter was increased 3.0-fold by aortic constriction (P<.005), an increment similar to the 3.2-fold increase in the level of the endogenous beta-MHC mRNA in the same left ventricles. Subsequent analysis identified a 107-bp beta-MHC promoter sequence (-303/-197) sufficient to convert a heterologous neutral promoter to one that is activated by aortic constriction. These sequences contain two M-CAT elements, which have previously been demonstrated to mediate inducible expression during alpha1-adrenergic-stimulated hypertrophy in cultured neonatal cardiac myocytes, and a GATA element. Although simultaneous mutation of both M-CAT elements markedly decreased the basal transcriptional activity of an injected 333-bp beta-MHC promoter, it had no effect on aortic constriction-stimulated transcription (3.5-fold increase, P<.005 for both wild type and mutant). In contrast, mutation of the GATA motif markedly attenuated aortic constriction-stimulated transcription (1.6-fold, P=NS) without affecting the basal transcriptional activity. This GATA site can interact with in vitro translated GATA-4 and compete with an established GATA site for GATA-4 binding activity in nuclear extracts from aortic constricted hearts.
Basal and aortic constriction-stimulated transcription of the beta-MHC gene is mediated, at least in part, through different mechanisms. A GATA element within beta-MHC sequences -303/-197 plays a role in the transcriptional activation of this gene by aortic constriction.
This study of temporal trends in mortality among extremely premature infants receiving care in U.S. centers showed declines in overall mortality and in deaths from pulmonary causes, immaturity, ...infection, and CNS injury. Deaths from necrotizing enterocolitis increased.
Although survival among premature infants has improved, prematurity is a leading contributor to neonatal mortality in the United States.
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Approximately one in four extremely premature infants born at 22 to 28 weeks of gestation does not survive the birth hospitalization; mortality rates decrease with each additional week of completed gestation.
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Historically, most extremely premature infants died within a few days after birth.
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Among extremely-low-birth-weight infants born at centers in the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network between 1993 and 1997, immaturity was the leading cause of death within 12 hours after birth, and . . .
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