Gatesmaclean7575

BACKGROUND There are limited data examining the diagnostic accuracy of thoracic ultrasonography (TUS) in distinguishing transudative from exudative pleural effusions. RESEARCH QUESTION What is the diagnostic accuracy of TUS in distinguishing transudative from exudative effusions in consecutive patients with pleural effusion? STUDY DESIGN AND METHODS Consecutive patients who underwent TUS and subsequently a diagnostic thoracentesis with a pleural fluid analysis were identified. TUS images of the pleural effusions were interpreted by previously published criteria. We evaluated the diagnostic performance of TUS findings in predicting a transudative versus exudative pleural effusions as well as specific pleural diagnoses. RESULTS We evaluated 300 consecutive pleural effusions in 285 patients. The pleural effusions were classified as exudative in 229/300 (76%) cases. TUS showed anechoic effusions in 122/300 (40%) cases and complex effusions in 178/300 (60%) cases. An anechoic appearance on TUS was associated with exudative effusions 68/122 (56%) as compared to transudative effusions 54/122 (44%). The presence of a complex-appearing effusion on TUS was highly predictive of and exudative effusion (positive predictive value of 90%). However, none of the four TUS characteristics were highly specific of a pleural diagnosis. INTERPRETATION Thoracic ultrasonography is inadequate to reliably diagnose a transudative pleural effusion. Although the TUS findings of a complex effusion may suggest an exudative pleural effusion, specific pleural diagnoses cannot be confidently predicted. BACKGROUND Sepsis is a major public health burden resulting in 25-30% in-hospital mortality and accounting for over 20 billion dollars of United States hospital costs. METHODS This was a randomized, double-blinded, placebo controlled trial conducted from February 2018 to June 2019 assessing an ascorbic acid (AA), thiamine, and hydrocortisone (HAT) treatment bundle for the management of septic and septic shock patients admitted to an intensive care unit (ICU). The primary outcomes were resolution of shock and change in Sequential Organ Failure Assessment (SOFA) score. Secondary outcomes included 28-day mortality, ICU mortality, hospital mortality, procalcitonin clearance (PCT-c), hospital length of stay (LOS), ICU LOS, and ventilator free days. RESULTS 137 patients were randomized to the treatment group (n = 68) and comparator group (n = 69) respectively with no significant differences in baseline characteristics. There was a statistically significant difference in the time patients required vasopressors indicating quicker reversal of shock in the HAT group compared to comparator group (27 ± 22 vs 53 ± 38 hours, p less then 0.001). There was no statistically significant change in SOFA score between groups 3 (1 - 6) vs. 2 (0 - 4), p = 0.17. There were no significant differences between study arms in ICU and hospital mortality, ICU and hospital LOS, ventilator free days, and PCT-c. CONCLUSION Our results suggest that the combination of intravenous ascorbic acid, thiamine, and hydrocortisone significantly reduced the time to resolution of shock. Additional studies are needed to confirm these findings and assess any potential mortality benefit from this treatment. Achilles tendinopathy has a high re-injury rate and poor prognosis. Development of effective therapy for Achilles tendinopathy is important. Excessive accumulation of ROS and resulting oxidative stress are believed to cause tendinopathy. Overproduction of hydrogen peroxide (H2O2), the most common ROS, could lead to the tendinopathy by causing oxidative damage, activation of endoplasmic reticulum (ER) stress and apoptotic death of tenocytes. Activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2) is expected to alleviate oxidative stress and ER stress. Alda-1 is a selective and potent activator of ALDH2. In this study, we examined the cytoprotective benefit of Alda-1, an activator of ALDH2, on H2O2-induced Achilles tendinopathy in cellular and mouse models. We prepared cellular and mouse models of Achilles tendinopathy by treating cultured Achilles tenocytes and Achilles tendons with oxidative stressor H2O2. Subsequently, we studied the protective benefit of Alda-1 on H2O2-induced Achilles tendinopathy. Alda-1 pretreatment attenuated H2O2-induced cell death of cultured Achilles tenocytes. Treatment of Alda-1 prevented H2O2-induced oxidative stress and depolarization of mitochondrial membrane potential in tenocytes. Application of Alda-1 attenuated H2O2-triggered mitochondria- and ER stress-mediated apoptotic cascades in cultured tenocytes. Alda-1 treatment ameliorated the severity of H2O2-induced Achilles tendinopathy in vivo by preventing H2O2-induced pathological histological features of Achilles tendons, apoptotic death of Achilles tenocytes and upregulated expression of inflammatory cytokines IL-1β and TNF-α. Our results provide the evidence that ALDH2 activator Alda-1 ameliorates H2O2-induced Achilles tendinopathy. Alda-1 could be used for preventing and treating Achilles tendinopathy. BACKGROUND Dexamethasone is widely used in the treatment of joint diseases due to its anti-inflammatory properties. However, it can cause serious adverse effects. The anterior cruciate ligament (ACL) is an important stabilizer of the knee joint. However, the effect of dexamethasone treatment on the ACL is unclear. OBJECTIVE This study aims to explore the effects of dexamethasone on ACL tissues and cells through in vitro and in vivo experiments. RESULTS In vitro, we found that after treatment with dexamethasone, human ACL cell apoptosis was increased, type I collagen (COL1A1) content was decreased, mineralization related genes (ENPP1 and ANKH) and calcified nodules were increased, and endoplasmic reticulum stress (ERS) was enhanced. However, ERS inhibitors could significantly inhibit the increase in calcification and the decrease in COL1A1 induced by dexamethasone. In vivo, Wistar rats received the infra-articular injection with dexamethasone (0.5 mg/kg) for 8 weeks. We found that dexamethasone treatment decreased the COL1A1 content and increased the COL2A1 content in the ACL tissues of rats and that chondroid differentiation and mineralization occurred. Meanwhile, the expression of ERS-related proteins was increased. CONCLUSION Dexamethasone increased the calcification of ACL cells and caused ACL degeneration through ERS, suggesting that long-term treatment with dexamethasone may cause adverse effects on ACL tissue and increase the risk of long-term rupture. GABAA receptors (GABAARs) mediate inhibitory neurotransmission in the mammalian brain. Recently, numerous GABAAR static structures have been published, but the molecular mechanisms of receptor activation remain elusive. Loop G is a rigid β-strand belonging to an extensive β-sheet that spans the regions involved in GABA binding and the interdomain interface which is important in receptor gating. It has been reported that loop G participates in ligand binding and gating of GABAARs, however, it remains unclear which specific gating transitions are controlled by this loop. Analysis of macroscopic responses revealed that mutation at the α1F45 residue (loop G midpoint) resulted in slower macroscopic desensitization and accelerated deactivation. Single-channel analysis revealed that these mutations also affected open and closed times distributions and reduced open probability. Kinetic modeling demonstrated that mutations affected primarily channel opening/closing and ligand binding with a minor effect on preactivation. Thus, α1F45 residue, in spite of its localization close to binding site, affects late gating transitions. In silico structural analysis suggested an important role of α1F45 residue in loop G stability and rigidity as well as in general structure of the binding site. We propose that the rigid β-sheet comprising loop G is well suited for long range communication within GABAAR but this mechanism becomes impaired when α1F45 is mutated. In conclusion, we demonstrate that loop G is crucial in controlling both binding and gating of GABAARs. These data shed new light on GABAAR activation mechanism and may also be helpful in designing clinically relevant modulators. Chronic kidney disease, commonly fostering non-renal complications, themselves more life-threatening than renal pathology, remain enigmatic. Despite more than a century of intense research, therapeutic options to halt or reverse renal disease are rather limited. Recently, similarity between manifestations of progressive chronic kidney disease and aging kidney has attracted investigative attention that revealed senescent cells, secreting proinflammatory and profibrotic mediators, in all renal compartments even at young age in patients with kidney maladies. The overlapping features of these categories have been noticed previously and are briefly summarized herein. I propose two hypothetical scenarios for interactive association of kidney diseases and cell senescence, both culminating in progressive deterioration of renal function. Persistence of senescent cells is considered as a critical contributor to this association and the mechanisms explaining persistence, such as activation of cell cycle regulators, anti-apoptotic stimuli, metabolic aberrations, and their interactions are discussed. The mutual encroachment of underlying kidney disease and cell senescence bring about the conclusion that both entities merge along the natural history of the disease. This putative interpretation of vicarious relation between cell senescence and chronic kidney disease may expand the arsenal of pharmacotherapy to include the judicious use of senotherapeutics in the management of renal disease. Epigenetic inhibitors library Osteomyelitis is an inflammation of the bone and bone marrow that is most commonly caused by a Staphylococcus aureus infection. Much of our understanding of the underlying pathophysiology of osteomyelitis, from the perspective of both host and pathogen, has been revised in recent years, with notable discoveries including the role played by osteocytes in the recruitment of immune cells, the invasion and persistence of S. aureus in sub-micron channels of cortical bone, and the diagnostic role of polymorphonuclear cells in implant associated osteomyelitis. Advanced in vitro cell culture models such as ex vivo culture models or organoids have also been developed over the past decade, and have become widespread in many fields, including infectious diseases. These models better mimic the in vivo environment, allow the use of human cells, and can reduce our reliance on animals in osteomyelitis research. In this review, we provide an overview of the main pathological concepts in osteomyelitis, with a focus on the new discoveries in recent years. Furthermore, we outline the value of modern in vitro cell culture techniques, with a focus on their current application to infectious diseases and osteomyelitis in particular. Lysosomal acid ceramidase (Ac) has been shown to be critical for ceramide hydrolysis and regulation of lysosome function and cellular homeostasis. In the present study, we generated a knockout mouse line (Asah1fl/fl/PodoCre) with a podocyte-specific deletion of the alpha subunit (main catalytic subunit) of Ac. Although no significant morphologic changes in glomeruli were observed in these mice under light microscope, severe proteinuria and albuminuria were found in these podocyte-specific KO mice compared to control genotype littermates. Transmission electron microscopic analysis showed that podocytes of the KO mice had distinctive foot process effacement and microvillus formation. These functional and morphologic changes indicate the development of nephrotic syndrome in mice bearing the Asah1 podocyte-specific gene deletion. Ceramide accumulation determined by LC-MS/MS was demonstrated in isolated glomeruli of Asah1fl/fl/PodoCre mice compared to their littermates. By cross breeding Asah1fl/fl/PodoCre mice with Smpd1-/- mice, we also produced a double KO strain, Smpd1-/-/Asah1fl/fl/PodoCre, that also lacks Smpd1, the acid sphingomyelinase that hydrolyzes sphingomyelin to ceramide.