BACKGROUND Spontaneous Achilles tendon rupture associated with long-term dexamethasone (Dex) use has been reported. However, few studies have investigated the potential mechanism. The aim of this study was to evaluate the effects of oral Dex on type I collagen in humans and rats and its association with tendon rupture. METHODS First, six Achilles tendons from patients who received long-term Dex treatment, and another six normal tendons were harvested for histological evaluation. Secondly, 8-week-old rats (n = 72) were randomly assigned to a Dex group or a control group. Type I collagen was studied at the mechanical, histological, and molecular levels after 3 and 5 weeks. Tenocytes isolated from normal human and rat tendon were used to investigate the effect of Dex on cellular scale. RESULTS Histological analysis of human and rat tendon tissue revealed an irregular, disordered arrangement of type I collagen in the Dex group compared with the control group. In addition, In the Dex+ group, type I collagen expression decreased in comparison with the Dex- group in both human and rat tenocytes. The mechanical strength of tendons was significantly reduced in the Dex group (68.87 ± 11.07 N) in comparison with the control group (81.46 ± 7.62 N, P = 0.013) after 5 weeks. Tendons in the Dex group were shorter with smaller cross-sectional areas (10.71 ± 0.34 mm2, 1.44 ± 0.22 mm2, respectively) after 5 weeks than those in the control group (11.13 ± 0.50 mm2, P = 0.050, 2.74 ± 0.34 mm2, P  less then  0.001, respectively).  https://www.selleckchem.com/products/pd-1-pd-l1-inhibitor-3.html  CONCLUSIONS This finding suggests long-term use of Dex that decreases the expression of type I collagen at molecular and tissue levels both in human and rat Achilles tendons. Furthermore, Dex decreases the mechanical strength of the tendon, thereby increasing the risk of Achilles tendon rupture.BACKGROUND Originally, the cranks of a handcycle were mounted with a 180° phase shift (asynchronous). However, as handcycling became more popular, the crank mode switched to a parallel mounting (synchronous) over the years. Differences between both modes have been investigated, however, not into great detail for propulsion technique or practice effects. Our aim is to compare both crank modes from a biomechanical and physiological perspective, hence considering force and power production as a cause of physiological outcome measures. This is done within a practice protocol, as it is expected that motor learning takes place in the early stages of handcycling in novices. METHODS Twelve able-bodied male novices volunteered to take part. The experiment consisted of a pre-test, three practice sessions and a post-test, which was subsequently repeated for both crank modes in a counterbalanced manner. In each session the participants handcycled for 3 × 4 minutes on a leveled motorized treadmill at 1.94 m/s. Inbetween sreduced in the asynchronous mode, we would advise to include a practice period, when comparing both modes in scientific experiments. For handcycle users, we would currently advise a synchronous set-up for daily use, as the force production is more effective in the synchronous mode, even after practice.BACKGROUND Candida albicans is the most common opportunistic human fungal pathogen. The chemokine ligand CXCL1 plays a protective role in fungal infection through the recruitment of neutrophils. TRAF1 (tumor necrosis factor-associated factor 1) can be highly induced by proinflammatory stimuli such as LPS and TNF and has been implicated in septic shock. However, the role of TRAF1 in infection, especially fungal infection, remains elusive. Herein, we reveal that TRAF1 suppresses the antifungal immune response to Candida albicans intradermal infection through the regulation of CXCL1 induction and neutrophil recruitment. METHODS A mouse model of C. albicans intradermal infection was established. The Traf1-/- mice and Traf1-/- immortalized human keratinocytes were generated. The p65 inhibitor triptolide, STAT1 inhibitor fludarabine, neutrophil-depletion antibody Ly6G, and neutralizing antibody for CXCL1 were utilized. The expression of proinflammatory cytokines and chemokines was assessed by real-time PCR and ELISscription factor STAT1. TRAF1-deficient macrophages played a critical role in containing the C. albicans skin infection in vivo. CONCLUSION TRAF1-deficient mice can better control fungal infection in the skin, a process attributable to the CXCL-neutrophil axis. Mechanistically, TRAF1 likely regulates CXCL1 expression in both macrophages and keratinocytes through the transcriptional factor NFκB and STAT1, respectively. Our finding offers new insight into the understanding of the immune regulatory mechanisms in host defense against C. albicans infection.BACKGROUND Lysosomal acid lipase deficiency (LALD) is an autosomal recessive inborn error of lipid metabolism characterized by impaired lysosomal hydrolysis and consequent accumulation of cholesteryl esters and triglycerides. The phenotypic spectrum is diverse, ranging from severe, neonatal onset failure to thrive, hepatomegaly, hepatic fibrosis, malabsorption and adrenal insufficiency to childhood-onset hyperlipidemia, hepatomegaly, and hepatic fibrosis. Sebelipase alfa enzyme replacement has been approved by the Food and Drug Administration for use in LALD after demonstrating dramatic improvement in transaminitis and dyslipidemia with initiation of enzyme replacement therapy. METHODS A chart review was performed on 2 patients with childhood-onset, symptomatic LALD with persistent dyslipidemia despite appropriate enzyme replacement therapy to identify biological pathways and risk factors for incomplete response to therapy. RESULTS Two patients with attenuated, symptomatic LALD had resolution of transaminitis on enzyme replacement therapy without concomitant effect on dyslipidemia despite dose escalation and no evidence of antibody response to enzyme. CONCLUSION Enzyme replacement therapy does not universally resolve all complications of LALD. Persistent dyslipidemia remains a clinically significant issue, likely related to the complex metabolic pathways implicated in LALD pathogenesis. We discuss the possible mechanistic basis for this unexpected finding and the implications for curative LALD therapy.