These preclinical studies aimed to 1) increase our understanding the dietary induction of nonalcoholic steatohepatitis (NASH), and, 2) further explore the utility and mechanisms of glucagon-like ...peptide-1 receptor (GLP-1R) agonism in NASH. We compared the effects of a high trans-fat (HTF) or high lard fat (HLF) diet on key facets of nonalcoholic fatty liver disease (NAFLD)/NASH in Lep(ob)/Lep(ob) and C57BL6J (B6) mice. Although HLF-fed mice experienced overall greater gains in weight and adiposity, the addition of trans-fat better mirrored pathophysiological features of NASH (e.g., hepatomegaly, hepatic lipid, and fibrosis). Administration of AC3174, an exenatide analog, and GLP-1R agonist to Lep(ob)/Lep(ob) and B6 ameliorated hepatic endpoints in both dietary models. Next, we assessed whether AC3174-mediated improvements in diet-induced NASH were solely due to weight loss in HTF-fed mice. AC3174-treatment significantly reduced body weight (8.3%), liver mass (14.2%), liver lipid (12.9%), plasma alanine aminotransferase, and triglycerides, whereas a calorie-restricted, weight-matched group demonstrated only modest nonsignificant reductions in liver mass (9%) and liver lipid (5.1%) relative to controls. Treatment of GLP-1R-deficient (GLP-1RKO) mice with AC3174 had no effect on body weight, adiposity, liver or plasma indices pointing to the GLP-1R-dependence of AC3174's effects. Interestingly, the role of endogenous GLP-1Rs in NASH merits further exploration as the GLP-1RKO model was protected from the deleterious hepatic effects of HTF. Our pharmacological data further support the clinical evaluation of the utility of GLP-1R agonists for treatment of NASH.
Background
Nearly 40% of trauma deaths result from uncontrolled hemorrhage. Most of these deaths occur within 24 hours, highlighting the importance of early resuscitation. Balanced component ...resuscitation has been shown to improve outcomes in hemorrhagic shock. However, hemostatic properties may then be decreased, leading to inadequate coagulopathy treatment or higher transfusion requirements. Data comparing the efficacy of component vs. whole blood (WB) resuscitation in early trauma is poor, particularly in the rural population. This study investigates WB use and resource utilization at a rural Level 1 trauma center.
Methods
A prospective cohort study with historical controls (HC) was performed using patients over age 17 presenting as the highest priority trauma. Two units of WB were available to patients with signs of hemorrhagic shock, with subsequent transfusions via massive transfusion protocol or thromboelastography guidance. Component utilization, time to hemorrhage control, complications, and transfer times were examined.
Results
Forty patients received WB vs. 153 HC. WB patients had lower complication rates (35% vs. 55.6%; P = .02), and a significant reduction in pRBC utilization in the emergency department (0 vs. 2; P < .0001) and throughout admission (2.0 vs. 4.0; P = .0003). All patients had prolonged transport times given the rural setting (1.42 hours HC vs. 2.03 hours WB; P = .002).
Discussion
Unlike most urban WB studies, this study occurred in a rural area with extended transportation times, when WB is inaccessible for patients. Despite this delay, WB patients demonstrated lower component utilization and complication rates. Further research is needed to characterize the impact of early WB access.
Graphical Abstract
Utilising dislocation-related vertical etching channels in gallium nitride, we have previously demonstrated a simple electrochemical etching (ECE) process that can create layered porous GaN ...structures to form distributed Bragg reflectors for visible light at wafer scale. Here, we apply the same ECE process to realise AlGaN-based ultraviolet distributed Bragg reflectors (DBRs). These are of interest because they could provide a pathway to non-absorbing UV reflectors to enhance the performance of UV LEDs, which currently have extremely low efficiency. We have demonstrated porous AlGaN-based UV DBRs with a peak reflectance of 89% at 324 nm. The uniformity of these devices is currently low, as the as-grown material has a high density of V-pits and these alter the etching process. However, our results indicate that if the material growth is optimised, the ECE process will be useful for the fabrication of UV reflectors.
When cauda equina betrays Dayal, Sahil; Pavlatos, Nicole; Griffin, Peter
Journal of the American College of Emergency Physicians Open,
April 2024, Letnik:
5, Številka:
2
Journal Article
The present studies aimed to identify mechanisms contributing to amylin/leptin synergy in reducing body weight and adiposity. We reasoned that if amylin/leptin harnessed complementary neuronal ...pathways, then in the leptin-sensitive state, amylin should augment leptin signaling/binding and that in the absence of endogenous amylin, leptin signaling should be diminished. Amylin (50 μg/kg, ip) amplified low-dose leptin-stimulated (15 μg/kg, ip) phosphorylated signal transducer and activator of transcription-3 signaling within the arcuate nucleus (ARC) in lean rats. Amylin (50 μg/kg · d) or leptin (125 μg/kg · d) infusion to lean rats decreased 28-d food intake (14 and 10%, respectively), body weight (amylin by 4.3%, leptin by 4.9%), and epididymal fat (amylin by 19%, leptin by 37%). Amylin/leptin co-infusion additively decreased food intake (by 26%) and reduced body weight (by 15%) and epididymal fat (by 78%; all P < 0.05 vs. all groups) in a greater than mathematically additive manner, consistent with synergy. Amylin increased leptin binding within the ventromedial hypothalamus (VMN) by 35% and dorsomedial hypothalamus by 47% (both P < 0.05 vs. vehicle). Amylin/leptin similarly increased leptin binding in the VMN by 40% and ARC by 70% (P < 0.05 vs. vehicle). In amylin-deficient mice, hypothalamic leptin receptor mRNA expression was reduced by 50%, leptin-stimulated phosphorylated signal transducer and activator of transcription-3 within ARC and VMN was reduced by 40%, and responsiveness to leptin’s (1 mg/kg · d for 28 d) weight-reducing effects was attenuated (all P < 0.05 vs. wild-type controls). We suggest that amylin/leptin’s marked weight- and fat-reducing effects are due to activation of intrinsic synergistic neuronal signaling pathways and further point to the integrated neurohormonal therapeutic potential of amylin/leptin agonism in obesity.
Amylin and leptin combine to exert marked weight- and fat-lowering effects by activating intrinsic physiological synergistic neuronal signaling pathways.
To evaluate the 5-year efficacy and safety of once weekly exenatide.
The Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once ...Weekly (DURATION-1) randomized clinical trial consisted of a 30-week controlled phase (2 mg of exenatide once weekly vs 10 μg of exenatide twice daily) with an open-ended uncontrolled extension (once weekly exenatide only) in patients with type 2 diabetes mellitus on background glucose-lowering therapies (April 15, 2006, through February 21, 2012). At week 30, patients initially receiving 10 μg of exenatide twice daily switched to 2 mg of exenatide once weekly. Study end points included changes from baseline in hemoglobin A1c, fasting plasma glucose, weight, lipids, and blood pressure. Long-term safety data included adverse events, liver and renal function, and heart rate.
Of 258 extension-phase patients, 153 (59.3%) completed 5 years of treatment. Hemoglobin A1c levels were significantly and durably reduced from baseline (least-squares mean, -1.6%; 95% CI, -1.8% to -1.4%; vs -1.9% for exenatide once weekly at week 30), and 65 (43.9%) of 148 patients achieved hemoglobin A1c levels of less than 7.0%. Significant improvements in fasting plasma glucose level (-28.8 mg/dL; 95% CI, -36.2 to -21.5 mg/dL), weight (-3.0 kg; 95% CI, -4.6 to -1.3 kg), lipids, and diastolic blood pressure were observed, with minimal heart rate increase. Frequencies of nausea and injection-site reactions or nodules were decreased vs the initial 30-week controlled phase. Minor hypoglycemia occurred predominantly with sulfonylurea use, and no major hypoglycemia or new safety signals were observed.
Long-term once weekly exenatide treatment was generally well tolerated with sustained glycemic improvement, weight reduction, and improved markers of cardiovascular risk in patients with type 2 diabetes.
clinicaltrials.gov Identifier: NCT00308139.
INTRODUCTIONLemierre's syndrome is septic thrombophlebitis of the internal jugular vein, most commonly associated with head and neck infections. While central catheters are associated with venous ...thromboembolism and catheter-associated bacterial infections, cases of Lemierre's syndrome caused by central catheters are extraordinarily rare. CASE REPORTWe detail a case of Lemierre's syndrome resulting from a peripherally inserted central catheter in a pregnant female patient. Diagnosis of this rare and potentially life-threatening disease process was expedited using point-of-care ultrasound. CONCLUSIONDiagnosis of rare but potentially life- or limb-threatening pathologies is paramount to the successful practice of emergency medicine. Identifying these rare disease processes requires a high index of suspicion and a work-up strategy that includes consideration of medical history in combination with lab and imaging findings to determine appropriate interventions.
A calibration-free, high-resolution analog-to-digital converter designed for a bioluminescence sensor array employs incremental sigma-delta (ΣΔ) modulation to combine the advantages of oversampling ...with an input multiplexing capability. The resolution of incremental ΣΔ modulators can be improved significantly by means of a technique similar to extended counting. In the approach proposed in this paper, analog-to-digital conversion is accomplished with a two-step process in which the residual error from a second-order incremental ΣΔ modulator is encoded using a successive approximation ADC. By this means it is possible to achieve enhanced resolution and improved static linearity while maintaining a one-to-one mapping between individual input and output samples. An experimental implementation of the proposed modulator has been integrated in a 0.18-μm CMOS technology. Operating from a 1.8-V supply, it achieves a dynamic range of 90.1 dB and a peak signal-to-noise and distortion ratio (SNDR) of 86.3 dB at a conversion rate of 1 MSample/s, with 38.1-mW power consumption.
One of the fundamental problems in the continued scaling of transistors is the 60 mV/dec room temperature limit in the subthreshold slope. In part I this work, a novel transistor based on the ...field-effect control of impact-ionization (I-MOS) is explored through detailed device and circuit simulations. The I-MOS uses gated-modulation of the breakdown voltage of a p-i-n diode to switch from the OFF state to the ON state and vice-versa. Device simulations using MEDICI show that the I-MOS has a subthreshold slope of 5 mV/dec or lower and I/sub ON/>1 mA//spl mu/m at 400 K. Simulations were used to further explore the characteristics of the I-MOS including the transients of the turn-on mechanism, the short-channel effect, scalability, and other important device attributes. Circuit mode simulations were also used to explore circuit design using I-MOS devices and the design of an I-MOS inverter. These simulations indicated that the I-MOS has the potential to replace CMOS in high performance and low power digital applications. Part II of this work focuses on I-MOS experimental results with emphasis on hot carrier effects, germanium p-i-n data and breakdown in recessed structure devices.
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