Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease

BACKGROUNDAn increase in intrahepatic triglyceride (IHTG) is the hallmark feature of nonalcoholic fatty liver disease (NAFLD) and is decreased by weight loss. Hepatic de novo lipogenesis (DNL) contributes to steatosis in individuals with NAFLD. The physiological factors that stimulate hepatic DNL and the effect of weight loss on hepatic DNL are not clear.METHODSHepatic DNL, 24-hour integrated plasma insulin and glucose concentrations, and both liver and whole-body insulin sensitivity were determined in individuals who were lean (n = 14), obese with normal IHTG content (n = 26), or obese with NAFLD (n = 27). Hepatic DNL was assessed using the deuterated water method corrected for the potential confounding contribution of adipose tissue DNL. Liver and whole-body insulin sensitivity was assessed using the hyperinsulinemic-euglycemic clamp procedure in conjunction with glucose tracer infusion. Six subjects in the obese-NAFLD group were also evaluated before and after a diet-induced weight loss of 10%.RESULTSThe contribution of hepatic DNL to IHTG-palmitate was 11%, 19%, and 38% in the lean, obese, and obese-NAFLD groups, respectively. Hepatic DNL was inversely correlated with hepatic and whole-body insulin sensitivity, but directly correlated with 24-hour plasma glucose and insulin concentrations. Weight loss decreased IHTG content, in conjunction with a decrease in hepatic DNL and 24-hour plasma glucose and insulin concentrations.CONCLUSIONSThese data suggest hepatic DNL is an important regulator of IHTG content and that increases in circulating glucose and insulin stimulate hepatic DNL in individuals with NAFLD. Weight loss decreased IHTG content, at least in part, by decreasing hepatic DNL.TRIAL REGISTRATIONClinicalTrials.gov NCT02706262.FUNDINGThis study was supported by NIH grants DK56341 (Nutrition Obesity Research Center), DK20579 (Diabetes Research Center), DK52574 (Digestive Disease Research Center), and RR024992 (Clinical and Translational Science Award), and by grants from the Academy of Nutrition and Dietetics Foundation, the College of Natural Resources of UCB, and the Pershing Square Foundation

Continuous Intravenous Sub-Dissociative Dose Ketamine Infusion for Managing Pain in the Emergency Department

Introduction: Our objective was to describe dosing, duration, and pre- and post-infusion analgesic administration of continuous intravenous sub-dissociative dose ketamine (SDK) infusion for managing a variety of painful conditions in the emergency department (ED).  Methods: We conducted a retrospective chart review of patients aged 18 and older presenting to the ED with acute and chronic painful conditions who received continuous SDK infusion in the ED for a period over six years (2010-2016). Primary data analyses included dosing and duration of infusion, rates of pre- and post-infusion analgesic administration, and final diagnoses. Secondary data included pre- and post-infusion pain scores and rates of side effects. Results: A total of 104 patients were enrolled in the study. Average dosing of SDK infusion was 11.26 mg/hr, and the mean duration of infusion was 135.87 minutes. There was a 38% increase in patients not requiring post-infusion analgesia. The average decrease in pain score was 5.04. There were 12 reported adverse effects, with nausea being the most prevalent. Conclusion: Continuous intravenous SDK infusion has a role in controlling pain of various etiologies in the ED with a potential to reduce the need for co-analgesics or rescue analgesic administration. There is a need for more robust, prospective, randomized trials that will further evaluate the analgesic efficacy and safety of this modality across a wide range of pain syndromes and different age groups in the ED

Lung Ultrasound Score in COVID-19 Patients Correlates with PO2/FiO2, Intubation Rates, and Mortality

Introduction: The point-of-care lung ultrasound (LUS) score has been used in coronavirus 2019 (COVID-19) patients for diagnosis and risk stratification, due to excellent sensitivity and infection control concerns. We studied the ratio of partial pressure of oxygen in arterial blood to the fraction of inspiratory oxygen concentration (PO2/FiO2), intubation rates, and mortality correlation to the LUS score.Methods: We conducted a systematic review using PRISMA guidelines. Included were articles published from December 1, 2019–November 30, 2021 using LUS in adult COVID-19 patients in the intensive care unit or the emergency department. Excluded were studies on animals and on pediatric and pregnant patients. We assessed bias using QUADAS-2. Outcomes were LUS score and correlation to PO2/FiO2, intubation, and mortality rates. Random effects model pooled the meta-analysis results.Results: We reviewed 27 of 5,267 studies identified. Of the 27 studies, seven were included in the intubation outcome, six in the correlation to PO2/FiO2 outcome, and six in the mortality outcome. Heterogeneity was found in ultrasound protocols and outcomes. In the pooled results of 267 patients, LUS score was found to have a strong negative correlation to PO2/FiO2 with a correlation coefficient of −0.69 (95% confidence interval [CI] −0.75, −0.62). In pooled results, 273 intubated patients had a mean LUS score that was 6.95 points higher (95% CI 4.58–9.31) than that of 379 non-intubated patients. In the mortality outcome, 385 survivors had a mean LUS score that was 4.61 points lower (95% CI 3.64–5.58) than that of 181 non-survivors. There was significant heterogeneity between the studies as measured by the I2 and Cochran Q test.Conclusion: A higher LUS score was strongly correlated with a decreasing PO2/FiO2 in COVID-19 pneumonia patients. The LUS score was significantly higher in intubated vs non-intubated patients with COVID-19. The LUS score was significantly lower in critically ill patients with COVID-19 pneumonia that survive

KSHV miRNAs Decrease Expression of Lytic Genes in Latently Infected PEL and Endothelial Cells by Targeting Host Transcription Factors

Kaposi’s sarcoma-associated herpesvirus (KSHV) microRNAs are encoded in the latency-associated region. Knockdown of KSHV miR-K12-3 and miR-K12-11 increased expression of lytic genes in BC-3 cells, and increased virus production from latently infected BCBL-1 cells. Furthermore, iSLK cells infected with miR-K12-3 and miR-K12-11 deletion mutant viruses displayed increased spontaneous reactivation and were more sensitive to inducers of reactivation than cells infected with wild type KSHV. Predicted binding sites for miR-K12-3 and miR-K12-11 were found in the 3’UTRs of the cellular transcription factors MYB, Ets-1, and C/EBPα, which activate RTA, the KSHV replication and transcription activator. Targeting of MYB by miR-K12-11 was confirmed by cloning the MYB 3’UTR downstream from the luciferase reporter. Knockdown of miR‑K12-11 resulted in increased levels of MYB transcript, and knockdown of miR-K12-3 increased both C/EBPα and Ets-1 transcripts. Thus, miR-K12-11 and miR-K12-3 contribute to maintenance of latency by decreasing RTA expression indirectly, presumably via down‑regulation of MYB, C/EBPα and Ets-1, and possibly other host transcription factors