Citations

AbstractRecent population studies suggest an intriguing inverse relationship between several types of cancer and neurodegenerative diseases, including Alzheimer's disease. Understanding the intersection of the underlying biology for these two distinct families of diseases with one another may offer novel approaches to identify new therapeutic approaches and possible opportunities to repurpose existing drug candidates. The Alzheimer's Association and the Alzheimer's Drug Discovery Foundation convened a one‐day workshop to delve into this discussion. Workshop participants outlined research focus areas, potential collaborations, and partnerships for future action.

AbstractLong‐term outcomes of the Fontan operation include Fontan failure and liver disease. Combined heart‐liver transplantation (CHLT) is an option for select patients although limited data exist on this strategy. A retrospective review of Fontan patients 18 years or older referred for cardiac transplant evaluation between 2000 and 2013 at the Hospital of the University of Pennsylvania was performed. All patients were considered for potential CHLT. Clinical variables such as demographics, perioperative factors, and short‐term outcomes were reviewed. Of 17 referrals for cardiac transplantation, seven Fontan patients underwent CHLT. All patients who underwent CHLT had either advanced fibrosis or cirrhosis on liver biopsy. There were no perioperative deaths. The most common postoperative morbidity was acute kidney injury. Short‐term complications include one episode of acute liver rejection but no cardiac rejection greater than 1R. CHLT is an acceptable therapeutic option for patients with failing Fontan physiology who exhibit concomitant advanced liver fibrosis. However, optimal patient selection is currently undefined, and long‐term outcomes are not known.

Prohibitin 1 (PHB1) is best known as a mitochondrial chaperone, and its role in cancer is conflicting. Mice lacking methionine adenosyltransferase α1 (MATα1) have lower PHB1 expression, and we reported that c‐MYC interacts directly with both proteins. Furthermore, c‐MYC and MATα1 exert opposing effects on liver cancer growth, prompting us to examine the interplay between PHB1, MATα1, and c‐MYC and PHB1's role in liver tumorigenesis. We found that PHB1 is highly expressed in normal hepatocytes and bile duct epithelial cells and down‐regulated in most human hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). In HCC and CCA cells, PHB1 expression correlates inversely with growth. PHB1 and MAT1A positively regulate each other's expression, whereas PHB1 negatively regulates the expression of c‐MYC, MAFG, and c‐MAF. Both PHB1 and MATα1 heterodimerize with MAX, bind to the E‐box element, and repress E‐box promoter activity. PHB1 promoter contains a repressive E‐box element and is occupied mainly by MAX, MNT, and MATα1 in nonmalignant cholangiocytes and noncancerous tissues that switched to c‐MYC, c‐MAF, and MAFG in cancer cells and human HCC/CCA. All 8‐month‐old liver‐specific Phb1 knockout mice developed HCC, and one developed CCA. Five‐month‐old Phb1 heterozygotes, but not Phb1 flox mice, developed aberrant bile duct proliferation; and one developed CCA 3.5 months after left and median bile duct ligation. Phb1 heterozygotes had a more profound fall in the expression of glutathione synthetic enzymes and higher hepatic oxidative stress following left and median bile duct ligation. Conclusion: We have identified that PHB1, down‐regulated in most human HCC and CCA, heterodimerizes with MAX to repress the E‐box and positively regulates MAT1A while suppressing c‐MYC, MAFG, and c‐MAF expression; in mice, reduced PHB1 expression predisposes to the development of cholestasis‐induced CCA. (Hepatology 2017;65:1249‐1266).

ABSTRACTIntroductionUltrasound is increasingly used as an adjunct in the diagnosis of neuromuscular disease by measuring muscle thickness and echointensity (EI). Reproducibility is limited because of variations in scanning technique and proprietary algorithms that alter EI values.MethodsWe developed a standardized scanning protocol and a portable machine without any postimaging processing. Ten subjects underwent scanning of 6 muscles by 3 sonographers on 2 separate days. One of the sonographers repeated the protocol with 4 different machine/transducer combinations. Gray‐scale values were measured from each image with the use of a region of interest (ROI) box.ResultsCombined intraclass correlation coefficients were 0.92 (intra‐rater), 0.88 (inter‐rater), and 0.96 (inter‐system). The biceps had the highest variability (coefficient of variance [COV] 12.7%), and the medial gastrocnemius had the lowest variability (COV 7.4%).ConclusionsWe demonstrate excellent reliability of a reproducible ultrasound system for gray‐scale analysis of muscle that has potential applicability as a screening tool for neuromuscular disease. Muscle Nerve 56: 408–412, 2017

Context Complete reporting of research is essential to enable consumers to accurately appraise, interpret and apply findings. Quality appraisal checklists are giving way to tools that judge the risk for bias. Objectives We sought to determine the prevalence of these complementary aspects of research reports (completeness of reporting and perceived risk for bias) of randomised studies in health professions education. Methods We searched bibliographic databases for randomised studies of health professions education. We appraised two cohorts representing different time periods (2008–2010 and 2014, respectively) and worked in duplicate to apply the CONSORT guidelines and Cochrane Risk of Bias tool. We explored differences between time periods using independent‐samples t ‐tests or the chi‐squared test, as appropriate. Results We systematically identified 180 randomised studies (2008–2010, n = 150; 2014, n = 30). Frequencies of reporting of CONSORT elements within full‐text reports were highly variable and most elements were reported in fewer than 50% of studies. We found a statistically significant difference in the CONSORT reporting index (maximum score: 500) between the 2008–2010 (mean ± standard deviation [SD]: 242.7 ± 55.6) and 2014 (mean ± SD: 311.6 ± 53.2) cohorts (p < 0.001). High or unclear risk for bias was most common for allocation concealment (157, 87%) and blinding of participants (147, 82%), personnel (152, 84%) and outcome assessors (112, 62%). Most risk for bias elements were judged to be unclear (range: 51–84%). Risk for bias elements significantly improved over time for blinding of participants (p = 0.007), incomplete data (p < 0.001) and the presence of other sources of bias (p < 0.001). Conclusions Reports of randomised studies in health professions education frequently omit elements recommended by the CONSORT statement. Most reports were assessed as having a high or unclear risk for bias. Greater attention to how studies are reported at study outset and in manuscript preparation could improve levels of complete transparent reporting.

BACKGROUND: Gabapentinoids are widely used in perioperative multimodal analgesic regimens. The primary aim of this study was to determine whether gabapentin was associated with respiratory depression during phase-I postanesthesia recovery after major laparoscopic procedures. METHODS: We retrospectively reviewed the electronic health records of 8567 patients who underwent major laparoscopic procedures (lasting ≥90 minutes) from January 1, 2010, to July 31, 2014. We assessed potential associations among patient and perioperative variables and episodes of respiratory depression during phase-I recovery. Multivariable and propensity score–matched analyses were performed to assess potential associations between preoperative gabapentin use and postoperative respiratory depression. RESULTS: The incidence of respiratory depression was 153 (95% confidence interval [CI], 146–161) episodes per 1000 cases. Multivariable analysis showed that gabapentin was associated with respiratory depression (odds ratio [OR], 1.47 [95% CI, 1.22–1.76]; P < .001). These results were confirmed by propensity score–matched analysis among a subset of patients who did not have analgesia supplemented by intrathecal opioids (OR, 1.26 [95% CI, 1.02–1.58]; P = .04). Older patients and those who received more intraoperative opioids had increased risk of respiratory depression. Those who had an episode of respiratory depression had a longer phase-I recovery ( P < .001) and an increased rate of admission to a higher level of care ( P = .03). CONCLUSIONS: The use of gabapentin is associated with increased rates of respiratory depression among patients undergoing laparoscopic surgery. When gabapentinoids are included in multimodal analgesic regimens, intraoperative opioids must be reduced, and increased vigilance for respiratory depression may be warranted, especially in elderly patients.

A novel protein complex facilitates lipid droplet autophagy.