Sarcopenia in cirrhosis: from pathogenesis to interventions

Journal of Gastroenterology - Sarcopenia (severe muscle depletion) is a prevalent muscle abnormality in patients with cirrhosis that confers poor prognosis both pre- and post-liver transplantation....     

The prevalence of gestational diabetes mellitus in Bangladesh: a systematic review and meta-analysis

International Journal of Diabetes in Developing Countries - Currently, gestational diabetes mellitus (GDM) is a major public health concern with a higher risk of adverse pregnancy outcomes for both...     

Bottom-up analysis of emergent properties of N-acetylcysteine as an adjuvant therapy for COVID-19

N-acetylcysteine (NAC) is an abundantly available antioxidant with a wide range of antidotal properties currently best studied for its use in treating acetaminophen overdose. It has a robustly established safety profile with easily tolerated side effects and presents the Food and Drug Administration's approval for use in treating acetaminophen overdose patients. It has been proven efficacious in off-label uses, such as in respiratory diseases, heart disease, cancer, human immunodeficiency virus infection, and seasonal influenza. Clinical trials have recently shown that NAC's capacity to replenish glutathione stores may significantly improve coronavirus disease 2019 (COVID-19) outcomes, especially in high risk individuals. Interestingly, individuals with glucose 6-phosphate dehydrogenase deficiency have been shown to experience even greater benefit. The same study has concluded that NAC's ability to mitigate the impact of the cytokine storm and prevent elevation of liver enzymes, C-reactive protein, and ferritin is associated with higher success rates weaning from the ventilator and return to normal function in COVID-19 patients. Considering the background knowledge of biochemistry, current uses of NAC in clinical practice, and newly acquired evidence on its potential efficacy against COVID-19, it is worthwhile to investigate further whether this agent can be used as a treatment or adjuvant for COVID-19.     

Diagnosis and management of acute cholecystitis: a single-centre audit of guideline adherence and patient outcomes

BackgroundThe Tokyo Guidelines were published in 2007 and updated in 2013 and 2018, with recommendations for the diagnosis and management of acute cholecystitis. We assessed guideline adherence at our academic centre and its impact on patient outcomes.MethodsThis is a retrospective chart review of patients with acute calculous cholecystitis who underwent cholecystectomy at our institution between November 2013 and March 2015. Severity of cholecystitis was graded retrospectively if it had not been documented preoperatively. Compliance with the Tokyo Guidelines’ recommendations on antibiotic use and time to operation was recorded. Cholecystitis severity groups were compared statistically, and logistic regression was used to determine predictors of complications.ResultsOne hundred and fifty patients were included in the study. Of these, 104 patients were graded as having mild cholecystitis, 45 as having moderate cholecystitis, and 1 as having severe cholecystitis. Severity was not documented preoperatively for any patient. Compliance with antibiotic recommendations was poor (18.0%) and did not differ by cholecystitis severity (p = 0.90). Compliance with the recommendation on time to operation was 86.0%, with no between-group differences (p = 0.63); it improved when an acute care surgery team was involved (91.0% v. 76.0%, p = 0.025). On multivariable analysis, comorbidities (odds ratio [OR] 1.47, 95% confidence interval [CI] 1.19–1.85, p < 0.001) and conversion to laparotomy (OR 13.45, 95% CI 2.16–125.49, p = 0.01) predicted postoperative complications, while severity of cholecystitis, antibiotic compliance and time to operation had no effect.ConclusionIn this study, compliance with the Tokyo Guidelines was acceptable only for time to operation. Although the poor compliance with recommendations relating to documentation of severity grading and antibiotic use did not have a negative affect on patient outcomes, these recommendations are important because they facilitate appropriate antibiotic use and patient risk stratification.     

Upfront DPYD Genotyping and Toxicity Associated with Fluoropyrimidine-Based Concurrent Chemoradiotherapy for Oropharyngeal Carcinomas: A Work in Progress

Simple SummaryThe combination of carboplatin and 5-fluorouracil (5-FU) is effective when used concurrently with radiotherapy for locoregionally advanced oropharyngeal carcinomas. DPYD polymorphisms can be associated with an increased risk of severe toxicity to fluoropyrimidines. Upfront screening for the DPYD*2A allele has been available in the province of Québec, Canada, since March 2017. This study aimed to determine the effect of upfront genotyping on the incidence of grade ≥3 toxicities. We included 181 patients in the analysis. Extended screening for three supplemental at-risk DPYD variants was also retrospectively performed in August 2019. The DPYD*2A, c.2846A>T and c.1236G>A polymorphisms were associated with an increased risk of grade ≥3 toxicity to 5-FU. Upfront DPYD genotyping can thus identify patients in whom 5-FU-related toxicity should be avoided.AbstractBackground: 5-FU-based chemoradiotherapy (CRT) could be associated with severe treatment-related toxicities in patients harboring at-risk DPYD polymorphisms. Methods: The studied population included consecutive patients with locoregionally advanced oropharyngeal carcinoma treated with carboplatin and 5-FU-based CRT one year before and after the implementation of upfront DPYD*2A genotyping. We aimed to determine the effect of DPYD genotyping on grade ≥3 toxicities. Results: 181 patients were analyzed (87 patients before and 94 patients following DPYD*2A screening). Of the patients, 91% (n = 86) were prospectively genotyped for the DPYD*2A allele. Of those screened, 2% (n = 2/87) demonstrated a heterozygous DPYD*2A mutation. Extended genotyping of DPYD*2A-negative patients later allowed for the retrospective identification of six additional patients with alternative DPYD variants (two c.2846A>T and four c.1236G>A mutations). Grade ≥3 toxicities occurred in 71% of the patients before DPYD*2A screening versus 62% following upfront genotyping (p = 0.18). When retrospectively analyzing additional non-DPYD*2A variants, the relative risks for mucositis (RR 2.36 [1.39–2.13], p = 0.0063), dysphagia (RR 2.89 [1.20–5.11], p = 0.019), and aspiration pneumonia (RR 13 [2.42–61.5)], p = 0.00065) were all significantly increased. Conclusion: The DPYD*2A, c.2846A>T, and c.1236G>A polymorphisms are associated with an increased risk of grade ≥3 toxicity to 5-FU. Upfront DPYD genotyping can identify patients in whom 5-FU-related toxicity should be avoided.     

Comparative pharmacological and histochemical evidence for purinergic inhibitory innervation of the portal vein of the rabbit, but not guinea-pig

1 Intramural nerve stimulation elicited a powerful relaxation of the longitudinal muscle of the rabbit portal vein in the presence of atropine and guanethidine, but not of the guinea-pig portal vein.

2 Intramural nerve stimulation of the rabbit portal vein produced a 13 fold increase in release of ³H-adenyl compounds after preloading with [³H]-adenosine. About 50% of this release was abolished by guanethidine. All release was abolished by tetrodotoxin. No significant release of radioactive compounds was observed during intramural nerve stimulation of the guinea-pig portal vein in the presence of guanethidine, although there was a 6 fold increase in release of radioactivity in the absence of drugs.

3 Histochemical studies using quinacrine, which binds ATP showed a fine fluorescent nerve plexus, nerve bundles, and ganglion cells in the rabbit portal vein, but not in the guinea-pig portal vein. This plexus was still present after chemical sympathectomy with 6-hydroxydopamine.

4 Adenosine 5′-triphosphate (ATP) relaxed the rabbit portal vein, but usually produced a biphasic response, consisting of a contraction followed by a relaxation, of the guinea-pig portal vein.

5 Prostaglandins E₁ and E₂ caused contraction of the rabbit portal vein. Indomethacin, a prostaglandin synthesis inhibitor, potentiated the relaxations of the rabbit portal vein produced by both non-adrenergic, non-cholinergic nerve stimulation and ATP.

6 High concentrations of antazoline and phentolamine, which antagonize purinergic responses in the guinea-pig taenia coli, caused a loss of basal tone so that it was not possible to assess their effects on the responses of the portal vein to either non-adrenergic, non-cholinergic nerve stimulation, or ATP.

7 Comparison of the results on the portal vein of the rabbit and guinea-pig provides support for the view that: (i) quinacrine fluorescence can be used to localize purinergic nerves and that the rabbit portal vein is supplied by these nerves; (ii) ATP is released from adrenergic nerve fibres, although, based on histochemical analysis, about 3 to 7 times less than is released from purinergic nerve fibres.

     

Telomerase subunits expression variation between biopsy samples and cell lines derived from malignant glioma

Although scientific advances have recognised the prognostic power of telomerase activity in different cancers, as yet there has been no investigation regarding the expression variation of telomerase subunits in glioma tissues and cell lines. In this study, a recurrent anaplastic ependymoma and seven glioblastoma biopsy samples, four cell lines and four controls including two normal brain tissues were analysed for telomerase subunit expression profiles together with telomerase activity. Since telomerase activity is linked to tumourgenesis, the genes were analysed with respect to their expression variation. TEP1 was expressed in all glioma cell lines and 70% of glioblastoma tissues, in addition to the control brain tissues. Tankyrase was expressed in 85% of the glioblastoma tissues and was down-regulated in the recurrent anaplastic ependymoma tissue control cell lines. However, it was expressed in the control tissues. Dyskerin was expressed in all cell lines and tissues apart from U87-MG and NHA cells and the recurrent anaplastic ependymoma tissue. As expected, PARP1 and GAPDH showed constitutive expression throughout all cell lines and tissues since both are known to be housekeeping genes. hTERT was expressed in all glioma cell lines and tissues but was absent in the control cells and tissues. Telomerase activity was absent in IPDDC-A2 cells and 57% of the glioblastoma tissues. These results suggest that hTERT expression and not telomerase activity possibly represents a simple and reliable biological diagnostic tool.