The role of autophagy in carcinogenesis is controversial and apparently complex. By using mice with hepatocyte-specific knockout of Atg5, a gene essential for autophagy, we longitudinally studied the ...role of autophagy in hepatocarcinogenesis. We found that impairing autophagy in hepatocytes would induce oxidative stress and DNA damage, followed by the initiation of hepatocarcinogenesis, which could be suppressed by the antioxidant N-acetylcysteine. Interestingly, these mice developed only benign tumors with no hepatocellular carcinoma (HCC), even after the treatment with diethylnitrosamine, which induced HCC in wild-type mice. The inability of mice to develop HCC when autophagy was impaired was associated with the induction of multiple tumor suppressors including p53. Further analysis indicated that the induction of p53 was associated with the DNA-damage response. Tumorigenesis studies using an established liver tumor cell line confirmed a positive role of autophagy in tumorigenesis and a negative role of p53 in this process when autophagy was impaired. Our studies thus demonstrate that autophagy is required to maintain healthy mitochondria and to reduce oxidative stress and DNA damage to prevent the initiation of hepatocarcinogenesis. However, once hepatocarcinogenesis has been initiated, its presence is also required to suppress the expression of tumor suppressors to promote the development of HCC.
Hepatitis C virus (HCV) is a leading cause of chronic liver disease that can progress to cirrhosis and/or hepatocellular carcinoma. Intrahepatic inflammation and liver cell injury are defining ...features of chronic HCV infection. Chemokines, chemotactic cytokines that attract leucocytes to inflammatory sites, may be important in the development of intrahepatic inflammation. As T‐helper (Th)1 inflammatory cells, characterized by interferon (IFN)‐γ and interleukin (IL)‐2 secretion, predominate in the liver during chronic HCV infection, chemokines that attract these cells might be particularly important in disease progression. In this review, we focus on the role of Th1 chemokines, which are all members of the CXC or CC subfamilies. Among the CXC chemokines, the non‐ELR group comprised of IFN‐γ‐inducible protein 10 (IP‐10), monokine induced by IFN‐γ (Mig) and IFN‐inducible T‐cell‐α chemoattractant (I‐TAC), attract Th1 cells through the interaction with their receptor, CXCR3. Among the CC subfamily, Th1‐associated chemokines include regulated upon activation, normal T‐cell expressed and secreted (RANTES) and macrophage inflammatory proteins (MIP)1α and β. These chemokines attract cells through an interaction with their receptor, CCR5. While peripheral blood and intrahepatic levels of all of these chemokines are elevated in chronic hepatitis C patients, only select chemokines have been found to be correlated with hepatic inflammation. Among the six chemokines, IP‐10 has uniquely been shown to have prognostic utility as a marker of treatment outcome. In the future, chemokines might be used to monitor the natural course and progression of HCV‐associated liver disease, to identify patients with a high likelihood of achieving a therapeutic response, and they may even have potential as therapeutic targets.
Data from animal models of fibrosis and fatty liver suggest that leptin may mediate the profibrogenic responses in the liver, but the association of leptin and liver fibrosis in human nonalcoholic ...fatty liver disease (NAFLD) remains undefined. We aimed at determining the relation between leptin and liver fibrosis in human NAFLD.
Human plasma leptin and several indicators of insulin resistance were measured in 88 NAFLD patients and matched controls.
Leptin levels were significantly greater in patients with more advanced fibrosis (
P=0.005). By multivariate analysis, the significant association between leptin and fibrosis was abolished (adjusted
P=0.3) when controlling for confounders including age, gender, BMI, diabetes and insulin resistance. Only age (adjusted
P=0.006) and insulin sensitivity (adjusted
P=0.04) correlated significantly with fibrosis stage. A second liver biopsy was performed in 39 out of the 88 patients at 27.9±16 months. Leptin levels were not significantly different between patients who had fibrosis progression (
n=10) and those who did not (
n=29).
In human NAFLD, no relationship between leptin levels and fibrosis stage was demonstrated. The correlation of leptin and fibrosis severity seems to be an indicator of the factors that determine leptin production.
The Medical Certificate of Stillbirth (MCS) records data about a baby's death after 24 weeks of gestation but before birth. Major errors that could alter interpretation of the MCS were widespread in ...two UK-based regional studies.
A multicentre evaluation was conducted, examining MCS issued 1 January 2018 to 31 December 2018 in 76 UK obstetric units. A systematic case-note review of stillbirths was conducted by Obstetric and Gynaecology trainees, generating individual 'ideal MCSs' and comparing these to the actual MCS issued. Anonymized central data analysis described rates and types of error, agreement and factors associated with major errors.
There were 1120 MCSs suitable for assessment, with 126 additional submitted data sets unsuitable for accuracy analysis (total 1246 cases). Gestational age demonstrated 'substantial' agreement K = 0.73 (95% CI 0.70-0.76). Primary cause of death (COD) showed 'fair' agreement K = 0.26 (95% CI 0.24-0.29). Major errors 696/1120; 62.1% (95% CI 59.3-64.9%) included certificates issued for fetal demise at <24 weeks' gestation 23/696; 3.3% (95% CI 2.2-4.9%) or neonatal death 2/696; 0.3% (95% CI 0.1-1.1%) or incorrect primary COD 667/696; 95.8% (95% CI 94.1-97.1%). Of 540/1246 43.3% (95% CI 40.6-46.1%) 'unexplained' stillbirths, only 119/540 22.0% (95% CI 18.8-25.7%) remained unexplained; the majority were redesignated as either fetal growth restriction FGR: 195/540; 36.1% (95% CI 32.2-40.3%) or placental insufficiency 184/540; 34.1% (95% CI 30.2-38.2). Overall, FGR 306/1246; 24.6% (95% CI 22.3-27.0%) was the leading primary COD after review, yet only 53/306 17.3% (95% CI 13.5-22.1%) FGR cases were originally attributed correctly.
This study demonstrates widespread major errors in MCS completion across the UK. MCS should only be completed following structured case-note review, with particular attention on the fetal growth trajectory.
BackgroundHepatic steatosis, a common histological finding in hepatitis C virus (HCV)–infected patients, is associated with severity of fibrosis. The prevalence and significance of steatosis in ...patients coinfected with human immunodeficiency virus (HIV) and HCV are not well characterized MethodsTo determine the prevalence and severity of steatosis, a single pathologist evaluated liver-biopsy samples from 106 patients coinfected with HIV and HCV but without hepatitis B infection (negative results for hepatitis B surface antigen) for findings associated with steatosis or steatohepatitis and viral hepatitis. Medical records were reviewed retrospectively to elucidate risk factors for steatosis ResultsSteatosis was present in 56% of biopsy samples, with moderate to severe grades in 9%. Severity of steatosis was associated with fibrosis (odds ratio OR, 1.84 95% confidence interval {CI}, 1.06–3.20; P=.03) but not with necroinflammation. In multivariate analysis, the severity of steatosis was associated with lower levels of high-density lipoprotein cholesterol (OR, 0.71 per 10-mg/dL increase 95% CI, 0.52–0.95; P=.02), higher body-mass index (OR, 1.30 per kg/m2 increase 95% CI, 1.13–1.49; P<.001), and the presence of lipodystrophy (OR, 3.82 95% CI, 1.13–12.88; P=.03). There was a trend toward an association between the severity of steatosis and fibrosis in multivariate analysis (OR, 1.69 95% CI, 0.91–3.16; P=.10) ConclusionsIn patients coinfected with HIV and HCV, hepatic steatosis is common and associated with more-advanced fibrosis. Lower levels of high-density lipoprotein cholesterol, higher body-mass index, and lipodystrophy are potentially modifiable risk factors associated with the severity of steatosis
Objectives
There is insufficient knowledge about the functional and medical recovery of older people infected with SARS-CoV-2. This study aims to gain insight into the course of functional and ...medical recovery of persons who receive geriatric rehabilitation (GR) following SARS-CoV-2 infection across Europe. Special attention will be paid to the recovery of activities of daily living (ADL) and to the GR services offered to these patients.
Design
A multi-center observational cohort study.
Setting and participants
This study will include several European countries (EuGMS member states) each providing at least 52 comparable routine datasets (core dataset) of persons recovering from a SARS-CoV-2 infection and receiving geriatric rehabilitation. The routine data will be anonymously collected in an online CASTOR database. The ethical regulations of each participating country will be followed.
Primary outcome
ADL functioning.
Secondary outcomes
Length of stay, discharge destination, hospital readmission and mortality. Other variables that will be collected are quality of life, treatment modalities, complications, cognition, frailty, mood/anxiety, BMI, nutrition and pain. All variables will be reported at admission and compared with follow-up scores (discharge, 6 weeks and 6 months follow-up).
Conclusion
This study will explore the effect of geriatric rehabilitation on post-COVID-19 patients, especially on ADL recovery, and the variety of geriatric rehabilitation services across Europe. Information from this study may help improve recovery of older persons infected with SARS-CoV-2 and improve geriatric rehabilitation services in the ongoing COVID-19 pandemic.
Frailty tends to be considered as a major risk for adverse outcomes in older persons, but some important aspects remain matter of debate. OBJECTIVES: The purpose of this paper is to present expert’s ...positions on the main aspects of the frailty syndrome in the older persons. PARTICIPANTS: Workshop organized by International Association of Gerontology and Geriatrics (IAGG), World Health Organization (WHO) and Société Française de Gériatrie et de Gérontologie (SFGG). RESULTS: Frailty is widely recognized as an important risk factor for adverse health outcomes in older persons. This can be of particular value in evaluating non-disabled older persons with chronic diseases but today no operational definition has been established. Nutritional status, mobility, activity, strength, endurance, cognition, and mood have been proposed as markers of frailty. Another approach calculates a multidimensional score ranging from “very fit” to “severely frail,” but it is difficult to apply into the medical practice. Frailty appears to be secondary to multiple conditions using multiple pathways leading to a vulnerability to a stressor. Biological (inflammation, loss of hormones), clinical (sarcopenia, osteoporosis etc.), as well as social factors (isolation, financial situation) are involved in the vulnerability process. In clinical practice, detection of frailty is of major interest in oncology because of the high prevalence of cancer in older persons and the bad tolerance of the drug therapies. Presence of frailty should also be taken into account in the definition of the cardiovascular risks in the older population. The experts of the workshop have listed the points reached an agreement and those must to be a priority for improving understanding and use of frailty syndrome in practice. CONCLUSION: Frailty in older adults is a syndrome corresponding to a vulnerability to a stressor. Diagnostic tools have been developed but none can integrate at the same time the large spectrum of factors and the simplicity asked by the clinical practice. An agreement with an international common definition is necessary to develop screening and to reduce the morbidity in older persons.
The aim of this two-year prospective clinical study was to evaluate and compare the clinical performance of three different adhesive esthetic materials in noncarious cervical lesions.
A total of 90 ...restorations (30 per material) were placed in 30 patients who ranged in age between 18 and 50 years and of both genders, by a single operator with no previous preparation. The restoration of noncarious cervical lesions was done with either a microfilled composite (Esthet.X/Dentsply/De Trey, Konstanz, Germany, and Prime&Bond NT/Dentsply/De Trey), a nanohybrid composite (TetricEvoCeram/Vivadent, Schaan, Liechtenstein, and AdheSE/Vivadent), or a compomer (Dyract eXtra/Dentsply/De Trey and Xeno III Dentsply/De Trey). All restorations were evaluated by independent examiners using a modified US Public Health Service criteria at baseline and after 12 and 24 months for six clinical categories. Data were analyzed statistically by Pearson's chi-square or the Fisher's exact test at 5% significance level (p<0.05).
Results showed that most of the restorations were clinically satisfactory after 12 and 24 months, with no statistically significant differences among the three groups for all evaluated criteria.
Treatment of noncarious cervical lesions using composite and compomer materials, combined with the appropriate adhesive systems and properly implemented restorative procedures, gives satisfactory results after a two-year evaluation period.
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