Hepatocellular organellar abnormalities following elimination of hepatitis C virus.

BACKGROUND AND AIMS: The future development of hepatocellular carcinoma (HCC) in patients after sustained virologic response (SVR) is an important issue. The purposes of this study were to investigate pathological alterations in organelle of the liver of SVR patients and to characterize organelle abnormalities that may be related to carcinogenesis after SVR. METHODS: The ultrastructure of liver biopsy specimens from patients with chronic hepatitis C (CHC) and SVR were compared to cell and mouse models and assessed semi-quantitatively using transmission electron microscopy. RESULTS: Hepatocytes in patients with CHC showed abnormalities in the nucleus, mitochondria, endoplasmic reticulum, lipid droplet, and pericellular fibrosis, comparable to those seen in hepatitis C virus (HCV)-infected mice and cells. DAA treatment significantly reduced organelle abnormalities such as the nucleus, mitochondria, and lipid droplet in the hepatocytes of patients and mice after SVR, and cured cells, but it did not change dilated/degranulated endoplasmic reticulum and pericellular fibrosis in patients and mice after SVR. Further, samples from patients with a post-SVR period of >1 year had significantly larger numbers of abnormalities in the mitochondria and endoplasmic reticulum than those of <1 year. A possible cause of organelle abnormalities in patients after SVR could be oxidative stress of the endoplasmic reticulum and mitochondria associated with abnormalities of the vascular system due to fibrosis. Interestingly, abnormal endoplasmic reticulum was associated with patients with HCC for >1 year after SVR. CONCLUSIONS: These results indicate that patients with SVR exhibit a persistent disease state and require long-term follow-up to detect early signs of carcinogenesis.

Silk sericin alleviates aberrant photoperiod-induced alterations in testicular and adrenal steroidogenesis in adult mice.

BACKGROUND: Steroidogenesis is a complex process of sequential enzymatic reactions affected by climate change. Animals respond to altered day length, the so-called photoperiod, with changes in physiology. The study aimed to an evaluation of sericin effect in alleviating steroidogenesis disorders induced by disturbed photoperiod in mice. METHODS: The animals were randomly divided into three groups according to the lighting cycle: a control group with a standard 12Light:12Dark cycle, a short-term photoperiod group with a 6Light:18Dark cycle, and a long-term photoperiod group with an 18Light:6Dark cycle. Both short and long-term groups were subdivided into two equal subgroups: The placebo and the sericin-treated subgroups received, for five weeks from prepubertal throughout adulthood, one intraperitoneal injection per week of the solvent and 1 g sericin/kg body weight, respectively. RESULTS: Selected oxidative stress parameters and testicular and adrenal steroidogenic capacities of adult mice were measured. After five weeks, the placebo group with impaired photoperiod showed a decrease in the quality and quantity of sperm and a reduction in testosterone, corticosterone, aldosterone, total antioxidant capacity, xanthine oxidase, and melatonin. At the same time, in these groups, there was an increase in the level of aromatase, malondialdehyde, cholesterol, and steroidogenic factor-1 (SF-1) expression in the adrenal cortex and an enhancement in histological lesions. Mice receiving sericin had parameters similar to the control group. CONCLUSION: Our findings reveal that silk sericin can reduce the stress caused by photoperiod disorders regarding testicular function, sex hormone levels, and sperm quantity and quality. Thus, sericin is a biocompatible protein with a promising potential for its use in the case of organisms living under an abnormal photoperiod.

Clinicopathological Impact of Gene Polymorphism of Nephrin and Glucocorticoid Receptor Genes in Egyptian Children with Nonfamilial Nephrotic Syndrome.

Idiopathic nephrotic syndrome (NS) is one of the most common primary glomerular diseases in children. In this study, we investigate the association of single-nucleotide polymorphisms of nephrin gene and glucocorticoid receptor gene (NR3C1) and susceptibility to develop NS and the response to steroid therapy in 100 Egyptian children with NS using polymerase chain reaction-restriction fragment length polymorphism. We also analyzed the correlation between the genotypes and clinicopathologic features of the patients. Thirty-four patients (34%) were initial steroid nonresponders, renal biopsy findings of those patients were available, of which 22 (64.7%) showed minimal change NS and 12 (35.3%) had focal segmental glomerulosclerosis. The distribution of the genotypes was comparable between the patient and control groups, allele frequencies showed no significant difference between the patient's group and the control group. The genotypes showed no correlation with the age of onset of NS, initial steroid responsiveness, renal pathologic findings, estimated glomerular filtration rate (eGFR), and serum albumin. However, 24-h protein in urine showed a significant association with the NR3C1 gene. These data suggested that the nephrin gene and NR3C1 gene SNPs do not affect the development of NS, initial steroid responsiveness, renal pathological lesion, eGFR, and serum albumin. However, 24-h protein in urine showed a significant association with the NR3C1 gene in Egyptian children with NS.

Identifying pathways for large-scale implementation of a school-based mental health programme in the Eastern Mediterranean Region: a theory-driven approach.

Globally there is a substantial burden of mental health problems among children and adolescents. Task-shifting/task-sharing mental health services to non-specialists, e.g. teachers in school settings, provide a unique opportunity for the implementation of mental health interventions at scale in low- and middle-income countries (LMICs). There is scant information to guide the large-scale implementation of school-based mental health programme in LMICs. This article describes pathways for large-scale implementation of a School Mental Health Program (SMHP) in the Eastern Mediterranean Region (EMR). A collaborative learning group (CLG) comprising stakeholders involved in implementing the SMHP including policymakers, programme managers and researchers from EMR countries was established. Participants in the CLG applied the theory of change (ToC) methodology to identify sets of preconditions, assumptions and hypothesized pathways for improving the mental health outcomes of school-aged children in public schools through implementation of the SMHP. The proposed pathways were then validated through multiple regional and national ToC workshops held between January 2017 and September 2019, as the SMHP was being rolled out in three EMR countries: Egypt, Pakistan and Iran. Preconditions, strategies and programmatic/contextual adaptations that apply across these three countries were drawn from qualitative narrative summaries of programme implementation processes and facilitated discussions during biannual CLG meetings. The ToC for large-scale implementation of the SMHP in the EMR suggests that identifying national champions, formulating dedicated cross-sectoral (including the health and education sector) implementation teams, sustained policy advocacy and stakeholders engagement across multiple levels, and effective co-ordination among education and health systems especially at the local level are among the critical factors for large-scale programme implementation. The pathways described in this paper are useful for facilitating effective implementation of the SMHP at scale and provide a theory-based framework for evaluating the SMHP and similar programmes in the EMR and other LMICs.

Study of the relationship between urinary level of uromodulin, renal involvement and disease activity in patients with systemic lupus erythrematosus.

Systemic lupus erythematosus (SLE) is a multifactorial chronic inflammatory autoimmune connective tissue disease. Lupus nephritis (LN) is a common and serious complication of SLE which can progress to end-stage renal disease. Renal biopsy is the gold standard in the diagnosis and classification of LN, but since it is an invasive procedure, it is neither desirable nor applicable for all cases. This has led to the search for an alternative, noninvasive, site-specific, and immune process-related biomarkers. Uromodulin (Tamm-Horsfall glycoprotein) is the most abundant urinary protein expressed exclusively by the thick ascending limb cells and released into urine of healthy controls. Studies showed that it may act as a danger signaling molecule eliciting an inflammatory response following conditions that damage the nephron integrity and leading to uromodulin release into the interstitial space. This study aimed to assess uromodulin as a screening biomarker of tubulointerstitial involvement in patients with SLE and to elucidate its correlation with disease activity and progression. The study was conducted on 70 patients divided into two groups: control group (Group I) consisted of 20 apparently healthy volunteers of comparable age and sex to the patients' group, and 50 SLE patients (Group II) diagnosed according to the 2012 Systemic Lupus Collaborating Clinics (SLICC) classification criteria. Group II was further subdivided into 23 patients without manifestations of LN (Group II A) and 27 patients with manifestations of LN (Group II B). Urinary uromodulin level showed statistically significant difference among the studied groups, being lowest among the LN patients with a mean value 5.6 ± 3.4, in SLE patients without nephritis 9.9 ± 5.2 and 12.9 ± 4.6 in the control group. Urinary uromodulin also correlated positively with estimated glome- rular filtration rate. A negative correlation was found between urinary uromodulin and serum creatinine, 24 h urinary proteins and SLICC renal activity score. No statistically significant correlation was found between urinary uromo- dulin and SLE disease activity index. Thus, decreasing urinary uromodulin levels can be a marker for renal involvement and tubulo- interstitial nephritis in active SLE patients and a marker for chronic kidney disease and nephron loss in the absence of activity markers.

Angiopoietin-2, endothelial dysfunction and renal involvement in patients with systemic lupus erythematosus.

BACKGROUND: Angiopoietin-2 (ang-2) that activates endothelial cells and increases vascular inflammation might have significant roles in the pathogenesis of glomerular diseases. This study aimed at assessing the level of ang-2 as a marker of renal involvement in SLE patients to elucidate its correlation with disease activity and endothelial dysfunction. METHODS: This study included 81 subjects. The control group included 21 healthy subjects. The patients group included 60 SLE patients, 24 patients without lupus nephritis (LN) and 36 patients with LN. Clinical examination and laboratory investigations including 24 hours urinary protein, estimation of serum ang-2 and creatinine and calculation of estimated glomerular filtration rate (eGFR). Measurement of SLE disease activity index (SLEDAI), flow mediated dilatation (FMD) and carotid intima media thickness (CIMT) were done. Renal biopsy was done for patients with LN. RESULTS: Ang2 level was significantly higher in subjects with FMD <=10%, than in subjects with FMD >10%. Ang2 level was significantly increased in SLE patients than controls, and it was significantly higher in patients with LN than in patients without nephritis. Ang2 was significantly positively correlated with SLEDAI, 24 hours urinary protein and histological activity index, and was negatively correlated with C3, eGFR and FMD. There were no significant differences between patients with proliferative and non proliferative LN regarding Ang2 level. CONCLUSIONS: Ang2 can reflect the extent of endothelial activation and may be used as a biomarker of both disease activity and renal involvement in SLE patients. Ang2 level cannot distinguish between proliferative and non proliferative lesions in LN.