MIR204 n.37C>T variant as a cause of chorioretinal dystrophy variably associated with iris coloboma,early-onset cataracts and congenital glaucoma

Four members of a three-generation Czech family with early-onset chorioretinal dystrophy were shown to be heterozygous carriers of the n.37C>T in MIR204. The identification of this previously reported pathogenic variant confirms the existence of a distinct clinical entity caused by a sequence change in MIR204. Chorioretinal dystrophy was variably associated with iris coloboma, congenital glaucoma, and premature cataracts extending the phenotypic range of the condition. In silico analysis of the n.37C>T variant revealed 713 novel targets. Additionally, four family members were shown to be affected by albinism resulting from biallelic pathogenic OCA2 variants. Haplotype analysis excluded relatedness with the original family reported to harbour the n.37C>T variant in MIR204. Identification of a second independent family confirms the existence of a distinct MIR204-associated clinical entity and suggests that the phenotype may also involve congenital glaucoma.     

Assessing the need to update prevention guidelines: a comparison of two methods.

BACKGROUND: An important concern for developers of clinical practice guidelines is how best to determine when guidelines require updating to ensure they remain current and evidence based. Because of the high costs associated with updating guidelines, recent attention has focused on approaches that can reliably assess the extent of updating required. Recently, Shekelle and colleagues proposed a model of limited literature searches with modest expert involvement as a way to reduce the cost and time requirements for assessing whether a guideline needs updating. METHODS: The main objective of this study was to compare the Shekelle et al. assessment model (review approach) and a conventional process using typical systematic review methods (traditional approach) in terms of comprehensiveness and effort. We modeled the review approach on that by Shekelle and colleagues but refined it iteratively over three phases to achieve greater efficiency. Using both methods independently, we assessed the need to update six topics from the 1996 Guide to Clinical Preventive Services from the US Preventive Services Task Force. Main outcomes included completeness of study identification, importance of missed studies and the effort involved. RESULTS: Although the review approach identified fewer eligible studies than the traditional approach, none of the studies missed was rated as important by task force members acting as liaisons to the project with respect to whether the topic required an update. On average, the review approach produced substantially fewer citations to review than the traditional approach. The effort involved and potential time saving depended largely on the scope of the topic. CONCLUSIONS: The revised review approach provides an efficient and acceptable method for judging whether a guideline requires updating.     

Effect of L-ascorbic add supplementation on testicular oxidative stress and endocrine disorders in mature male rats exposed to intensive swimming exercise

In order to investigate the ameliorative potential of L-ascorbic acid on intensive swimming exercise induced testicular oxidative stress, 18 Wistar male rats (age: 3 months, weight: 127.5 ± 5.3 g) were randomly divided into the following groups: (i) control group (CG,n = 6); (ii) experimental group (EG,n = 6); and (iii) supplemented group (SG,n = 6). An exercise protocol of 3 h swimming per day, five days per week was followed for 6 weeks in EG and SG with no exercise in CG. In SG, L-ascorbic acid was supplied orally at a dose of 25-mg/kg of bodyweight each day for 6 weeks. A significant decrease (P < 0.05) was noted in paired testicular weights, epididymal sperm count, testicular Δ⁵, 3β-hydroxyseroid dehydrogenase, 17β-hydroxyseroid dehydrogenase, plasma levels of testosterone luteinizing hormone, follicle stimulating hormone, prolactin, the numbers of preleptotine spermatocytes, midpachytene spermatocytes and stage 7 spermatids of stage VII seminiferous epithelium cycle in EG when compared with CG. A significant elevation (P < 0.05) in plasma corticosterone and testicular content of malondialdehyde along with a significant reduction (P < 0.05) in glutathione, ascorbic acid, α-tocopherol, superoxide dismutase, catalase and glutathione-peroxidase, and glutathione-S-transferase were noted in testes of EG compared with CG. No significant change was noted in final bodyweight or numbers of spermatogonia-A among the groups. Furthermore, L-ascorbic acid supplementation restored the above parameters to the control level. Conclusion  It can be concluded that intensive swimming exercise induced oxidative stress causes dysfunctions in the male reproductive system, which can be protected by L-ascorbic acid.     

Therapy for minimal residual tumor disease: β‐Galactosylceramide inhibits the growth of recurrent HPV16‐associated neoplasms after surgery and chemotherapy

Natural killer T (NKT) cells are potent modulators of antitumor immunity. Their protective effects can be achieved upon their activation by glycolipid ligands presented in the context of the CD1d molecule. These CD1d‐binding glycolipid antigens have been described as potent therapeutic agents against tumors, infections, as well as autoimmune diseases. Immunoregulatory and therapeutic effects of glycolipid ligands depend on their structure and modes of administration. Therefore, more studies are needed for optimization of the particular therapeutic settings. This study was focused on the tumor‐inhibitory effects of 12 carbon acyl chain β‐galactosyl ceramide (C12 β‐D ‐Galactosyl Ceramide; β‐GalCer(C12)) on the growth of human papillomavirus type 16 (HPV16)‐associated neoplasms transplanted in syngeneic mice. Treatment of tumor‐bearing mice with β‐GalCer(C12) 3–14 days after tumor cell transplantation significantly inhibited the growth of the major histocompatability complex (MHC) Class I‐positive (TC‐1), as well as MHC Class I‐deficient (TC‐1/A9) HPV16‐asssociated tumors. Moreover, administration of β‐GalCer(C12) after surgical removal of TC‐1 tumors inhibited the growth of tumor recurrences. Similar results were obtained in the treatment of tumors after chemotherapy. β‐GalCer(C12) treatment turned out to be also synergistic with immunotherapy based on administration of IL‐12‐producing cellular vaccines. These results suggest that β‐GalCer(C12), whose antitumor effects have so far not been studied in detail, can be effective for the treatment of minimal residual tumor disease as well as an adjuvant for cancer immunotherapy.     

Multi-Objective Optimization of Process Parameters during Micro-Milling of Nickel-Based Alloy Inconel 718 Using Taguchi-Grey Relation Integrated Approach

This research investigates the machinability of Inconel 718 under conventional machining speeds using three different tool coatings in comparison with uncoated tool during milling operation. Cutting speed, feed rate and depth of cut were selected as variable machining parameters to analyze output responses including surface roughness, burr formation and tool wear. It was found that uncoated and AlTiN coated tools resulted in lower tool wear than nACo and TiSiN coated tools. On the other hand, TiSiN coated tools resulted in highest surface roughness and burr formation. Among the three machining parameters, feed was identified as the most influential parameter affecting burr formation. Grey relational analysis identified the most optimal experimental run with a speed of 14 m/min, feed of 1 μm/tooth, and depth of cut of 70 μm using an AlTiN coated tool. ANOVA of the regression model identified the tool coating parameter as most effective, with a contribution ratio of 41.64%, whereas cutting speed and depth of cut were found to have contribution ratios of 18.82% and 8.10%, respectively. Experimental run at response surface optimized conditions resulted in reduced surface roughness and tool wear by 18% and 20%, respectively.     

Bovine Polyomavirus-1 (Epsilonpolyomavirus bovis): An Emerging Fetal Pathogen of Cattle That Causes Renal Lesions Resembling Polyomavirus-Associated Nephropathy of Humans

Bovine polyomavirus-1 (BoPyV-1, Epsilonpolyomavirus bovis) is widespread in cattle and has been detected in commercialized beef at supermarkets in the USA and Germany. BoPyV-1 has been questioned as a probable zoonotic agent with documented increase in seropositivity in people exposed to cattle. However, to date, BoPyV-1 has not been causally associated with pathology or disease in any animal species, including humans. Here we describe and illustrate pathological findings in an aborted bovine fetus naturally infected with BoPyV-1, providing evidence of its pathogenicity and probable abortigenic potential. Our results indicate that: (i) BoPyV-1 can cause severe kidney lesions in cattle, including tubulointerstitial nephritis with cytopathic changes and necrosis in tubular epithelial cells, tubular and interstitial inflammation, and interstitial fibroplasia; (ii) lesions are at least partly attributable to active viral replication in renal tubular epithelial cells, which have abundant intranuclear viral inclusions; (iii) BoPyV-1 large T (LT) antigen, resulting from early viral gene expression, can be detected in infected renal tubular epithelial cells using a monoclonal antibody raised against Simian Virus-40 polyomavirus LT antigen; and (iv) there is productive BoPyV-1 replication and virion assembly in the nuclei of renal tubular epithelial cells, as demonstrated by the ultrastructural observation of abundant arrays of viral particles with typical polyomavirus morphology. Altogether, these lesions resemble the “cytopathic-inflammatory pathology pattern” proposed in the pathogenesis of Human polyomavirus-1-associated nephropathy in immunocompromised people and kidney allograft recipients. Additionally, we sequenced the complete genome of the BoPyV-1 infecting the fetus, which represents the first whole genome of a BoPyV-1 from the Southern Hemisphere. Lastly, the BoPyV-1 strain infecting this fetus was isolated, causing a cytopathic effect in Madin–Darby bovine kidney cells. We conclude that BoPyV-1 is pathogenic to the bovine fetus under natural circumstances. Further insights into the epidemiology, biology, clinical relevance, and zoonotic potential of BoPyV-1 are needed.