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.     

The role of pancreatic venous sampling in the localization of occult insulinomas

The palpation and enucleation of occult insulinomas (less than 15 mm) can be a difficult surgical problem even with good arteriographic localization. In the authors' limited experience, confirmation of arteriographic findings by pancreatic venous sampling provided little additional localizing information. However, if arteriography is negative or equivocal, venous sampling can indicate the segment of pancreas to be "blindly" resected if the adenoma is not palpable. Venous sampling may be misleading in polyendocrine syndromes because of the frequency of multiple adenomas and variable hormone production.     

Takayasu''s aortitis with renovascular hypertension

We report a case of Takayasu's disease with severe renovascular hypertension in a girl from Eritrea. In the "burn-out" phase after the erythrocyte sedimentation rate had normalized, reconstructive vascular surgery was performed as further progression of the disease seemed unlikely. However, probably due to her growth, the graft rotated and a second operation was successfully performed.     

Rising incidence of type 1 diabetes in Scottish children, 1984-93. The Scottish Study Group for the Care of Young Diabetics

OBJECTIVES: To calculate the incidence of type 1 diabetes in Scottish children aged less than 15 years between 1984 and 1993; to examine changes in incidence; and to calculate the prevalence of diabetes at the end of this period. DESIGN: Three data sources were used to construct the Scottish Study Group for the Care of Young Diabetics register: active reporting of all new cases; reports from the Scottish Morbidity Register 1; and local registers. SUBJECTS: All children resident in Scotland diagnosed with primary insulin dependent diabetes mellitus when less than 15 years of age between 1984 and 1993. MAIN OUTCOME MEASURES: Annual incidence and prevalence rate for Scotland; time trend in incidence over the 10 years; differences in incidence between the three different age groups; and completeness of the register. RESULTS: The average annual incidence for Scotland was 23.9/100,000 children. The prevalence rate was 1.5/1000 in 1993. A total of 2326 cases was identified from the three sources. Capture-recapture analysis suggests a case ascertainment of 98.6%. The annual incidence rates increased at a rate of 2% each year (rate ratio = 1.02, 95% confidence interval (CI) 1.01 to 1.03). The incidence was higher in boys than girls (rate ratio = 1.08, 95% CI 1.00 to 1.18), and the incidence rates increased with age: 15.3/100,000/year for age 0-4 years, 24.4/ 100,000/year for age 5-9 years, and 31.9/ 100,000/year for age 10-14 years. CONCLUSIONS: The incidence of type 1 diabetes in Scotland is increasing and the prevalence is relatively high. These findings have important implications for health service resource allocation. The Scottish Study Group for the Care of Young Diabetics' register provides a base for monitoring and research.     

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.     

Molecular basis of telomere syndrome caused by CTC1 mutations

Mutations in CTC1 lead to the telomere syndromes Coats Plus and dyskeratosis congenita (DC), but the molecular mechanisms involved remain unknown. CTC1 forms with STN1 and TEN1 a trimeric complex termed CST, which binds ssDNA, promotes telomere DNA synthesis, and inhibits telomerase-mediated telomere elongation. Here we identify CTC1 disease mutations that disrupt CST complex formation, the physical interaction with DNA polymerase α-primase (polα-primase), telomeric ssDNA binding in vitro, accumulation in the nucleus, and/or telomere association in vivo. While having diverse molecular defects, CTC1 mutations commonly lead to the accumulation of internal single-stranded gaps of telomeric DNA, suggesting telomere DNA replication defects as a primary cause of the disease. Strikingly, mutations in CTC1 may also unleash telomerase repression and telomere length control. Hence, the telomere defect initiated by CTC1 mutations is distinct from the telomerase insufficiencies seen in classical forms of telomere syndromes, which cause short telomeres due to reduced maintenance of distal telomeric ends by telomerase. Our analysis provides molecular evidence that CST collaborates with DNA polα-primase to promote faithful telomere DNA replication.     

Optimization of the High-Shear Wet Granulation Wetting Process Using Fuzzy Logic Modeling

A fuzzy model has been developed for the optimization of high-shear wet granulation wetting on a plant scale depending on the characteristics of pharmaceutical active substance particles. The model optimized on the basis of experimental data involves a set of rules obtained from expert knowledge and full-scale process data. The skewness coefficient of particle size distribution and the tapped density of the granulated mixture were chosen as the model input variables. The output of the fuzzy ruled system is the optimal quantity of wetting liquid. In comparison to manufacturing practice, a very strong sensitivity of the optimal quantity of the added wetting liquid to the size and shape of the active substance particles has been identified by fuzzy modeling.