A clinical and genetic study of 56 Saudi Wilson disease patients: identification of Saudi-specific mutations

Wilson disease (WD) is a hereditary disorder, with recessive transmission and genetic heterogeneity. Several mutations of ATP7B, the gene underlying WD, were reported in many ethnic groups. In this study, mutation screening in ATP7B of 56 Saudi Arabian WD patients was undertaken. The clinical data of all patients were recorded. The entire ATP7B coding sequence, including intron-exon boundaries were screened for mutation by the polymerase chain reaction (PCR)-based mutation detection technique and DNA sequencing. Thirty-nine patients were symptomatic at presentation and 17 subjects were pre-symptomatic siblings of affected patients. Fourteen patients had neurological, 11 patients had mixed (hepatic and neurological), and 14 patients had hepatic presentations. Family history suggestive of WD was present in 72% of cases and 68% had consanguineous parents. Genetic analysis showed disease-causing mutations in three exons (exons 8, 19 and 21) of the ATP7B gene in 28 patients (50%). Mutations in exons 21 (18 cases) and 19 (one case) were unique for Saudis. This large series of Saudi patients with WD has shown wide variability in the genomic substrate of WD. There is no correlation between genotype and clinical presentation.     

Safety and efficacy of weight training in recent breast cancer survivors to alter body composition, insulin, and insulin-like growth factor axis proteins.

BACKGROUND: This randomized controlled trial assessed the safety and effects of twice-weekly weight training among recent breast cancer survivors. Outcomes included body size and biomarkers hypothesized to link exercise and breast cancer risk. METHODS: A convenience sample of 85 recent survivors was randomized into immediate and delayed treatment groups. The immediate group trained from months 0 to 12; the delayed treatment group served as a no exercise parallel comparison group from months 0 to 6 and trained from months 7 to 12. Measures at baseline, 6 and 12 months included body weight, height, body fat, lean mass, body fat %, and waist circumference, as well as fasting glucose, insulin, insulin resistance, insulin-like growth factor-I (IGF-I), IGF-II, and IGF-binding protein-1, IGFBP-2, and IGFBP-3. Injury reporting was standardized. RESULTS: The intervention resulted in significant increases in lean mass (0.88 versus 0.02 kg, P < 0.01), as well as significant decreases in body fat % (-1.15% versus 0.23%, P = 0.03) and IGF-II (-6.23 versus 28.28 ng/mL, P = 0.02) comparing immediate with delayed treatment from baseline to 6 months. Within-person changes experienced by delayed treatment group participants during training versus no training were similar. Only one participant experienced a study related injury that prevented continued participation. CONCLUSION: Twice-weekly weight training is a safe exercise program for recent breast cancer survivors that may result in increased muscle mass, as well as decreased body fat % and IGF-II. The implications of these results on cancer recurrence or survival may become more evident with longer exercise intervention trials among breast cancer survivors.     

Teaching Pharmacology Graduate Students how to Write an NIH Grant Application

Objective. To fill the gap in grant writing training in pharmacology graduate education using an active-learning strategy.Design. Graduate students wrote subsections of a grant according to NIH guidelines. Students revised their applications based on multiple rounds of critiques from professors and peers throughout a semester-long scientific writing course.Assessment. Prerevision and postrevision grant drafts were graded. Students were provided with questionnaires assessing their perception of the process. To determine the impact of feedback on the proposals, the quality of the pre/postrevision drafts was assessed by professors who were blinded and unaffiliated with the course.Conclusion. Student grades improved significantly upon resubmission. Perceptions of the proposals by blinded faculty members favored revised submissions based on multiple criteria. Survey feedback indicated an increase in student confidence in grant writing ability. The results of 3 independent measures demonstrate that intensive feedback on scientific writing improved the quality of student proposals.     

Hybrid BiOBr/UiO-66-NH2 composite with enhanced visible-light driven photocatalytic activity toward RhB dye degradation

Metal–organic framework (MOFs) based composites have received more research interest for photocatalytic applications during recent years. In this work, a highly active, visible light photocatalyst BiOBr/UiO-66-NH₂ hybrid composite was successfully prepared by introducing various amounts of UiO-66-NH₂ with BiOBr through a co-precipitation method. The composites were applied for the photocatalytic degradation of RhB (rhodamine B) dye. The developed BiOBr/UiO-66-NH₂ composites exhibited higher photocatalytic activity than the pristine material. In RhB degradation experiments the hybrid composite with 15 wt% of UiO-66-NH₂ shows degradation efficiency conversion of 83% within two hours under visible light irradiation. The high photodegradation efficiency of BUN-15 could be ascribed to efficient interfacial charge transfer at the heterojunction and the synergistic effect between BiOBr/UiO-66-NH₂. In addition, an active species trapping experiment confirmed that photo-generated hole⁺ and O₂⁻ radicals are the major species involved in RhB degradation under visible light.

Metal–organic framework (MOFs) based composites have received more research interest for photocatalytic applications during recent years.     

The effect of different storage media on the monomer elution and hardness of CAD/CAM composite blocks

ObjectiveThis study aimed to assess the effect of different storage media on the hardness and monomer elution of CAD/CAM composite blocks.MethodsFive resin-composite blocks (RCB), one polymer-infiltrated ceramic network (PICN) block (Enamic (EN)), one ceramic-filled poly ether ether ketone (PEEK) block (Dentokeep (DK)), and one feldspathic ceramic block. Microhardness was measured using a Vickers indenter tester (FM-700, Future Tech Corp., Japan). In addition 4 conventional resin-composites were investigated for monomer elution using high performance liquid chromatography (HPLC) after storage in different media for 3 months. The data were analysed by three-way ANOVA, two-way ANOVA, one-way ANOVA, Tukey’s post hoc test and the independent t-test (α = 0.05 for all tests).ResultsThe specimens stored in the water had a hardness reduction ranging from 0.9% to 24.4%. In artificial saliva, the specimens had a hardness reduction ranging from 2.8% to 23.2%. The hardness reduction percentage in 75% Ethanol/Water (E/W) ranged between 3.8% and 35.3%. All materials, except GR (resin-composite block) and DK (Polyetheretherketone (PEEK)), showed a variable extent of monomer elution into 75% E/W with significantly higher amounts eluted from conventional composites. GRA and GND (conventional resin-composites) eluted TEGDMA in artificial saliva and GRA eluted TEGDMA in water.SignificanceThe hardness of CAD/CAM composite blocks was affected by different storage media, and they were not as stable as ceramic, with PICN exhibited superior hardness stability to all of the resin-composite blocks in all the storage media and was comparable to ceramic block. The hardness reduction percentage of the CAD/CAM composite blocks was influenced by the filler loading and resin-matrix composition.Minimal or no monomer elution from CAD/CAM blocks was detected.     

Association Between Gut Microbial Abundance and Sight-Threatening Diabetic Retinopathy

PurposeTo study the association between gut microbial abundance and sight-threatening diabetic retinopathy among patients with a history of type 2 diabetes mellitus.MethodsAn observational case-control study was performed using a sample population of diabetics referred to a tertiary eye institute. Sample subjects were identified as cases if they were diagnosed with sight-threatening diabetic retinopathy and controls if they were not but had at least a 10-year history of diabetes. Fecal swabs for all patients were collected for enumeration and identification of sequenced gut microbes. Statistical analyses were performed to associate the clinically relevant Bacteroidetes to Firmicutes relative abundance ratio (B/F ratio) with sight-threatening diabetic retinopathy and an optimal cutoff value for the ratio was identified using Youden''s J statistics.ResultsA sample size of 58 diabetic patients was selected (37 cases, 21 controls). No statistically significant difference in the relative abundance among the predominant phyla between the groups were found. In our univariate analysis, the B/F ratio was elevated in cases compared to controls (cases, 1.45; controls, 0.94; P = 0.049). However, this statistically significant difference was not seen in our multivariate regression model. Optimal cutoff value of 1.05 for the B/F ratio was identified, and significant clustering of cases above this value was noted in beta diversity plotting.ConclusionsNo difference in gut microbial abundance for any particular phylum was noted between the control and diseased population. Increased gut microbial B/F ratio can be a potential biomarker for the development of sight-threatening diabetic retinopathy among type 2 diabetic patients.     

CD28:B7 interaction is necessary for the protective effect of T cell vaccination in EAE

The mechanisms of T cell vaccination (TCV) are still unclear, especially the molecular interactions for recognition of autoreactive T cells by the immune system. Here we investigated the role of CD28:B7 interaction in TCV-induced protection in the murine EAE model. We demonstrate that there is increased expression of both B7-1 and B7-2 on autoreactive Th1 cells compared to Th2 cells. Blockade of B7 on the vaccinating autoreactive T cell surface or blockade of CD28 in recipient mice reduced the protective effect of TCV. Furthermore, we showed that TCV significantly inhibited Ag-specific CD4 and CD8 T cell proliferation and decreased Ag-specific IFN-gamma production by CD4 T cells in mice undergoing TCV, and blocking of B7 on the surface of vaccinating T cells reduced this inhibition on Ag-specific CD4 and CD8 T cell proliferation, more significantly on Ag-specific CD4 T cell proliferation. These data indicated that B7 expression on autoreactive T cells is necessary for the recognition of autoreactive T cells by the immune system and subsequent protection from EAE in mice undergoing TCV.     

A qualitative assessment of health seeking practices among and provision practices for men who have sex with men in Malawi

Background

In the context of a generalized epidemic and criminalization of homosexuality, men who have sex with men (MSM) in Malawi have a disproportionate burden of HIV compared to other adults. Past research has documented low uptake of HIV prevention and health services among MSM, self-reported fear of seeking health services, and concerns of disclosure of sexual orientation and discrimination in health settings. Qualitative research was conducted among MSM and health service providers in Blantyre, Malawi to understand underlying factors related to disclosure and health seeking behaviors and inform the development of a community-based comprehensive HIV prevention intervention.

Methods

Using peer recruitment, eight MSM participants representing a range of ages, orientations, and social and behavioral characteristics were enrolled for in-depth interviews. Five service providers were recruited from the district hospital, local health and STI clinics, and a HIV prevention service organization. We use the Health Belief Model as a framework to interpret the influential factors on 1) health seeking and uptake among MSM, and 2) influences on provision of services by healthcare providers for MSM.

Results

Results highlight disclosure fears among MSM and, among providers, a lack of awareness and self-efficacy to provide care in the face of limited information and political support. Service providers reported concerns of adverse repercussions related to the provision of services to men in same sex sexual relationships. Some MSM demonstrated awareness of HIV risk but believed that within the wider MSM community, there was a general lack of HIV information for MSM, low awareness of appropriate prevention, and low perception of risks related to HIV infection.

Conclusions

Qualitative research highlights the need for appropriate information on both HIV risks and acceptable, effective HIV prevention options for MSM. Information and educational opportunities should be available to the wider MSM community and the health sector. Health sector interventions may serve to increase cultural and clinical competency to address health problems experienced by MSM. To ensure availability and use of services in light of the criminalization and stigmatization of same sex practices, there is need to increase the safety of uptake and provision of these services for MSM.

     

Complement C3 isoforms in Austrelaps superbus

Complement C3 plays a pivotal role in both classical and alternate pathways. Lower organisms (urochordates and fishes) have multiple isoforms whereas higher organisms have a single C3 gene. In cobras, a closely related protein cobra venom factor (CVF) is expressed in their venom gland. We have recently shown that Austrelaps superbus contains two isoforms (AVF-1 and AVF-2) of CVF-like proteins in the venom gland. To understand the origin of these proteins and their similarity to C3 protein, we examined C3-like proteins in the liver. Here we describe the complete cDNA sequences of two isoforms (AsC3-1 and AsC3-2) of complement C3 found in A. superbus liver. This is the first report of molecular isoforms of C3 in a reptilian organism. These isoforms display the overall domain structure of complement C3 proteins. Real-time quantitative analysis shows that there is a 144-fold difference in their mRNA expression levels. We also demonstrate by Southern blot experiments that the venom gland isoforms (AVF-1 and AVF-2) and the liver isoforms (AsC3-1 and AsC3-2) are the products of four individual genes. The putative promoter regions of these four genes are highly similar ( approximately 99% identical) to each other. These genes represent a unique case where despite being identical at the genomic level, exhibit tissue specificity and differential gene regulation. These genes offer a system to identify the tissue-specific regulatory proteins that are responsible for the constitutive expression of complement C3 in liver and inducible expression of AVF genes in the venom gland of A. superbus.