Rpgrip1 is required for rod outer segment development and ciliary protein trafficking in zebrafish

The authors would like to thank the Royal Society of London, the National Eye Research Centre, the Visual Research Trust, Fight for Sight, the W.H. Ross Foundation, the Rosetrees Trust, and the Glasgow Children’s Hospital Charity for supporting this work. This work was also supported by the Deanship of Scientific Research at King Saud University for funding this research (Research Project) grant number ‘RGP – VPP – 219’.Mutations in the RPGR-interacting protein 1 (RPGRIP1) gene cause recessive Leber congenital amaurosis (LCA), juvenile retinitis pigmentosa (RP) and cone-rod dystrophy. RPGRIP1 interacts with other retinal disease-causing proteins and has been proposed to have a role in ciliary protein transport; however, its function remains elusive. Here, we describe a new zebrafish model carrying a nonsense mutation in the rpgrip1 gene. Rpgrip1homozygous mutants do not form rod outer segments and display mislocalization of rhodopsin, suggesting a role for RPGRIP1 in rhodopsin-bearing vesicle trafficking. Furthermore, Rab8, the key regulator of rhodopsin ciliary trafficking, was mislocalized in photoreceptor cells of rpgrip1 mutants. The degeneration of rod cells is early onset, followed by the death of cone cells. These phenotypes are similar to that observed in LCA and juvenile RP patients. Our data indicate RPGRIP1 is necessary for rod outer segment development through regulating ciliary protein trafficking. The rpgrip1 mutant zebrafish may provide a platform for developing therapeutic treatments for RP patients.Publisher PDFPeer reviewe

Nonlinear mixed effects modeling of gametocyte carriage in patients with uncomplicated malaria

<p>Abstract</p> <p>Background</p> <p>Gametocytes are the sexual form of the malaria parasite and the main agents of transmission. While there are several factors that influence host infectivity, the density of gametocytes appears to be the best single measure that is related to the human host's infectivity to mosquitoes. Despite the obviously important role that gametocytes play in the transmission of malaria and spread of anti-malarial resistance, it is common to estimate gametocyte carriage indirectly based on asexual parasite measurements. The objective of this research was to directly model observed gametocyte densities over time, during the primary infection.</p> <p>Methods</p> <p>Of 447 patients enrolled in sulphadoxine-pyrimethamine therapeutic efficacy studies in South Africa and Mozambique, a subset of 103 patients who had no gametocytes pre-treatment and who had at least three non-zero gametocyte densities over the 42-day follow up period were included in this analysis.</p> <p>Results</p> <p>A variety of different functions were examined. A modified version of the critical exponential function was selected for the final model given its robustness across different datasets and its flexibility in assuming a variety of different shapes. Age, site, initial asexual parasite density (logged to the base 10), and an empirical patient category were the co-variates that were found to improve the model.</p> <p>Conclusions</p> <p>A population nonlinear modeling approach seems promising and produced a flexible function whose estimates were stable across various different datasets. Surprisingly, dihydrofolate reductase and dihydropteroate synthetase mutation prevalence did not enter the model. This is probably related to a lack of power (quintuple mutations n = 12), and informative censoring; treatment failures were withdrawn from the study and given rescue treatment, usually prior to completion of follow up.</p

HealthKick: a nutrition and physical activity intervention for primary schools in low-income settings

<p>Abstract</p> <p>Background</p> <p>The burden of non-communicable diseases, including type 2 diabetes, is growing in South Africa. This country has a complex mix of over- and under-nutrition, especially in low-income communities, and concerning levels of physical inactivity in children and youth. This paper describes HealthKick, a school-based nutrition and physical activity intervention in primary schools in these settings aimed at reducing diabetes risk factors.</p> <p>Methods/Design</p> <p>This study includes schools within historically disadvantaged, low-income communities from an urban area close to the city of Cape Town and from two rural areas outside of Cape Town, South Africa. The three Educational Districts involved are Metropole North, Cape Winelands and the Overberg. The study has three phases: intervention mapping and formative assessment, intervention development, and outcome and process evaluation. Sixteen schools were purposively selected to participate in the study and randomly allocated as intervention (eight schools) and control (eight schools).</p> <p>The primary aims of HealthKick are to promote healthful eating habits and increase regular participation in health-enhancing physical activity in children, parents and teachers, to prevent overweight, and reduce risk of chronic diseases (particularly type 2 diabetes); as well as to promote the development of an environment within the school and community that facilitates the adoption of healthy lifestyles.</p> <p>The components of HealthKick are: action planning, toolkit (resource guide, a resource box and physical activity resource bin), and an Educators' Manual, which includes a curriculum component.</p> <p>Discussion</p> <p>This study continues to highlight the key role that educators play in implementing a school-based intervention, but that developing capacity within school staff and stakeholders is not a simple or easy task. In spite of the challenges experienced thus far, valuable findings are being produced from this study, especially from Phase 1. Materials developed could be disseminated to other schools in low-income settings both within and outside of South Africa. Owing to the novelty of the HealthKick intervention in low-income South African primary schools, the findings of the evaluation phase have the potential to impact on policy and practice within these settings.</p

Culture Adaptation Alters Transcriptional Hierarchies among Single Human Embryonic Stem Cells Reflecting Altered Patterns of Differentiation

We have used single cell transcriptome analysis to re-examine the substates of early passage, karyotypically Normal, and late passage, karyotypically Abnormal (‘Culture Adapted’) human embryonic stem cells characterized by differential expression of the cell surface marker antigen, SSEA3. The results confirmed that culture adaptation is associated with alterations to the dynamics of the SSEA3(+) and SSEA3(-) substates of these cells, with SSEA3(-) Adapted cells remaining within the stem cell compartment whereas the SSEA3(-) Normal cells appear to have differentiated. However, the single cell data reveal that these substates are characterized by further heterogeneity that changes on culture adaptation. Notably the Adapted population includes cells with a transcriptome substate suggestive of a shift to a more naïve-like phenotype in contrast to the cells of the Normal population. Further, a subset of the Normal SSEA3(+) cells expresses genes typical of endoderm differentiation, despite also expressing the undifferentiated stem cell genes, POU5F1 (OCT4) and NANOG, whereas such apparently lineage-primed cells are absent from the Adapted population. These results suggest that the selective growth advantage gained by genetically variant, culture adapted human embryonic stem cells may derive in part from a changed substate structure that influences their propensity for differentiation

Olive Oil effectively mitigates ovariectomy-induced osteoporosis in rats

<p>Abstract</p> <p>Background</p> <p>Osteoporosis, a reduction in bone mineral density, represents the most common metabolic bone disease. Postmenopausal women are particularly susceptible to osteoporosis when their production of estrogen declines. For these women, fracture is a leading cause of morbidity and mortality. This study was conducted to evaluate the protective effects of olive oil supplementation against osteoporosis in ovariectomized (OVX) rats.</p> <p>Methods</p> <p>We studied adult female Wistar rats aged 12-14 months, divided into three groups: sham-operated control (SHAM), ovariectomized (OVX), and ovariectomized rats supplemented with extravirgin olive oil (Olive-OVX) orally for 12 weeks; 4 weeks before ovariectomy and 8 weeks after. At the end of the experiment, blood samples were collected. Plasma levels of calcium, phosphorus, alkaline phosphatase (ALP), malondialdehyde (MDA), and nitrates were assayed. Specimens from both the tibia and the liver were processed for light microscopic examination. Histomorphometric analysis of the tibia was also performed.</p> <p>Results</p> <p>The OVX-rats showed a significant decrease in plasma calcium levels, and a significant increase in plasma ALP, MDA, and nitrates levels. These changes were attenuated by olive oil supplementation in the Olive-OVX rats. Light microscopic examination of the tibia of the OVX rats revealed a significant decrease in the cortical bone thickness (CBT) and the trabecular bone thickness (TBT). In addition, there was a significant increase in the osteoclast number denoting bone resorption. In the Olive-OVX rats these parameters were markedly improved as compared to the OVX group. Examination of the liver specimens revealed mononuclear cellular infiltration in the portal areas in the OVX-rats which was not detected in the Olive-OVX rats.</p> <p>Conclusions</p> <p>Olive oil effectively mitigated ovariectomy-induced osteoporosis in rats, and is a promising candidate for the treatment of postmenopausal osteoporosis.</p

Clinical Symptoms in Fibromyalgia Are Better Associated to Lipid Peroxidation Levels in Blood Mononuclear Cells Rather than in Plasma

This is an open-access article distributed under the terms of the Creative Commons Attribution License.[Background] We examined lipid peroxidation (LPO) in blood mononuclear cells (BMCs) and plasma, as a marker of oxidative damage, and its association to clinical symptoms in Fibromyalgia (FM) patients. [Methods]: We conducted a case–control and correlational study comparing 65 patients and 45 healthy controls. Clinical parameters were evaluated using the Fibromyalgia Impact Questionnaire (FIQ), visual analogues scales (VAS), and the Beck Depression Inventory (BDI). Oxidative stress was determined by measuring LPO in BMCs and plasma. [Results]: We found increased LPO levels in BMCs and plasma from FM patients as compared to normal control (P<0.001). A significant correlation between LPO in BMCs and clinical parameters was observed (r = 0.584, P<0.001 for VAS; r = 0.823, P<0.001 for FIQ total score; and r = 0.875, P<0.01 for depression in the BDI). We also found a positive correlation between LPO in plasma and clinical symptoms (r = 0.452, P<0.001 for VAS; r = 0.578, P<0.001 for FIQ total score; and r = 0.579, P<0.001 for depression in the BDI). Partial correlation analysis controlling for age and BMI, and sex, showed that both LPO in cells and plasma were independently associated to clinical symptoms. However, LPO in cells, but not LPO in plasma, was independently associated to clinical symptoms when controlling for depression (BDI scores). [Discussion]: The results of this study suggest a role for oxidative stress in the pathophysiology of fibromyalgia and that LPO in BMCs rather than LPO in plasma is better associated to clinical symptoms in FM.This work was supported by Spanish FIS PI080500 grant, and FIS EC08/00076 grant, Ministerio de Sanidad, Spain, and Federación Andaluza de Fibromialgia y Fatiga Crónica (ALBA Andalucía). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewe

Effect of venlafaxine on bone loss associated with ligature-induced periodontitis in Wistar rats

<p>Abstract</p> <p>Background</p> <p>The present study investigated the effects of venlafaxine, an antidepressant drug with immunoregulatory properties on the inflammatory response and bone loss associated with experimental periodontal disease (EPD).</p> <p>Materials and Methods</p> <p>Wistar rats were subjected to a ligature placement around the second upper left molar. The treated groups received orally venlafaxine (10 or 50 mg/kg) one hour before the experimental periodontal disease induction and daily for 10 days. Vehicle-treated experimental periodontal disease and a sham-operated (SO) controls were included. Bone loss was analyzed morphometrically and histopathological analysis was based on cell influx, alveolar bone, and cementum integrity. Lipid peroxidation quantification and immunohistochemistry to TNF-α and iNOS were performed.</p> <p>Results</p> <p>Experimental periodontal disease rats showed an intense bone loss compared to SO ones (SO = 1.61 ± 1.36; EPD = 4.47 ± 1.98 mm, p < 0.001) and evidenced increased cellular infiltration and immunoreactivity for TNF-α and iNOS. Venlafaxine treatment while at low dose (10 mg/kg) afforded no significant protection against bone loss (3.25 ± 1.26 mm), a high dose (50 mg/kg) caused significantly enhanced bone loss (6.81 ± 3.31 mm, p < 0.05). Venlafaxine effectively decreased the lipid peroxidation but showed no significant change in TNF-α or iNOS immunoreactivity.</p> <p>Conclusion</p> <p>The increased bone loss associated with high dose venlafaxine may possibly be a result of synaptic inhibition of serotonin uptake.</p

Antihypertensive and antioxidant effects of dietary black sesame meal in pre-hypertensive humans

<p>Abstract</p> <p>Background</p> <p>It has been known that hypertension is an independent risk factor for cardiovascular disease (CVD). CVD is the major cause of morbidity and mortality in developed and developing countries. Elevation of blood pressure (BP) increases the adverse effect for cardiovascular outcomes. Prevention of increased BP plays a crucial role in a reduction of those outcomes, leading to a decrease in mortality. Therefore, the purpose of this study was to investigate the effects of dietary black sesame meal on BP and oxidative stress in individuals with prehypertension.</p> <p>Methods</p> <p>Twenty-two women and eight men (aged 49.8 ± 6.6 years) with prehypertension were randomly divided into two groups, 15 subjects per group. They ingested 2.52 g black sesame meal capsules or placebo capsules each day for 4 weeks. Blood samples were obtained after overnight fasting for measurement of plasma lipid, malondialdehyde (MDA) and vitamin E levels. Anthropometry, body composition and BP were measured before and after 4-week administration of black sesame meal or a placebo.</p> <p>Results</p> <p>The results showed that 4-week administration of black sesame meal significantly decreased systolic BP (129.3 ± 6.8 vs. 121.0 ± 9.0 mmHg, <it>P </it>< 0.05) and MDA level (1.8 ± 0.6 vs. 1.2 ± 0.6 μmol/L, <it>P </it>< 0.05), and increased vitamin E level (29.4 ± 6.0 vs. 38.2 ± 7.8 μmol/L, <it>P </it>< 0.01). In the black sesame meal group, the change in SBP tended to be positively related to the change in MDA (<it>R = 0.50, P </it>= 0.05), while the change in DBP was negatively related to the change in vitamin E (<it>R = -0.55, P </it>< 0.05). There were no correlations between changes in BP and oxidative stress in the control group.</p> <p>Conclusions</p> <p>These results suggest the possible antihypertensive effects of black sesame meal on improving antioxidant status and decreasing oxidant stress. These data may imply a beneficial effect of black sesame meal on prevention of CVD.</p