The association of maternal nutrition and children's pre-primary experience with over-age attendance in secondary school: evidence from lowland Nepal.

•Over-age attendance is increasing but remains under-studied in South Asia.•Children fall behind by entering pre-primary or primary late, and by repeating a grade during/after primary school.•Rural location, thin and uneducated mothers predicted late pre-primary entry.•Educational research and interventions need to focus on the earlier time-point of pre-primary.•Improving maternal nutrition and education may ensure timely progression of children in school.

Pulse wave velocity during re-feeding and with weight gain in underweight female adolescents with anorexia nervosa.

Anorexia Nervosa (AN) causes harmful underweight and important cardiovascular acute complications however less is known about longer-term cardiovascular risk. We measured carotid femoral pulse wave velocity (PWV) in a group of underweight young women with AN at baseline and weekly as they were refed and gained weight. PWV decreased over time and was negatively associated with increasing BMI and calorific meal content suggesting potential positive cardiovascular benefits for refeeding and weight gain in AN and supports current consensus for the importance of weight gain in underweight young women with AN.

Estimating the number of vertically HIV-infected children eligible for antiretroviral treatment in resource-limited settings.

BACKGROUND: With the gradual roll-out of antiretroviral therapy (ART) to delay progression of HIV disease in children in programmes across sub-Saharan Africa and resource-limited settings elsewhere, reliable information on the number of vertically infected children eligible for such treatment is urgently required. METHODS: We present a model to estimate the number of vertically HIV-infected children by age who have progressed to moderate to severe disease (MSD) and as such are eligible for ART on the basis of clinical disease, allowing for: antenatal HIV prevalence, use of interventions to prevent mother-to-child transmission (PMTCT), infant feeding policies and availability of co-trimoxazole to prevent opportunistic infections that may hasten the onset of serious disease. The model assumptions were informed by published evidence and expert opinion; rates of progression to serious disease were inferred from mortality of infected and uninfected children of HIV-infected mothers; and mortality among children treated with ART was based on a study of treated children in Abidjan. To allow widespread use the model has been developed using the Excel spreadsheet software. RESULTS: With South Africa as a hypothetical example, published antenatal prevalence and demographic data, and assuming PMTCT coverage with single dose nevirapine of 11%, all exposed and infected children receive co-trimoxazole, and various infant feeding policy scenarios, estimated numbers of children eligible for ART are presented. CONCLUSIONS: This model is easy to implement and flexible and can be used in ART programmes at national and local level.

Expression of nitric oxide synthase immunoreactivity in the human female intramural striated urethral sphincter.

PURPOSE: While we have recently detected neuronal nitric oxide synthase (nNOS) immunoreactivity in a heterogeneous population of human male urethral striated muscle, to our knowledge the association of nNOS in the female counterpart is unknown. We investigated the association of nNOS with female urethral striated muscle and re-investigated muscle fiber types. MATERIALS AND METHODS: Cryostat sections were taken from the middle third of 4 human female urethras. Nicotinamide adenine dinucleotide phosphate diaphorase histochemistry and nNOS immunohistochemistry were performed. Muscle fiber types were identified by myofibrillar adenosine triphosphatase histochemistry and fast twitch troponin T immunohistochemistry. The association between nNOS immunoreactivity and muscle fiber type was analyzed. RESULTS: Positive staining for nicotinamide adenine dinucleotide phosphate diaphorase histochemistry and nNOS immunoreactivity were recognized in the sarcolemma of 43.9% of female urethral striated muscle fibers. Immunoreactivity for fast twitch troponin T immunohistochemistry was demonstrated by 2% of the striated fibers. The use of myofibrillar adenosine triphosphatase showed that all fibers darkly stained uniformly at a pH of 9.6, 4.6 and 4.3, suggesting that they were myofibrillar intermediate muscle fibers. The results allowed the differentiation of 2 subgroups of fibers, namely smaller fibers (modal diameter 10.1 to 15.0 microm.) without nNOS immunoreactivity and larger fibers (modal diameter 15.1 to 20.0 microm.) with nNOS immunoreactivity. CONCLUSIONS: To our knowledge female urethral striated muscle has for the first time been found to consist of myofibrillar intermediate fibers and nNOS was positively localized in the sarcolemma of a subgroup of the fibers. This study provides a basis for further investigation into female urethral striated sphincter function and changes in pathological conditions.

Improved outcome of N-butyldeoxygalactonojirimycin-mediated substrate reduction therapy in a mouse model of Sandhoff disease.

Sandhoff disease is a severe neurodegenerative glycosphingolipid (GSL) lysosomal storage disorder, currently without treatment options. One therapeutic approach under investigation is substrate reduction therapy (SRT). By partially inhibiting GSL biosynthesis, the impaired rate of GSL catabolism is balanced by a slower rate of influx of GSLs into the lysosome. In a previous study, we reported the beneficial effects of treating Sandhoff disease mice with the glucose analogue N-butyldeoxynojirimycin (NB-DNJ), a compound that inhibits the first step of GSL biosynthesis catalysed by the ceramide specific glucosyltransferase. NB-DNJ, however, exhibits adverse effects at high doses such as weight loss and GI tract distress (due to glucosidase inhibition). This might limit the therapeutic potential of NB-DNJ for treating diseases affecting the CNS where high dose therapy may be required to achieve therapeutic levels of the drug in the brain. In the present study, a more selective compound, the galactose analogue N-butyldeoxygalactonojirimycin (NB-DGJ), was evaluated in the Sandhoff disease mouse model. Treatment with NB-DGJ showed greater therapeutic efficacy than NB-DNJ with no detectable side effects. The ability to escalate the dose of NB-DGJ, leading to extended life expectancy and increased delay in symptom onset, demonstrates the greater therapeutic potential of NB-DGJ for the treatment of the human gangliosidoses.

Prediction of improved vision in the amblyopic eye after visual loss in the non-amblyopic eye.

Amblyopia arises from abnormal visual experiences in early childhood. Improved function of the amblyopic eye after visual loss in the non-amblyopic eye could be a model for residual neural plasticity. We aimed to establish the likelihood of, and predictive factors for, this improvement in function. We identified 254 individuals aged 11 years or older with unilateral amblyopia who were visually impaired after loss of vision in their non-amblyopic eye but had no other disorder affecting their amblyopic eye. 25 (10%) of 254 people had improved visual acuity in their amblyopic eye. These findings suggest there is some plasticity in the visual system of a few visually mature individuals with amblyopia, which warrants further study. Children should remain the focus of detection and treatment.

NSAIDs increase survival in the Sandhoff disease mouse: synergy with N-butyldeoxynojirimycin.

The GM2 gangliosidoses are caused by incomplete catabolism of GM2 ganglioside in the lysosome, leading to progressive storage and a neurodegenerative clinical course. An inflammatory response (microglial activation, macrophage infiltration, oxidative damage) has been found to be a consequence of GM2 storage in the brain, although it remains unclear whether this contributes to pathogenesis or disease progression. In this study, we treated Sandhoff disease mice with nonsteroidal antiinflammatory drugs (indomethacin, aspirin, and ibuprofen) and antioxidants (L-ascorbic acid and alpha-tocopherol acetate). The treated mice lived significantly longer than untreated littermates (12-23%, p <0.0001) and showed a slower rate of disease progression (p <0.001). When aspirin treatment was combined with substrate reduction therapy, synergy resulted (11%, p <0.05) with a maximum improvement of 73% in survival (p <0.00001). This study demonstrates that inflammation contributes to disease progression and identifies antiinflammatory and antioxidant therapies as a potential adjunctive approach to slow the clinical course of this and related disorders.