Transgenic Rescue of the LARGEmyd Mouse: A LARGE Therapeutic Window?

LARGE is a glycosyltransferase involved in glycosylation of α-dystroglycan (α-DG). Absence of this protein in the LARGEmyd mouse results in α-DG hypoglycosylation, and is associated with central nervous system abnormalities and progressive muscular dystrophy. Up-regulation of LARGE has previously been proposed as a therapy for the secondary dystroglycanopathies: overexpression in cells compensates for defects in multiple dystroglycanopathy genes. Counterintuitively, LARGE overexpression in an FKRP-deficient mouse exacerbates pathology, suggesting that modulation of α-DG glycosylation requires further investigation. Here we demonstrate that transgenic expression of human LARGE (LARGE-LV5) in the LARGEmyd mouse restores α-DG glycosylation (with marked hyperglycosylation in muscle) and that this corrects both the muscle pathology and brain architecture. By quantitative analyses of LARGE transcripts we also here show that levels of transgenic and endogenous LARGE in the brains of transgenic animals are comparable, but that the transgene is markedly overexpressed in heart and particularly skeletal muscle (20–100 fold over endogenous). Our data suggest LARGE overexpression may only be deleterious under a forced regenerative context, such as that resulting from a reduction in FKRP: in the absence of such a defect we show that systemic expression of LARGE can indeed act therapeutically, and that even dramatic LARGE overexpression is well-tolerated in heart and skeletal muscle. Moreover, correction of LARGEmyd brain pathology with only moderate, near-physiological LARGE expression suggests a generous therapeutic window

An assessment of routine primary care health information system data quality in Sofala Province, Mozambique

<p>Abstract</p> <p>Background</p> <p>Primary health care is recognized as a main driver of equitable health service delivery. For it to function optimally, routine health information systems (HIS) are necessary to ensure adequate provision of health care and the development of appropriate health policies. Concerns about the quality of routine administrative data have undermined their use in resource-limited settings. This evaluation was designed to describe the availability, reliability, and validity of a sample of primary health care HIS data from nine health facilities across three districts in Sofala Province, Mozambique. HIS data were also compared with results from large community-based surveys.</p> <p>Methodology</p> <p>We used a methodology similar to the Global Fund to Fight AIDS, Tuberculosis and Malaria data verification bottom-up audit to assess primary health care HIS data availability and reliability. The quality of HIS data was validated by comparing three key indicators (antenatal care, institutional birth, and third diptheria, pertussis, and tetanus [DPT] immunization) with population-level surveys over time.</p> <p>Results and discussion</p> <p>The data concordance from facility clinical registries to monthly facility reports on five key indicators--the number of first antenatal care visits, institutional births, third DPT immunization, HIV testing, and outpatient consults--was good (80%). When two sites were excluded from the analysis, the concordance was markedly better (92%). Of monthly facility reports for immunization and maternity services, 98% were available in paper form at district health departments and 98% of immunization and maternity services monthly facility reports matched the Ministry of Health electronic database. Population-level health survey and HIS data were strongly correlated (R = 0.73), for institutional birth, first antenatal care visit, and third DPT immunization.</p> <p>Conclusions</p> <p>Our results suggest that in this setting, HIS data are both reliable and consistent, supporting their use in primary health care program monitoring and evaluation. Simple, rapid tools can be used to evaluate routine data and facilitate the rapid identification of problem areas.</p

A global climatology of the mesospheric sodium layerfrom GOMOS data during the 2002-2008 period

This paper presents a climatology of the mesospheric sodium layer built from the processing of 7 years of GOMOS data. With respect to preliminary results already published for the year 2003, a more careful analysis was applied to the averaging of occultations inside the climatological bins (10° in latitude-1 month). Also, the slant path absorption lines of the Na doublet around 589 nm shows evidence of partial saturation that was responsible for an underestimation of the Na concentration in our previous results. The sodium climatology has been validated with respect to the Fort Collins lidar measurements and, to a lesser extent, to the OSIRIS 2003–2004 data. Despite the important natural sodium variability, we have shown that the Na vertical column has a marked semi-annual oscillation at low latitudes that merges into an annual oscillation in the polar regions, a spatial distribution pattern that was unreported so far. The sodium layer seems to be clearly influenced by the mesospheric global circulation and the altitude of the layer shows clear signs of subsidence during polar winter. The climatology has been parameterized by time-latitude robust fits to allow for easy use. Taking into account the non-linearity of the transmittance due to partial saturation, an experimental approach is proposed to derive mesospheric temperatures from limb remote sounding measurements

Overexpression of transmembrane protein 168 in the mouse nucleus accumbens induces anxiety and sensorimotor gating deficit

Transmembrane protein 168 (TMEM168) comprises 697 amino acid residues, including some putative transmembrane domains. It is reported that TMEM168 controls methamphetamine (METH) dependence in the nucleus accumbens (NAc) of mice. Moreover, a strong link between METH dependence-induced adaptive changes in the brain and mood disorders has been evaluated. In the present study, we investigated the effects of accumbal TMEM168 in a battery of behavioral paradigms. The adeno-associated virus (AAV) Tmem168 vector was injected into the NAc of C57BL/6J mice (NAc-TMEM mice). Subsequently, the accumbal TMEM168 mRNA was increased approximately by seven-fold when compared with the NAc-Mock mice (controls). The NAc-TMEM mice reported no change in the locomotor activity, cognitive ability, social interaction, and depression-like behaviors; however, TMEM168 overexpression enhanced anxiety in the elevated-plus maze and light/dark box test. The increased anxiety was reversed by pretreatment with the antianxiety drug diazepam (0.3 mg/kg i.p.). Moreover, the NAc-TMEM mice exhibited decreased prepulse inhibition (PPI) in the startle response test, and the induced schizophrenia-like behavior was reversed by pretreatment with the antipsychotic drug risperidone (0.01 mg/kg i.p.). Furthermore, accumbal TMEM168 overexpression decreased the basal levels of extracellular GABA in the NAc and the high K+ (100 mM)-stimulated GABA elevation; however, the total contents of GABA in the NAc remained unaffected. These results suggest that the TMEM168-regulated GABAergic neuronal system in the NAc might become a novel target while studying the etiology of anxiety and sensorimotor gating deficits

Non-invasive ventilation in obesity hypoventilation syndrome without severe obstructive sleep apnoea

Background Non-invasive ventilation (NIV) is an effective form of treatment in patients with obesity hypoventilation syndrome (OHS) who have concomitant severe obstructive sleep apnoea (OSA). However, there is a paucity of evidence on the efficacy of NIV in patients with OHS without severe OSA. We performed a multicentre randomised clinical trial to determine the comparative efficacy of NIV versus lifestyle modification (control group) using daytime arterial carbon dioxide tension (PaCO2) as the main outcome measure. Methods Between May 2009 and December 2014 we sequentially screened patients with OHS without severe OSA. Participants were randomised to NIV versus lifestyle modification and were followed for 2 months. Arterial blood gas parameters, clinical symptoms, health-related quality of life assessments, polysomnography, spirometry, 6-min walk distance test, blood pressure measurements and healthcare resource utilisation were evaluated. Statistical analysis was performed using intention-to-treat analysis. Results A total of 365 patients were screened of whom 58 were excluded. Severe OSA was present in 221 and the remaining 86 patients without severe OSA were randomised. NIV led to a significantly larger improvement in PaCO2 of -6 (95% CI -7.7 to -4.2) mm Hg versus -2.8 (95% CI -4.3 to -1.3) mm Hg, (p<0.001) and serum bicarbonate of -3.4 (95% CI -4.5 to -2.3) versus -1 (95% CI -1.7 to -0.2 95% CI) mmol/L (p<0.001). PaCO2 change adjusted for NIV compliance did not further improve the inter-group statistical significance. Sleepiness, some health-related quality of life assessments and polysomnographic parameters improved significantly more with NIV than with lifestyle modification. Additionally, there was a tendency towards lower healthcare resource utilisation in the NIV group. Conclusions NIV is more effective than lifestyle modification in improving daytime PaCO2, sleepiness and polysomnographic parameters. Long-term prospective studies are necessary to determine whether NIV reduces healthcare resource utilisation, cardiovascular events and mortality

Inhibitory Role of Inducible cAMP Early Repressor (ICER) in Methamphetamine-Induced Locomotor Sensitization

BACKGROUND: The inducible cyclic adenosine monophosphate (cAMP) early repressor (ICER) is highly expressed in the central nervous system and functions as a repressor of cAMP response element-binding protein (CREB) transcription. The present study sought to clarify the role of ICER in the effects of methamphetamine (METH). METHODS AND FINDINGS: We tested METH-induced locomotor sensitization in wildtype mice, ICER knockout mice, and ICER I-overexpressing mice. Both ICER wildtype mice and knockout mice displayed increased locomotor activity after continuous injections of METH. However, ICER knockout mice displayed a tendency toward higher locomotor activity compared with wildtype mice, although no significant difference was observed between the two genotypes. Moreover, compared with wildtype mice, ICER I-overexpressing mice displayed a significant decrease in METH-induced locomotor sensitization. Furthermore, Western blot analysis and quantitative real-time reverse transcription polymerase chain reaction demonstrated that ICER overexpression abolished the METH-induced increase in CREB expression and repressed cocaine- and amphetamine-regulated transcript (CART) and prodynorphin (Pdyn) expression in mice. The decreased CART and Pdyn mRNA expression levels in vivo may underlie the inhibitory role of ICER in METH-induced locomotor sensitization. CONCLUSIONS: Our data suggest that ICER plays an inhibitory role in METH-induced locomotor sensitization