A nitric oxide synthase transgene ameliorates muscular dystrophy in mdx mice.

Dystrophin-deficient muscles experience large reductions in expression of nitric oxide synthase (NOS), which suggests that NO deficiency may influence the dystrophic pathology. Because NO can function as an antiinflammatory and cytoprotective molecule, we propose that the loss of NOS from dystrophic muscle exacerbates muscle inflammation and fiber damage by inflammatory cells. Analysis of transgenic mdx mice that were null mutants for dystrophin, but expressed normal levels of NO in muscle, showed that the normalization of NO production caused large reductions in macrophage concentrations in the mdx muscle. Expression of the NOS transgene in mdx muscle also prevented the majority of muscle membrane injury that is detectable in vivo, and resulted in large decreases in serum creatine kinase concentrations. Furthermore, our data show that mdx muscle macrophages are cytolytic at concentrations that occur in dystrophic, NOS-deficient muscle, but are not cytolytic at concentrations that occur in dystrophic mice that express the NOS transgene in muscle. Finally, our data show that antibody depletions of macrophages from mdx mice cause significant reductions in muscle membrane injury. Together, these findings indicate that macrophages promote injury of dystrophin-deficient muscle, and the loss of normal levels of NO production by dystrophic muscle exacerbates inflammation and membrane injury in muscular dystrophy

Adaptive Prediction Error Coding in the Human Midbrain and Striatum Facilitates Behavioral Adaptation and Learning Efficiency.

Effective error-driven learning benefits from scaling of prediction errors to reward variability. Such behavioral adaptation may be facilitated by neurons coding prediction errors relative to the standard deviation (SD) of reward distributions. To investigate this hypothesis, we required participants to predict the magnitude of upcoming reward drawn from distributions with different SDs. After each prediction, participants received a reward, yielding trial-by-trial prediction errors. In line with the notion of adaptive coding, BOLD response slopes in the Substantia Nigra/Ventral Tegmental Area (SN/VTA) and ventral striatum were steeper for prediction errors occurring in distributions with smaller SDs. SN/VTA adaptation was not instantaneous but developed across trials. Adaptive prediction error coding was paralleled by behavioral adaptation, as reflected by SD-dependent changes in learning rate. Crucially, increased SN/VTA and ventral striatal adaptation was related to improved task performance. These results suggest that adaptive coding facilitates behavioral adaptation and supports efficient learning.This study was supported by the Wellcome Trust (W.S., P.C.F.), Bernard Wolfe Health Neuroscience Fund (P.C.F.) and the Niels Stensen Foundation (K.M.J.D.). We thank William Stauffer, Armin Lak and Joost Haarsma for useful discussions.This is the final version of the article. It first appeared from Cell Press via http://dx.doi.org/10.1016/j.neuron.2016.04.01

Changing indications and socio-demographic determinants of (adeno)tonsillectomy among children in England--are they linked? A retrospective analysis of hospital data.

OBJECTIVE: To assess whether increased awareness and diagnosis of obstructive sleep apnoea syndrome (OSAS) and national guidance on tonsillectomy for recurrent tonsillitis have influenced the socio-demographic profile of children who underwent tonsillectomy over the last decade. METHOD: Retrospective time-trends study of Hospital Episodes Statistics data. We examined the age, sex and deprivation level, alongside OSAS diagnoses, among children aged <16 years who underwent (adeno)tonsillectomy in England between 2001/2 and 2011/12. RESULTS: Among children aged <16 years, there were 29,697 and 27,732 (adeno)tonsillectomies performed in 2001/2 and 2011/12, respectively. The median age at (adeno)tonsillectomy decreased from 7 (IQR: 5-11) to 5 (IQR: 4-9) years over the decade. (Adeno)tonsillectomy rates among children aged 4-15 years decreased by 14% from 350 (95%CI: 346-354) in 2001/2 to 300 (95%CI: 296-303) per 100,000 children in 2011/12. However, (adeno)tonsillectomy rates among children aged <4 years increased by 58% from 135 (95%CI: 131-140) to 213 (95%CI 208-219) per 100,000 children in 2001/2 and 2011/2, respectively. OSAS diagnoses among children aged <4 years who underwent surgery increased from 18% to 39% between these study years and the proportion of children aged <4 years with OSAS from the most deprived areas increased from 5% to 12%, respectively. CONCLUSIONS: (Adeno)tonsillectomy rates declined among children aged 4-15 years, which reflects national guidelines recommending the restriction of the operation to children with more severe recurrent throat infections. However, (adeno)tonsillectomy rates among pre-school children substantially increased over the past decade and one in five children undergoing the operation was aged <4 years in 2011/12.The increase in surgery rates in younger children is likely to have been driven by increased awareness and detection of OSAS, particularly among children from the most deprived areas

Mapping HIV-related behavioural surveillance among injecting drug users in Europe, 2008.

The systematic collection of behavioural information is an important component of second-generation HIV surveillance. The extent of behavioural surveillance among injecting drug users (IDUs) in Europe was examined using data collected through a questionnaire sent to all 31 countries of the European Union and European Free Trade Association as part of a European-wide behavioural surveillance mapping study on HIV and other sexually transmitted infections. The questionnaire was returned by 28 countries during August to September 2008: 16 reported behavioural surveillance studies (two provided no further details). A total of 12 countries used repeated surveys for behavioural surveillance and five used their Treatment Demand Indicator system (three used both approaches). The data collected focused on drug use, injecting practices, testing for HIV and hepatitis C virus and access to healthcare. Eight countries had set national indicators: three indicators were each reported by five countries: the sharing any injecting equipment, uptake of HIV testing and uptake of hepatitis C virus testing. The recall periods used varied. Seven countries reported conducting one-off behavioural surveys (in one country without a repeated survey, these resulted an informal surveillance structure). All countries used convenience sampling, with service-based recruitment being the most common approach. Four countries had used respondent-driven sampling. Three fifths of the countries responding (18/28) reported behavioural surveillance activities among IDUs; however, harmonisation of behavioural surveillance indicators is needed

Absence of the spleen(s) in conjoined twins: a diagnostic clue of laterality defects? Radiological study of historical specimens

Laterality defects are quite common in thoracoileopagus and parapagus dicephalus but rare in other types of conjoined twins. To present the presumed laterality defects in cephalothoracoileopagus and prosopothoracoileopagus conjoined twins, based on the unilateral or bilateral absence or duplication of the spleen. Three human anatomical specimens of craniothoracoileopagus (CTIP) twins and one of prosopothoracoileopagus (PTIP) twins were investigated. The specimens were part of the Museum Vrolik collection of the Department of Anatomy and Embryology of the Academic Medical Centre, University of Amsterdam, The Netherlands. The specimens were taken out of their jars and scanned with multidetector CT and volumetric T2-weighted MRI at 1.5 T. The internal anatomy of the specimens was largely in accordance with previous reports. However, there was no recognisable spleen in the right twin in one CTIP specimen, in the left twin in one other CTIP specimen, and in both twins in the third CTIP specimen and in the PTIP specimen. Asplenia and polysplenia are considered reliable indicators of right and left isomerism, respectively. However, three of our four specimens had laterality patterns that did not correspond with those previously reported. Since no other parameters of laterality defects could be verified in these specimens, we concluded that asplenia was unlikely to be caused by laterality defect

Behavioural and Cognitive Associations of Short Stature at 5 Years

Objectives To determine the extent to which childhood short stature is associated with cognitive, behavioural and chronic health problems, and whether these problems could be attributed to recognized adverse biological, psychosocial or psychological factors. Methodology At their first antenatal session, 8556 women were enrolled in a prospective study of pregnancy. When their children were 4 and 6 years of age, mothers completed a detailed questionnaire concerning their child's health and behaviour. A Peabody Picture Vocabulary Test-Revised (PPVT-R) was completed by the child at 5 years of age. Z scores were used to categorize height measurements in 3986 children. The relationship of these height categories with the child's health, and behavioural and cognitive problems was then examined. Results No association was found between height and symptoms of chronic disease or behaviour problems in boys or girls. On the unadjusted analysis, mean PPVT-R scores were significantly lower in boys with heights < 3 percentile and 3-10 percentile compared with study children between 10 to 90 percentile (P < 0.01). Scores were similarly significantly lower in girls with heights < 3 percentile and 3-10 percentile (P = 0.01). Even after adjusting for psychosocial and biological confounders, short stature remained a significant predictor for lower PPVT-R scores in both boys and girls, although height only accounted for 1.1% of the variance in scores in boys and 0.5% of the variance in PPVT-R scores in girls. Psychosocial factors had a greater role than height in determining PPVT-R scores at 5 years of age. Conclusions These findings suggest a significant, though small, association between height and PPVT-R scores at 5 years of age, independent of psychosocial disadvantage and known biological risk factors

Solubility evaluation of murine hybridoma antibodies

The successful development of antibody therapeutics depends on the molecules having properties that are suitable for manufacturing, as well as use by patients. Because high solubility is a desirable property for antibodies, screening for solubility has become an essential step during the early candidate selection process. In considering the screening process, we formed a hypothesis that hybridoma antibodies are filtered by nature to possess high solubility and tested this hypothesis using a large number of murine hybridoma-derived antibodies. Using the cross-interaction chromatography (CIC) method, we screened the solubility of 92 murine hybridoma-derived monoclonal antibodies and found that all of these molecules exhibited CIC profiles that are indicative of high solubility (>100mg/mL). Further investigations revealed that variable region N-linked glycosylation or isoelectric parameters are unlikely to contribute to the high solubility of these antibodies. These results support the general hypothesis that hybridoma monoclonal antibodies are highly soluble

Climate Change Effects on Slope Stability

Global warming is taking place and there is no doubt that the stability of natural and artificial slopes is influenced by climate change. In this context, the present study intends to show, as more quantitatively as possible, the effects of climate change on slopes stability. The analysis was developed considering a non-static approach suitable for meteorological phenomena which are expected to change in the next years. In the analysis a statistical method was combined with a mechanical one: the forecasts of the intensity growth of heavy precipitation were used, as well as the physical laws for describing the response of groundwater table to these rainfall events and the resulting slopes stability. A case study located in Monchiero (Cn), Italy, was used as a test for the analysis and the forecasts described above