Cuprizone‐induced demyelination and demyelination‐associated inflammation result in different proton magnetic resonance metabolite spectra

Conventional MRI is frequently used during the diagnosis of multiple sclerosis but provides only little additional pathological information. Proton MRS (¹H‐MRS), however, provides biochemical information on the lesion pathology by visualization of a spectrum of metabolites. In this study we aimed to better understand the changes in metabolite concentrations following demyelination of the white matter. Therefore, we used the cuprizone model, a well‐established mouse model to mimic type III human multiple sclerosis demyelinating lesions. First, we identified CX₃CL1/CX₃CR1 signaling as a major regulator of microglial activity in the cuprizone mouse model. Compared with control groups (heterozygous CX₃CR1^+/? C57BL/6 mice and wild type CX₃CR1^+/+ C57BL/6 mice), microgliosis, astrogliosis, oligodendrocyte cell death and demyelination were shown to be highly reduced or absent in CX₃CR1^?/? C57BL/6 mice. Second, we show that ¹H‐MRS metabolite spectra are different when comparing cuprizone‐treated CX₃CR1^?/? mice showing mild demyelination with cuprizone‐treated CX₃CR1^+/+ mice showing severe demyelination and demyelination‐associated inflammation. Following cuprizone treatment, CX₃CR1^+/+ mice show a decrease in the Glu, tCho and tNAA concentrations as well as an increased Tau concentration. In contrast, following cuprizone treatment CX₃CR1^?/? mice only showed a decrease in tCho and tNAA concentrations. Therefore, ¹H‐MRS might possibly allow us to discriminate demyelination from demyelination‐associated inflammation via changes in Tau and Glu concentration. In addition, the observed decrease in tCho concentration in cuprizone‐induced demyelinating lesions should be further explored as a possible diagnostic tool for the early identification of human MS type III lesions. Copyright © 2015 John Wiley & Sons, Ltd.     

SMAD2 Mutations Are Associated with Arterial Aneurysms and Dissections

We report three families with arterial aneurysms and dissections in which variants predicted to be pathogenic were identified in SMAD2. Moreover, one variant occurred de novo in a proband with unaffected parents. SMAD2 is a strong candidate gene for arterial aneurysms and dissections given its role in the TGF‐β signaling pathway. Furthermore, although SMAD2 and SMAD3 probably have functionally distinct roles in cell signaling, they are structurally very similar. Our findings indicate that SMAD2 mutations are associated with arterial aneurysms and dissections and are in accordance with the observation that patients with pathogenic variants in genes encoding proteins involved in the TGF‐β signaling pathway exhibit arterial aneurysms and dissections as key features     

Measuring wearing time of knee-ankle-foot orthoses in children with cerebral palsy: comparison of parent-report and objective measurement

Purpose state: Orthotic wearing time may be an important confounder in efficacy studies of treatment in children with spastic cerebral palsy (SCP). Most studies measure parent-reported wearing time (WT_parent) with questionnaires, but it is questionable whether this yields valid results. This study aims to compare WT_parent with objectively measured wearing time (WT_obj) in children with SCP receiving orthotic treatment.

Method: Eight children with SCP participated in this observational study. For one year, they received knee-ankle-foot orthosis (KAFO) treatment. WT_parent was measured using questionnaires. WT_obj was measured using temperature sensor-data-loggers that were attached to the KAFOs. The 2.5th and 97.5th percentiles and median of differences between methods (per participant) were used to calculate limits of agreement and systematic differences.

Results: There was no systematic difference between WT_parent and WT_obj (0.1?h per week), but high inter-individual variation of the difference was found, as reflected by large limits of agreement (lower limit/2.5th percentile: ?1.7?h/week; upper limit/97.5th percentile: 11.1?h/week).

Conclusions: Parent-reported wearing time (WTparent) of a KAFO differs largely from objectively measured wearing time (WT_obj) using temperature sensors. Therefore, parent-reported wearing time (WT_parent) of KAFOs should be interpreted with utmost care.

• Implications for Rehabilitation

• Low wearing time of orthoses may be a cause of inefficacy of orthotic treatment and incorrect reported wearing time may bias results of efficacy studies.

• Results of this study show that parent-reported wearing time is not in agreement with objectively measured wearing time.

• Parent-reported wearing time of KAFOs should be interpreted with utmost care.

• Objective methods are recommended for measuring orthotic wearing time.

     

Monitoring mosquito net coverage for malaria control in Africa: possession vs. use by children under 5 years

OBJECTIVES: To investigate the strengths and weaknesses of the indicators 'proportion of households possessing mosquito net(s)' and 'proportion of children under 5 years of age who slept under a net the preceding night' for monitoring malaria control. METHODS: Review of data from household surveys including demographic and health surveys in sub-Saharan African countries. RESULTS: Net possession ranged among 14 surveyed regions from 0.1% to 28.5% for insecticide-treated nets (ITNs) and among 69 regions from 3.6% to 79.7% for any net. Reported use during the preceding night by children under 5 years of age was between 0% and 16% for ITNs and between 0.7% and 74.5% for any net. On average, in households owning ITN(s), 55% of children slept under it (R2 = 0.97, P < 0.001). For any net, use was -4.2% + 0.875 x possession (R2 = 0.89, P < 0.001); the use of nets, however, also varied somewhat among the surveyed countries (P = 0.003). In-depth surveys suggested that use was lower than possession because: (i). nets were scarce (mean 1.8 per possessing household); (ii). nets were not always used for children and (iii). use was lower during hot, dry months than during cool rainy months, and many surveys had been conducted in the dry season. CONCLUSIONS: Not all mosquito nets owned by African households are being used for young children. Household education on the consistent use of nets for this vulnerable group is called for in malaria control programmes. Regular, district-level rapid assessments of household possession of nets should complement ongoing in-depth surveys. Data on 'use during the preceding night' must be interpreted taking the survey season into account.     

Adenoviral low density lipoprotein receptor attenuates progression of atherosclerosis and decreases tissue cholesterol levels in a murine model of familial hypercholesterolemia

Familial hypercholesterolemia is an autosomal codominant disease characterized by high concentrations of pro-atherogenic lipoproteins and premature atherosclerosis secondary to low density lipoprotein receptor (LDLr) deficiency. In the current study, the effects of gene transfer with 5 x 10(10) particles of E1E3E4-deleted adenoviral vectors expressing the LDLr (AdLDLr) or VLDLr (AdVLDLr) under control of the hepatocyte-specific human alpha(1)-antitrypsin promoter and 4 copies of the human apo E enhancer in C57BL/6 LDLr(-/-) mice were investigated. Evaluation was performed in both sexes and in mice fed either standard chow or an atherogenic diet containing 0.2% cholesterol and 10% coconut oil. Compared to control mice, AdLDLr and AdVLDLr persistently decreased plasma non-HDL cholesterol in both sexes and on both diets. Six months after LDLr gene transfer in mice fed the atherogenic diet, average intimal area was 2.5-fold (p<0.01) and 3.2-fold (p<0.001) lower in male and female mice, respectively, compared to controls. In mice fed standard chow, intimal area was reduced 22-fold (p<0.001) and 21-fold (p<0.001) after LDLr gene transfer in male and female mice, respectively. We show that non-HDL lipoproteins are more atherogenic in female mice, independent of sex differences of plasma HDL cholesterol levels, and that saturated fat does not have an effect on atherosclerosis independent of plasma cholesterol levels. Finally, quantification of tissue cholesterol levels indicates that AdLDLr does not induce cholesterol accumulation in the liver and reduces cholesterol content in the myocardium, quadriceps muscle and kidney. In conclusion, hepatocyte-specific LDLr gene transfer significantly improves cholesterol homeostasis in LDLr(-/-) mice.     

Get secure soon: attachment in abused adolescents and young adults before and after trauma-focused cognitive processing therapy

Severe posttraumatic stress symptoms (PTSS) are connected to a variety of health-related and interpersonal problems, among them are the insecure attachment orientations. However, psychotherapy seems to improve not only PTSS but also attachment insecurities. In a large multicenter, randomized clinical trial, the attachment characteristics and PTSS of 85 adolescents and young adults (aged 14–21 years) with clinically relevant abuse-related PTSS were assessed at study entry, at the end of treatment, and 3 months after the end of treatment. Participants were randomized either to a developmentally adapted cognitive processing therapy (D-CPT) or to a wait-list with treatment advice (WL/TA). The purpose of the study was to analyze the association between PTSS and attachment at study entry as well as changes in attachment during the trial. We found that attachment-related avoidance (AR avoidance) was positively associated with PTSS from both self-reports and clinician ratings, whereas attachment-related anxiety (AR anxiety) was only related to self-reported PTSS (Pearson correlation coefficients between 0.37 and 0.46). Changes in AR anxiety occurred in both conditions at some point during the study (baseline to 3-month follow-up effect size was d = 0.60 for D-CPT and d = 0.44 for WL/TA) whereas for AR avoidance, only participants in D-CPT improved significantly (baseline to 3-month follow-up effect size was d = 0.75). The results indicate that PTSS and attachment are connected. Positive changes in attachment insecurities brought about by trauma-focused psychotherapy seem possible.

Trial registration: German Clinical Trials Register (DRKS); Germanctr.de; identifier: DRKS00004787; date of registration: 18 March 2013.

     

Meta-analysis of telomere length in 19?713 subjects reveals high heritability,stronger maternal inheritance and a paternal age effect

Telomere length (TL) has been associated with aging and mortality, but individual differences are also influenced by genetic factors, with previous studies reporting heritability estimates ranging from 34 to 82%. Here we investigate the heritability, mode of inheritance and the influence of parental age at birth on TL in six large, independent cohort studies with a total of 19 713 participants. The meta-analysis estimate of TL heritability was 0.70 (95% CI 0.64–0.76) and is based on a pattern of results that is highly similar for twins and other family members. We observed a stronger mother–offspring (r=0.42; P-value=3.60 × 10⁻⁶¹) than father–offspring correlation (r=0.33; P-value=7.01 × 10⁻⁵), and a significant positive association with paternal age at offspring birth (β=0.005; P-value=7.01 × 10⁻⁵). Interestingly, a significant and quite substantial correlation in TL between spouses (r=0.25; P-value=2.82 × 10⁻³⁰) was seen, which appeared stronger in older spouse pairs (mean age ≥55 years; r=0.31; P-value=4.27 × 10⁻²³) than in younger pairs (mean age<55 years; r=0.20; P-value=3.24 × 10⁻¹⁰). In summary, we find a high and very consistent heritability estimate for TL, evidence for a maternal inheritance component and a positive association with paternal age.     

The influence of clan structure on the genetic variation in a single Ghanaian village

Socioeconomic and cultural factors are thought to have an important role in influencing human population genetic structure. To explain such population structure differences, most studies analyse genetic differences among widely dispersed human populations. In contrast, we have studied the genetic structure of an ethnic group occupying a single village in north-eastern Ghana. We found a markedly skewed male population substructure because of an almost complete lack of male gene flow among Bimoba clans in this village. We also observed a deep male substructure within one of the clans in this village. Among all males, we observed only three Y-single-nucleotide polymorphism (SNP) haplogroups: E1b1a*-M2, E1b1a7a*-U174 and E1b1a8a*-U209, P277, P278. In contrast to the marked Y-chromosomal substructure, mitochondrial DNA HVS-1 sequence variation and autosomal short-tandem repeats variation patterns indicate high genetic diversities and a virtually random female-mediated gene flow among clans. On the extreme micro-geographical scale of this single Bimoba village, correspondence between the Y-chromosome lineages and clan membership could be due to the combined effects of the strict patrilocal and patrilineal structure. If translated to larger geographic scales, our results would imply that the extent of variation in uniparentally inherited genetic markers, which are typically associated with historical migration on a continental scale, could equally likely be the result of many small and different cumulative effects of social factors such as clan membership that act at a local scale. Such local scale effects should therefore be considered in genetic studies, especially those that use uniparental markers, before making inferences about human history at large.     

Theoretical study of the flow rate toward the right heart territory in case of total occlusion of the right coronary artery

In this work, patients with severe coronary disease and chronic occlusion of the right coronary artery (RCA) are studied. In this clinical situation, the collateral circulation is an important factor in the preservation of the myocardium until reperfusion of the area at risk. An accurate estimation of collateral flow is crucial in surgical bypass planning as it can influence the outcome of a given treatment for a given patient. The evaluation of collateral flow is frequently achieved using an index (CFI, Collateral Flow Index) based on pressure measurements.Using a model of the coronary circulation based on hydraulic/electric analogy, we demonstrate, through theoretical simulations, that a wide range of fractional collateral flow values can be obtained for any given distal pressure difference depending on the values of the capillary and collateral resistances.