The Fluctuating Natural Course of CCSVI in MS Patients and Controls,a Prospective Follow-Up

Objectives

A new treatable venous disorder, chronic cerebrospinal venous insufficiency (CCSVI), has been proposed in patients with multiple sclerosis. The natural course of CCSVI has not been examined yet. This is crucial given the fact that surgical procedures are increasingly offered to MS patients to treat venous stenosis.

Methods

To document the natural course of venous haemodynamics we performed extra- and transcranial echo colour Doppler (ECD) in 52 multiple sclerosis patients and 28 healthy controls (HC) and re-examined this group after a median period of 16 weeks. The reexamination was done being blinded to the initial findings and the patients did not undergo any intervention.

Results

The ECD examination at baseline showed CCSVI in 5 (9.6%) of the 52 multiple sclerosis patients and 0 HC (P = 0.26). At follow-up the diagnosis CCSVI could not be reconfirmed in 3 out of 5 patients at follow-up, while 2 new CCSVI-positive multiple sclerosis patients were detected.

Conclusions

ECD examination shows a fluctuating natural course of the extracranial venous haemodynamics, which makes determination of CCSVI by ECD examination unreliable.     

Enhancing Psychosocial Support for HIV Positive Adolescents in Harare,Zimbabwe

Background

There is a recognized gap in the evidence base relating to the nature and components of interventions to address the psycho-social needs of HIV positive young people. We used mixed methods research to strengthen a community support group intervention for HIV positive young people based in Harare, Zimbabwe.

Methods

A quantitative questionnaire was administered to HIV positive Africaid support group attendees. Afterwards, qualitative data were collected from young people aged 15–18 through tape-recorded in-depth interviews (n = 10), 3 focus group discussions (FGDs) and 16 life history narratives. Data were also collected from caregivers, health care workers, and community members through FGDs (n = 6 groups) and in-depth interviews (n = 12). Quantitative data were processed and analysed using STATA 10. Qualitative data were analysed using thematic analysis.

Results

229/310 young people completed the quantitative questionnaire (74% participation). Median age was 14 (range 6–18 years); 59% were female. Self-reported adherence to antiretrovirals was sub-optimal. Psychological well being was poor (median score on Shona Symptom Questionnaire 9/14); 63% were at risk of depression. Qualitative findings suggested that challenges faced by positive children include verbal abuse, stigma, and discrimination. While data showed that support group attendance is helpful, young people stressed that life outside the confines of the group was more challenging. Caregivers felt ill-equipped to support the children in their care. These data, combined with a previously validated conceptual framework for family-centred interventions, were used to guide the development of the existing programme of adolescent support groups into a more comprehensive evidence-based psychosocial support programme encompassing caregiver and household members.

Conclusions

This study allowed us to describe the lived experiences of HIV positive young people and their caregivers in Zimbabwe. The findings contributed to the enhancement of Africaid’s existing programme of support to better promote psychological well being and ART adherence.     

Enhanced polyamine catabolism alters homeostatic control of white adipose tissue mass, energy expenditure, and glucose metabolism

Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha) is an attractive candidate gene for type 2 diabetes, as genes of the oxidative phosphorylation (OXPHOS) pathway are coordinatively downregulated by reduced expression of PGC-1 alpha in skeletal muscle and adipose tissue of patients with type 2 diabetes. Here we demonstrate that transgenic mice with activated polyamine catabolism due to overexpression of spermidine/spermine N(1)-acetyltransferase (SSAT) had reduced white adipose tissue (WAT) mass, high basal metabolic rate, improved glucose tolerance, high insulin sensitivity, and enhanced expression of the OXPHOS genes, coordinated by increased levels of PGC-1 alpha and 5'-AMP-activated protein kinase (AMPK) in WAT. As accelerated polyamine flux caused by SSAT overexpression depleted the ATP pool in adipocytes of SSAT mice and N(1),N(11)-diethylnorspermine-treated wild-type fetal fibroblasts, we propose that low ATP levels lead to the induction of AMPK, which in turn activates PGC-1 alpha in WAT of SSAT mice. Our hypothesis is supported by the finding that the phenotype of SSAT mice was reversed when the accelerated polyamine flux was reduced by the inhibition of polyamine biosynthesis in WAT. The involvement of polyamine catabolism in the regulation of energy and glucose metabolism may offer a novel target for drug development for obesity and type 2 diabetes.     

Chromosome X-Wide Association Study Identifies Loci for Fasting Insulin and Height and Evidence for Incomplete Dosage Compensation

The X chromosome (chrX) represents one potential source for the “missing heritability” for complex phenotypes, which thus far has remained underanalyzed in genome-wide association studies (GWAS). Here we demonstrate the benefits of including chrX in GWAS by assessing the contribution of 404,862 chrX SNPs to levels of twelve commonly studied cardiometabolic and anthropometric traits in 19,697 Finnish and Swedish individuals with replication data on 5,032 additional Finns. By using a linear mixed model, we estimate that on average 2.6% of the additive genetic variance in these twelve traits is attributable to chrX, this being in proportion to the number of SNPs in the chromosome. In a chrX-wide association analysis, we identify three novel loci: two for height (rs182838724 near FGF16/ATRX/MAGT1, joint P-value = 2.71×10⁻⁹, and rs1751138 near ITM2A, P-value = 3.03×10⁻¹⁰) and one for fasting insulin (rs139163435 in Xq23, P-value = 5.18×10⁻⁹). Further, we find that effect sizes for variants near ITM2A, a gene implicated in cartilage development, show evidence for a lack of dosage compensation. This observation is further supported by a sex-difference in ITM2A expression in whole blood (P-value = 0.00251), and is also in agreement with a previous report showing ITM2A escapes from X chromosome inactivation (XCI) in the majority of women. Hence, our results show one of the first links between phenotypic variation in a population sample and an XCI-escaping locus and pinpoint ITM2A as a potential contributor to the sexual dimorphism in height. In conclusion, our study provides a clear motivation for including chrX in large-scale genetic studies of complex diseases and traits.     

Selective Plating Underestimates Abundance and Shows Differential Recovery of Bifidobacterial Species from Human Feces

The aim of the present work was to compare the efficacies and levels of selectivity of different culture-dependent and -independent methods for analyzing bifidobacteria in human stool samples. The three different culture media used here significantly differed from each other, particularly with regard to the recovery of Bifidobacterium adolescentis. Bifidobacterium medium failed to recover B. adolescentis; Beerens medium recovered some B. adolescentis organisms (17% of total bifidobacteria), whereas tomato-Eugon medium recovered mainly B. adolescentis organisms (58% of total bifidobacteria). A culture-independent method that combines GC fractionation of bacterial community DNA and 16S rRNA sequencing indicated that B. adolescentis organisms accounted for 85% of all bifidobacteria. Methodological biases, such as those described in this paper, should be taken into account in interpreting earlier studies and designing future experiments.     

Culture-Independent Microbial Community Analysis Reveals that Inulin in the Diet Primarily Affects Previously Unknown Bacteria in the Mouse Cecum

Inulin is a well-known fructose-based prebiotic which has been shown to stimulate the growth of bifidobacteria, a bacterial group generally considered beneficial for intestinal health. In the present study, we analyzed inulin-associated shifts in the total bacterial community of wild-type mice and mice carrying a genetically inactivated adenomatous polyposis coli tumor suppressor gene by using DNA-based approaches independent of bacterial culturability. Mice were fed a high-fat, nonfiber diet with or without inulin inclusion at a 10% (wt/wt) concentration. Cecal contents were analyzed after 0, 3, and 9 weeks on the experimental diets. Inulin inclusion significantly affected the total bacterial community structure of the cecum as determined by both a nonselective percent-guanine-plus-cytosine-based profiling analysis and a more specific 16S ribosomal DNA sequence analysis. The shifts included stimulation of bifidobacteria and suppression of clostridia, but sequence comparison revealed that the major shifts were within previously unknown bacterial taxa. Concomitantly, significantly higher bacterial densities, determined by flow cytometry, were observed with the inulin-amended diet, and the metabolism of the cecal bacterial community was altered, as indicated by higher levels of residual short-chain fatty acids, particularly lactic acid. With regard to all of the microbiological parameters measured, the wild-type mice and mice carrying a genetically inactivated adenomatous polyposis coli tumor suppressor gene were essentially identical. Studies of the implications of pre- and probiotics may need to be expanded to include careful analysis of their effects on the entire microbial community, rather than just a few well-known species. Further studies are needed to increase our understanding of the possible roles of currently unknown gastrointestinal bacteria in health and disease.     

Peritoneal dialysis fluid activates calcium signaling and apoptosis in mesothelial cells

A larger diffusion of peritoneal dialysis (PD) is limited by the progressive deterioration of the dialysis membrane structure and function, characterized in vitro and in vivo by mesothelial cell loss and closely related to the use of bioincompatible dialysis solutions. The apoptosis rate of rat and human mesothelial cells incubated in commercial PD fluid (PDF, 4.25 g/dL dextrose) became significant as early as 1 h after PDF addition and reached a plateau at 4–5 h. This pattern was unchanged after exposure to 1.5 g/dL dextrose PDF or freshly prepared PDF, indicating that effects were independent on the dextrose strength and manufacturing procedures but strictly dependent on PDF composition. Molecular studies revealed that PDF exposure inactivated the physiological volume recovery from hypertonic shrinkage, accompanied by an abnormal Ca²⁺ signaling: a progressive intracellular Ca²⁺ ([Ca²⁺]_i) rise resulting from an increased Ca²⁺ entry. PDF also affected cytoskeleton integrity: early dissolution of actin filaments occurred well before the appearance of typical apoptosis features. Lastly, the PDF dependent apoptosis was almost completely prevented by the contemporary Ca²⁺ concentration decrease and K⁺ addition. This study suggests that the PDF dependent apoptosis arises from the extreme volume perturbations in mesothelial cells, turned out unable to regulate their volume back once exposed to a hyperosmolal medium containing high Ca²⁺ levels in the absence of K⁺, such PDF.     

ATP and light regulate D1 protein modification and degradation. Role of D1* in photoinhibition.

We have recently shown that during in vivo photoinhibition the D1 protein is degraded via a modified form, designated D1*. Depending on light conditions, the amount of D1* varies in leaves between 0 and 50% of total D1 content. By isolating thylakoids from leaves acclimated to different light levels, and performing photoinhibition experiments on these thylakoids, the following results on D1 protein degradation were obtained: (i) the protease involved in D1 degradation requires activation by light; (ii) neither acceptor nor donor side photoinhibition of PSII induces formation of D1* in vitro; (iii) in isolated thylakoids, the transformation of D1 to D1* can be induced in low light in the presence of ATP, which suggests that D1* is a phosphorylated form of the D1 protein; (iv) D1*, induced either in vivo or in vitro, is much less susceptible to degradation during illumination of isolated thylakoids than the original D1 protein. We suggest that the modification to D1* is a means to prevent disassembly of photodamaged photosystem II complex in appressed membranes.     

Invasive Acacia auriculiformis Benth. in different habitats in Unguja, Zanzibar

Acacia auriculiformis Benth., Mimosaceae, has been introduced relatively recently as a plantation tree to the island of Unguja, Zanzibar. It has been reported to establish itself outside the plantations, but it is not known if the success of establishment depends on habitat quality. We investigated the occurrence of A. auriculiformis in 5-m-wide sample lines, which started from the edge of acacia plantations and reached farthermost the distance of 1 km. The results of 7.24 ha studied showed that: (1) A. auriculiformis occurred in most of the studied habitats in Unguja and appeared to be more abundant in deep soils than in shallow coral-derived soils. However, statistical analyses suggested that the species has little preference or avoidance towards any of the habitats, even though forests – the least disturbed habitats – seemed to have less acacias than other more disturbed habitats. (2) The number of acacias decreased rapidly with the distance from an acacia plantation, and most of the found acacias were still young, below three metres tall. Our results suggest that the invasion of A. auriculiformis is at its beginning in Unguja. If no preventive measures are taken, A. auriculiformis may have an increasing impact on local ecosystem in the future.