Proteasome inhibitors increase missense mutated dysferlin in patients with muscular dystrophy

No treatment is available for patients affected by the recessively inherited, progressive muscular dystrophies caused by a deficiency in the muscle membrane repair protein dysferlin. A marked reduction in dysferlin in patients harboring missense mutations in at least one of the two pathogenic DYSF alleles encoding dysferlin implies that dysferlin is degraded by the cell's quality control machinery. In vitro evidence suggests that missense mutated dysferlin might be functional if salvaged from degradation by the proteasome. We treated three patients with muscular dystrophy due to a homozygous Arg555Trp mutation in dysferlin with the proteasome inhibitor bortezomib and monitored dysferlin expression in monocytes and in skeletal muscle by repeated percutaneous muscle biopsy. Expression of missense mutated dysferlin in the skeletal muscle and monocytes of the three patients increased markedly, and dysferlin was correctly localized to the sarcolemma of muscle fibers on histological sections. Salvaged missense mutated dysferlin was functional in a membrane resealing assay in patient-derived muscle cells treated with three different proteasome inhibitors. We conclude that interference with the proteasomal system increases expression of missense mutated dysferlin, suggesting that this therapeutic strategy may benefit patients with dysferlinopathies and possibly other genetic diseases.

Reading performance is not affected by a prism induced increase of horizontal and vertical vergence demand

PURPOSE Dyslexia is the most common developmental reading disorder that affects language skills. Latent strabismus (heterophoria) has been suspected to be causally involved. Even though phoria correction in dyslexic children is commonly applied, the evidence in support of a benefit is poor. In order to provide experimental evidence on this issue, we simulated phoria in healthy readers by modifying the vergence tone required to maintain binocular alignment. METHODS Vergence tone was altered with prisms that were placed in front of one eye in 16 healthy subjects to induce exophoria, esophoria, or vertical phoria. Subjects were to read one paragraph for each condition, from which reading speed was determined. Text comprehension was tested with a forced multiple choice test. Eye movements were recorded during reading and subsequently analyzed for saccadic amplitudes, saccades per 10 letters, percentage of regressive (backward) saccades, average fixation duration, first fixation duration on a word, and gaze duration. RESULTS Acute change of horizontal and vertical vergence tone does neither significantly affect reading performance nor reading associated eye movements. CONCLUSION Prisms in healthy subjects fail to induce a significant change of reading performance. This finding is not compatible with a role of phoria in dyslexia. Our results contrast the proposal for correcting small angle heterophorias in dyslexic children.

Does upward social mobility increase life satisfaction? A longitudinal analysis using British and Swiss panel data

A main assumption of social production function theory is that status is a major determinant of subjective well-being (SWB). From the perspective of the dissociative hypothesis, however, upward social mobility may be linked to identity problems, distress, and reduced levels of SWB because upwardly mobile people lose their ties to their class of origin. In this paper, we examine whether or not one of these arguments holds. We employ the United Kingdom and Switzerland as case studies because both are linked to distinct notions regarding social inequality and upward mobility. Longitudinal multilevel analyses based on panel data (UK: BHPS, Switzerland: SHP) allow us to reconstruct individual trajectories of life satisfaction (as a cognitive component of SWB) along with events of intragenerational and intergenerational upward mobility—taking into account previous levels of life satisfaction, dynamic class membership, and well-studied determinants of SWB. Our results show some evidence for effects of social class and social mobility on well-being in the UK sample, while there are no such effects in the Swiss sample. The UK findings support the idea of dissociative effects in terms of a negative effect of intergenerational upward mobility on SWB.

Does Climbing the ‘Social Ladder’ Increase Life Satisfaction? A Comparison of the UK and Switzerland

It is a widely held belief that status and wealth affect subjective well-being (SWB). This is reflected in the efforts of many people to climb up the ‘social ladder’ and to transcend their social background. By being upwardly mobile, they hope to benefit from various rewards they believe to be associated with desirable societal positions. However, findings from a range of disciplines provide evidence that these benefits are not to be taken for granted. Thus, we decided investigate the question of how upward social mobility impacts life satisfaction, the cognitive component of SWB.

Volatiles produced by soil-borne endophytic bacteria increase plant pathogen resistance and affect tritrophic interactions

Volatile organic compounds (VOCs) released by soil microorganisms influence plant growth and pathogen resistance. Yet, very little is known about their influence on herbivores and higher trophic levels. We studied the origin and role of a major bacterial VOC, 2,3-butanediol (2,3-BD), on plant growth, pathogen and herbivore resistance, and the attraction of natural enemies in maize. One of the major contributors to 2,3-BD in the headspace of soil-grown maize seedlings was identified as Enterobacter aerogenes, an endophytic bacterium that colonizes the plants. The production of 2,3-BD by E. aerogenes rendered maize plants more resistant against the Northern corn leaf blight fungus Setosphaeria turcica. On the contrary, E. aerogenes-inoculated plants were less resistant against the caterpillar Spodoptera littoralis. The effect of 2,3-BD on the attraction of the parasitoid Cotesia marginiventris was more variable: 2,3-BD application to the headspace of the plants had no effect on the parasitoids, but application to the soil increased parasitoid attraction. Furthermore, inoculation of seeds with E. aerogenes decreased plant attractiveness, whereas inoculation of soil with a total extract of soil microbes increased parasitoid attraction, suggesting that the effect of 2,3-BD on the parasitoid is indirect and depends on the composition of the microbial community.

Depletion of regulatory T cells augments a vaccine-induced T effector cell response against the liver-stage of malaria but fails to increase memory

Regulatory T cells (T(reg)) have been shown to restrict vaccine-induced T cell responses in different experimental models. In these studies CD4(+)CD25(+) T(reg) were depleted using monoclonal antibodies against CD25, which might also interfere with CD25 on non-regulatory T cell populations and would have no effect on Foxp3(+)CD25(-) T(reg). To obtain more insights in the specific function of T(reg) during vaccination we used mice that are transgenic for a bacterial artificial chromosome expressing a diphtheria toxin (DT) receptor-eGFP fusion protein under the control of the foxp3 gene locus (depletion of regulatory T cell mice; DEREG). As an experimental vaccine-carrier recombinant Bordetella adenylate cyclase toxoid fused with a MHC-class I-restricted epitope of the circumsporozoite protein (ACT-CSP) of Plasmodium berghei (Pb) was used. ACT-CSP was shown by us previously to introduce the CD8+ epitope of Pb-CSP into the MHC class I presentation pathway of professional antigen-presenting cells (APC). Using this system we demonstrate here that the number of CSP-specific T cells increases when T(reg) are depleted during prime but also during boost immunization. Importantly, despite this increase of T effector cells no difference in the number of antigen-specific memory cells was observed.

Dimethyloxalylglycine lyophilized onto bone substitutes increase vessel area in rat calvarial defects.

AIM Pharmacological inhibitors of prolyl hydroxylases, also termed hypoxia-mimetic agents (HMAs), when repeatedly injected can support angiogenesis and bone regeneration. However, the possible role of HMA loaded onto bone substitutes to support angiogenesis and bone regeneration under diabetic condition is unknown. The capacity of HMA loaded onto deproteinized bovine bone mineral (DBBM) to support angiogenesis and bone formation was examined in diabetic Wistar rats. METHODS Diabetes was induced by intraperitoneal injection of streptozotocin. The HMA dimethyloxalylglycine (DMOG) and desferrioxamine (DFO) were lyophilized onto DBBM. Calvarial defects were created with a trephine drill and filled with the respective bone substitutes. After 4 weeks of healing, the animals were subjected to histological and histomorphometric analysis. RESULTS In this report, we provide evidence that DMOG loaded onto DBBM can support angiogenesis in vivo. Specifically, we show that DMOG increased the vessel area in the defect site to 2.4% ± 1.3% compared with controls 1.1% ± 0.48% (P = 0.012). There was a trend toward an increased vessel number in the defect site with 38.6 ± 17.4 and 31.0 ± 10.3 in the DMOG and the control group (P = 0.231). The increase in angiogenesis, however, did not translate into enhanced bone formation in the defect area with 9.2% ± 7.1% and 8.4% ± 5.6% in DMOG and control group, respectively. No significant changes were caused by DFO. CONCLUSIONS The results suggest that DMOG loaded onto DBBM can support angiogenesis, but bone formation does not increase accordingly in a type 1 diabetic rat calvarial defect model at the indicated time point.

Synchronous carotid and coronary bypass surgery using minimal extracorporeal circulation does not increase the risk of in-hospital stroke compared to isolated carotid endarterectomy under general anaesthesia

Gebiet: Chirurgie Abstract: Introduction: Carotid endarterectomy (CEA) and coronary artery bypass grafting (CABG) could be approached in a combined or a staged fashion. Some crucial studies have shown no significant difference in peri-operative stroke and death rate in combined versus staged CEA/CABG. At present conventional extracorporeal circulation (CECC) is regarded as the gold standard for performing on-pump coronary artery bypass grafting. On contrary, the use of minimized extracorporeal circulation (MECC) for CABG diminishes hemodilution, blood-air contact, foreign surface contact and inflammatory response. At the same time, general anaesthesia (GA) is a potential risk factor for higher perioperative stroke rate after isolated CEA, not only for the ipsilateral but also for the contralateral side especially in case of contralateral high-grade stenosis or occlusion. The aim of the study was to analyze if synchronous CEA/CABG using MECC (CEA/CABG group) allows reducing the perioperative stroke risk to the level of isolated CEA performed under GA (CEA-GA group). – Methods: A retrospective analysis of all patients who underwent CEA at our institution between January 2005 and December 2012 was performed. We compared outcomes between all patients undergoing CEA/CABG to all isolated CEA-GA during the same time period. The CEA/CABG group was additionally compared to a reference group consisting of patients undergoing isolated CEA in local anaesthesia. Primary outcome was in-hospital stroke. – Results: A total of 367 CEAs were performed, from which 46 patients were excluded having either off-pump CABG or other cardiac surgery procedures than CABG combined with CEA. Out of 321 patients, 74 were in the CEA/CABG and 64 in the CEA-GA group. There was a significantly higher rate of symptomatic stenoses among patients in the CEA-GA group (p<0.002). Three (4.1%) strokes in the CEA/CABG group were registered, two ipsilateral (2.7%) and one contralateral (1.4%) to the operated side. In the CEA-GA group 2 ipsilateral strokes (3.1%) occurred. No difference was noticed between the groups (p=1.000). One patient with stroke in each group had a symptomatic stenosis preoperatively. – Conclusions: Outcome with regard to mortality and neurologic injury is very good in both -patients undergoing CEA alone as well as patients undergoing synchronous CEA and CABG using the MECC system. Although the CEA/CABG group showed slightly increased risk of stroke, it can be considered as combined treatment in particular clinical situations.

Encouragement to Increase the Use of Psychosocial Skills in the Diagnosis and Therapy of Patients With Functional Dysphonia.

Clinicians believe that psychosocial factors play a causal role in the etiology of many forms of functional dysphonia (FD). But for decades, all attempts to confirm such causation have failed. This paper aims to show the logic of this failure, to discuss the possibilities of employing psychology in therapy nonetheless, and to encourage clinicians to use their psychosocial knowledge and skills. The failure to confirm psychic and social factors as causal in the etiology of FD is basically a consequence of a principal shortcoming of evidence-based medicine (EBM). As the gold standard for validity, reliability, and objectivity in medical research, EBM is based on calculability and hence the processing of quantitative data. But life paths and life situations are best or sometimes only expressible in qualitative, experiential, and idiographic terms. Thus EBM-guided evaluation undervalues most psychosocial studies. This report of an experienced multidisciplinary voice team proposes alternative pathways for integrating psychosocial knowledge into the diagnosis and the treatment of FD. The difference between the fields of activity of psychotherapists and speech-language pathologists is discussed, and the latter group is shown the potential benefits of using more of their psychosocial knowledge and skills.

Telomere length increase after weight loss induced by bariatric surgery: results from a 10 years prospective study

BACKGROUND/OBJECTIVES Obesity contributes to telomere attrition. Studies focusing on short-term effects of weight loss have been unable to identify protection of telomere length. This study investigates long-term effects of pronounced weight loss induced by bariatric surgery on telomere length. SUBJECTS/METHODS One hundred forty-two patients were recruited in a prospective, controlled intervention study, follow-up investigations were done after 10.46±1.48 years. A control group of normal weight participants was recruited and followed from 1995 to 2005 in the Bruneck Study. A total of 110 participants from each study was matched by age and sex to compare changes in telomere length. Quantitative PCR was used to determine telomere length. RESULTS Telomere length increased significantly by 0.024±0.14 (P=0.047) in 142 bariatric patients within 10 years after surgery. The increase was different from telomere attrition in an age- and sex-matched cohort population of the Bruneck Study (-0.057±0.18; β=0.08; P=0.003). Significant changes in telomere length disappeared after adjusting for baseline body mass index (BMI) because of general differences in BMI and telomere length between the two study populations (β=0.07; P=0.06). Age was proportional to telomere length in matched bariatric patients (r=0.188; P=0.049) but inversely correlated with telomere length in participants of the Bruneck Study (r=-0.197; P=0.039). There was no association between percent BMI/excess weight loss and telomere attrition in bariatric patients. Baseline telomere length in bariatric patients was inversely associated with baseline plasma cholesterol and triglyceride concentrations. Telomere shortening was associated with lower high-density lipoprotein cholesterol and higher fasting glucose concentration at baseline in bariatric patients. CONCLUSIONS Increases in relative telomere length were found after bariatric surgery in the long term, presumably due to amelioration of metabolic traits. This may overrule the influence of age and baseline telomere length and facilitate telomere protection in patients experiencing pronounced weight loss.

Shorter telomeres correlate with an increase in the number of uniparental disomies in patients with chronic lymphocytic leukemia.

This study investigated the correlation of the extent of chromosomal aberrations including uniparental disomies (UPDs) by SNP-chip analysis and FISH to telomere length in 46 patients with CLL. CLL harboring high risk aberrations, i.e. deletions of 11q22-23 or 17p13, had significantly shorter telomeres (higher ΔTL) compared to patients with CLL without such abnormalities. Patients with high chromosomal aberration rates had a worse overall survival compared to cases with lower aberration rates. Interestingly, however, an increase was found in the number of UPDs with shorter telomeres. These findings support the idea that telomeres in CLL cells play a role in the overall chromosome stability and could be involved in the occurrence of UPDs.

Do Labor Market Imperfections Increase Trade Protection? A Theoretical Investigation

Labor market imperfections are commonly believed to be a major reason for imposing trade impediments. In this paper, I introduce labor market rigidities that are prevalent in continental European countries into the well-known protection for sale model proposed by Grossman and Helpman (1994). I show that contrary to commonly held views, imperfections in the labor market do not necessarily increase equilibrium trade protection. A testable equilibrium trade protection equation is also derived. The findings in this paper are hence particularly relevant for empirical tests of trade policy determinants in economies with more regulated labor markets.

An evaluation of the impact of Inner City Development's Cooperative Home School: An educational alternative program to increase the quality and level of education in San Antonio's West Side community

The research study was intended to evaluate the effectiveness of Inner City Development's (I.C.D.) Cooperative Home School, an educational alternative program to the Title I public schools of San Antonio's West Side community. The study investigated students', parents' and tutors' perception of parental involvement and educational resources. The study also investigated each student's academic achievement. ^ The study found that students progressed toward expected math proficiency at a faster rate than they did in reading proficiency. However, because the target population size was small and a comparison group was not used, the results of this study are only suggestive. This research also indicated that study subjects believed students' quality and level of education increased substantially since program exposure. Study subjects mainly attributed the students' strides in academic performance to the increased amount of individualized attention students received in the small twelve-student class size. Study subjects were more satisfied with the home school's educational resources than those of the Title I public schools. Study subjects also perceived that parental involvement both at home and at school increased since enrollment in the home school program because: (1) there were more opportunities for involvement in the home school; and (2) parents felt closer to the tutors than the teachers in public school. ^ This evaluation also suggested improvements to program operations. With the help of additional volunteers, I.C.D. program operators could improve collection and organization of academic records. Furthermore, as suggested by program participants, science could be added to the curriculum. Lastly, a formal tutor orientation could be implemented to familiarize and train tutors on classroom management procedures. ^

The Skip To Breakfast project: Development, implementation, and feasibility evaluation of an intervention to increase healthful breakfast consumption among fifth grade students and their families

Children and adults frequently skip breakfast and rates are currently increasing. In addition, the food choices made for breakfast are not always healthy ones. Breakfast skipping, in conjunction with unhealthy breakfast choices, leads to impaired cognitive functioning, poor nutrient intake, and overweight. In response to these public health issues, Skip To Breakfast, a behaviorally based school and family program, was created to increase consistent and healthful breakfast consumption among ethnically diverse fifth grade students and their families, using Intervention Mapping™. Four classroom lessons and four parent newsletters were used to deliver the intervention. For this project, a healthy, "3 Star Breakfast" was promoted, and included a serving each of dairy product, whole grain, and fruit, each with an emphasis on being low in fat and sugar. The goal of this project was to evaluate the feasibility and acceptability of the intervention. A pilot-test of the intervention was conducted in one classroom, in a school in Houston, during the Fall 2007 semester. A qualitative evaluation of the intervention was conducted, which included focus groups with students, phone interviews of parents, process evaluation data from the classroom teacher, and direct observation. Sixteen students and six parents participated in the study. Data were recorded and themes were identified. Initial results showed there is a need for such programs. Based on the initial feedback, edits were made to the intervention and program. Results showed high acceptability among the teacher, students, and parents. It became apparent that students were not reliably getting the parent newsletters to their parents to read, so a change to the protocol was made, in which students will receive incentives for having parents read newsletters and return signed forms, to increase parent participation. Other changes included small modifications to the curriculum, such as, clarifying instructions, changing in-class assignments to homework assignments, and including background reading materials for the teacher. The main trial is planned to be carried out in Spring 2008, in two elementary schools, utilizing four, fifth grade classes from each, with one school acting as the control and one as the intervention school. Results from this study can be used as an adjunct to the Coordinated Approach To Child Health (CATCH) program. ^