What went wrong? The flawed concept of cerebrospinal venous insufficiency

In 2006, Zamboni reintroduced the concept that chronic impaired venous outflow of the central nervous system is associated with multiple sclerosis (MS), coining the term of chronic cerebrospinal venous insufficiency ('CCSVI'). The diagnosis of 'CCSVI' is based on sonographic criteria, which he found exclusively fulfilled in MS. The concept proposes that chronic venous outflow failure is associated with venous reflux and congestion and leads to iron deposition, thereby inducing neuroinflammation and degeneration. The revival of this concept has generated major interest in media and patient groups, mainly driven by the hope that endovascular treatment of 'CCSVI' could alleviate MS. Many investigators tried to replicate Zamboni's results with duplex sonography, magnetic resonance imaging, and catheter angiography. The data obtained here do generally not support the 'CCSVI' concept. Moreover, there are no methodologically adequate studies to prove or disprove beneficial effects of endovascular treatment in MS. This review not only gives a comprehensive overview of the methodological flaws and pathophysiologic implausibility of the 'CCSVI' concept, but also summarizes the multimodality diagnostic validation studies and open-label trials of endovascular treatment. In our view, there is currently no basis to diagnose or treat 'CCSVI' in the care of MS patients, outside of the setting of scientific research

Effects of school-based physical activity and multi-micronutrient supplementation intervention on growth, health and well-being of schoolchildren in three African countries: the KaziAfya cluster randomised controlled trial protocol with a 2 x 2 factorial design

Background In low- and middle-income countries, infectious diseases remain a key public health issue. Additionally, non-communicable diseases are a rapidly growing public health problem that impose a considerable burden on population health. One way to address this dual disease burden, is to incorporate (lifestyle) health promotion measures within the education sector. In the planned study, we will (i) assess and compare physical activity, physical fitness, micronutrient status, body composition, infections with soil-transmitted helminths, Schistosoma mansoni, malaria, inflammatory and cardiovascular health risk markers, cognitive function, health-related quality of life, and sleep in schoolchildren in Côte d’Ivoire, South Africa and Tanzania. We will (ii) determine the bi- and multivariate associations between these variables and (iii) examine the effects of a school-based health intervention that consists of physical activity, multi-micronutrient supplementation, or both. Methods Assuming that no interaction occurs between the two interventions (physical activity and multi-micronutrient supplementation), the study is designed as a cluster-randomised, placebo-controlled trial with a 2 × 2 factorial design. Data will be obtained at three time points: at baseline and at 9 months and 21 months after the baseline assessment. In each country, 1320 primary schoolchildren from grades 1–4 will be recruited. In each school, classes will be randomly assigned to one of four interventions: (i) physical activity; (ii) multi-micronutrient supplementation; (iii) physical activity plus multi-micronutrient supplementation; and (iv) no intervention, which will serve as the control. A placebo product will be given to all children who do not receive multi-micronutrient supplementation. After obtaining written informed consent from the parents/guardians, the children will be subjected to anthropometric, clinical, parasitological and physiological assessments. Additionally, fitness tests will be performed, and children will be invited to wear an accelerometer device for 7 days to objectively assess their physical activity. Children infected with S. mansoni and soil-transmitted helminths will receive deworming drugs according to national policies. Health and nutrition education will be provided to the whole study population independently of the study arm allocation. Discussion The study builds on the experience and lessons of a previous study conducted in South Africa. It involves three African countries with different social-ecological contexts to investigate whether results are generalisable across the continent

In situ quantification of HER2–protein tyrosine kinase 6 (PTK6) protein–protein complexes in paraffin sections from breast cancer tissues

BACKGROUND: Protein tyrosine kinase 6 (PTK6; breast tumour kinase) is overexpressed in up to 86% of the invasive breast cancers, and its association with the oncoprotein human epidermal growth factor receptor 2 (HER2) was shown in vitro by co-precipitation. Furthermore, expression of PTK6 in tumours is linked with the expression of HER2. METHOD AND RESULTS: In this study, we used the proximity ligation assay (PLA) technique on formalin-fixed paraffin sections from eighty invasive breast carcinoma tissue specimens to locate PTK6-HER2 protein-protein complexes. Proximity ligation assay signals from protein complexes were assessed quantitatively, and expression levels showed a statistically significant association with tumour size (P=0.015) and course of the cancer disease (P=0.012). CONCLUSION: Protein tyrosine kinase 6 forms protein complexes with HER2 in primary breast cancer tissues, which can be visualised by use of the PLA technique. Human epidermal growth factor receptor 2-PTK6 complexes are of prognostic relevance

Prognostic value of protein tyrosine kinase 6 (PTK6) for long-term survival of breast cancer patients

The cytoplasmic tyrosine kinase PTK6 (BRK) shows elevated expression in approximately two-thirds of primary breast tumours, and is implicated in EGF receptor-dependent signalling and epithelial tumorigenesis. Using immunohistochemistry, we performed a retrospective study on 426 archival breast cancer samples from patients with long-term follow-up and compared the protein expression levels of PTK6, the HER receptors, Sam68 (a substrate of PTK6), and signalling proteins including MAP kinase (MAPK), phosphorylated MAPK (P-MAPK), and PTEN. We show that PTK6 expression is of significant prognostic value in the outcome of breast carcinomas. In multivariate analysis, the disease-free survival of patients of ⩾240 months was directly associated with the protein expression level of PTK6 (P⩽0.001), but was also inversely associated with nodal status (P⩽0.001) and tumour size (P⩽0.01). PTK6 expression in tumour tissue significantly correlated (P⩽0.05) with the expression of PTEN, MAPK, P-MAPK, and Sam68. To investigate whether these correlations may be due to molecular interactions between PTK6 and these proteins, we used protein extracts from the T47D cell line for immunoprecipitation and western blot analysis. By this, interactions could be demonstrated between PTK6 and MAPK, P-MAPK, HER2/neu, HER3, HER4, PTEN, and Sam68. On the basis of these results, we suggest that PTK6 may serve as a future target for the development of novel treatments in breast cancer

Impact of protein tyrosine kinase 6 (PTK6) on human epidermal growth factor receptor (HER) signalling in breast cancer.

PTK6, also known as Brk, is highly expressed in over 80% of breast cancers. In the last decade several substrates and interaction partners were identified localising PTK6 downstream of HER receptors. PTK6 seems to be involved in progression of breast tumours, in particular in HER receptor signalling. Here, we show the down-regulation effects of PTK6 in the T47D, BT474 and JIMT-1 breast cancer cell lines. PTK6 knockdown leads to a decreased phosphorylation of HER2, PTEN, MAPK (ERK), p38 MAPK, STAT3 and to a reduced expression of cyclin E. Our findings show that silencing PTK6 impairs the downstream targets of HER receptors and consequently the activation of signalling molecules. Furthermore, lower levels of PTK6 result in reduced migration of T47D and JIMT-1 breast cancer cells. Due to decreased migration, the PTK6 RNA interference might contribute to reduced metastasis and malignant potential of breast cancer cells. Since PTK6 plays an important role in HER receptor signal transduction, its down-regulation might be suitable for future therapy approaches in breast cancer

Systematic review and meta-analysis investigating moderators of long-term effects of exercise on cognition in healthy individuals

As cognitive function is linked with academic achievement, career success and mental health, there is a need to understand how the cognitive benefits of long-term exercise can be optimized. Our meta-regression included 80 randomized controlled trials and examined moderators of the effects of exercise on cognition in healthy individuals. The summary effect was small and did not differ between cognitive domains. Higher benefits of exercise on cognitive function were found after coordinative exercise compared with other exercise types. With longer intervention length, the effect size increased with longer session duration. Exercise was less effective in female compared with male individuals, and the dose-response relationship differed between sexes. Our findings suggest a general rather than domain-specific effect of exercise on cognition, which is influenced by sex, exercise type and reciprocal relationships between dose parameters. We derive sex-specific recommendations on how cognitive benefits can be optimized by exercise intensity, its progression and exercise type