High level expression of differentially localized BAG-1 isoforms in some oestrogen receptor-positive human breast cancers

Sensitivity to oestrogens and apoptosis are critical determinants of the development and progression of breast cancer and reflect closely linked pathways in breast epithelial cells. For example, induction of BCL-2 oncoprotein expression by oestrogen contributes to suppression of apoptosis and BCL-2 and oestrogen receptor (ER) are frequently co-expressed in tumours. BAG-1/HAP is a multifunctional protein which complexes with BCL-2 and steroid hormone receptors (including the ER), and can suppress apoptosis and influence steroid hormone-dependent transcription. Therefore, analysis of expression of BAG-1 in human breast cancer is of considerable interest. BAG-1 was readily detected by immunostaining in normal breast epithelial cells and most ER-positive tumours, but was undetectable or weakly expressed in ER-negative tumours. BAG-1 positive cells showed a predominantly cytoplasmic or cytoplasmic plus nuclear distribution of staining. A correlation between ER and BAG-1 was also evident in breast cancer derived cell lines, as all lines examined with functional ER expression also expressed high levels of BAG-1. In addition to the prototypical 36 kDa BAG-1 isoform, breast cancer cells expressed higher molecular weight isoforms and, in contrast to BCL-2, BAG-1 expression was independent of oestrogens. BAG-1 isoforms were differentially localized to the nucleus or cytoplasm and this was also independent of oestrogens. These results demonstrate a close association between BAG-1 and functional ER expression and suggest BAG-1 may be useful as a therapeutic target or prognostic marker in breast cancer. © 1999 Cancer Research Campaig

Cause of Death and Predictors of All-Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation : Data From ROCKET AF

M. Kaste on työryhmän ROCKET AF Steering Comm jäsen.Background-Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions. Methods and Results-In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention-to-treat population. The median age was 73 years, and the mean CHADS(2) score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P= 75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P Conclusions-In a large population of patients anticoagulated for nonvalvular atrial fibrillation, approximate to 7 in 10 deaths were cardiovascular, whereasPeer reviewe

Review of methods used by chiropractors to determine the site for applying manipulation

Background: With the development of increasing evidence for the use of manipulation in the management of musculoskeletal conditions, there is growing interest in identifying the appropriate indications for care. Recently, attempts have been made to develop clinical prediction rules, however the validity of these clinical prediction rules remains unclear and their impact on care delivery has yet to be established. The current study was designed to evaluate the literature on the validity and reliability of the more common methods used by doctors of chiropractic to inform the choice of the site at which to apply spinal manipulation. Methods: Structured searches were conducted in Medline, PubMed, CINAHL and ICL, supported by hand searches of archives, to identify studies of the diagnostic reliability and validity of common methods used to identify the site of treatment application. To be included, studies were to present original data from studies of human subjects and be designed to address the region or location of care delivery. Only English language manuscripts from peer-reviewed journals were included. The quality of evidence was ranked using QUADAS for validity and QAREL for reliability, as appropriate. Data were extracted and synthesized, and were evaluated in terms of strength of evidence and the degree to which the evidence was favourable for clinical use of the method under investigation. Results: A total of 2594 titles were screened from which 201 articles met all inclusion criteria. The spectrum of manuscript quality was quite broad, as was the degree to which the evidence favoured clinical application of the diagnostic methods reviewed. The most convincing favourable evidence was for methods which confirmed or provoked pain at a specific spinal segmental level or region. There was also high quality evidence supporting the use, with limitations, of static and motion palpation, and measures of leg length inequality. Evidence of mixed quality supported the use, with limitations, of postural evaluation. The evidence was unclear on the applicability of measures of stiffness and the use of spinal x-rays. The evidence was of mixed quality, but unfavourable for the use of manual muscle testing, skin conductance, surface electromyography and skin temperature measurement. Conclusions: A considerable range of methods is in use for determining where in the spine to administer spinal manipulation. The currently published evidence falls across a spectrum ranging from strongly favourable to strongly unfavourable in regard to using these methods. In general, the stronger and more favourable evidence is for those procedures which take a direct measure of the presumptive site of care– methods involving pain provocation upon palpation or localized tissue examination. Procedures which involve some indirect assessment for identifying the manipulable lesion of the spine–such as skin conductance or thermography–tend not to be supported by the available evidence.https://doi.org/10.1186/2045-709X-21-3

Role of vitamin D in the physiopathology of neurodegenerative diseases|Rôle de la vitamine D dans la physiopathologie des maladies neurodégénératives

The involvement of vitamin D in brain function has been discovered in the past 25 years by epidemiological and fundamental studies. Research on neurodegenerative diseases and their animal or cellular models unveiled converging lines of evidence indicating that hypovitaminosis D is not just an effect of the progression of neurodegenerative diseases, but truly an aggravating co-factor, sometimes very closely related to their physiopathology. Vitamin D is a steroid hormone capable of regulating the expression of hundreds of genes through both genetic and epigenetic mechanisms. This reflects the highly pleiotropic nature of its action in its conventional bone and phosphocalcic metabolism targets. Its role in the central nervous system and neurodegenerative diseases makes no exception to this rule. Here we focus on the identified role and mechanisms of vitamin D in multiple sclerosis, Alzheimer's disease and Parkinson's disease. The important prevalence of hypovitaminosis D under our latitudes in general and in at-risk groups in particular, its easy evaluation and correction, and the results of early clinical studies, suggest that vitamin D supplementation could usefully complement our therapeutic armory to fight these diseases

Vitamin D Improves Neurogenesis and Cognition in a Mouse Model of Alzheimer’s Disease

The impairment of hippocampal neurogenesis at the early stages of Alzheimer's disease (AD) is believed to support early cognitive decline. Converging studies sustain the idea that vitamin D might be linked to the pathophysiology of AD and to hippocampal neurogenesis. Nothing being known about the effects of vitamin D on hippocampal neurogenesis in AD, we assessed them in a mouse model of AD. In a previous study, we observed that dietary vitamin D supplementation in female AD-like mice reduced cognitive decline only when delivered during the symptomatic phase. With these data in hand, we wondered whether the consequences of vitamin D administration on hippocampal neurogenesis are stage-dependent. Male wild-type and transgenic AD-like mice (5XFAD model) were fed with a diet containing either no vitamin D (0VD) or a normal dose of vitamin D (NVD) or a high dose of vitamin D (HVD), from month 1 to month 6 (preventive arm) or from month 4 to month 9 (curative arm). Working memory was assessed using the Y-maze, while amyloid burden, astrocytosis, and neurogenesis were quantified using immunohistochemistry. In parallel, the effects of vitamin D on proliferation and differentiation were assayed on primary cultures of murine neural progenitor cells. Improved working memory and neurogenesis were observed when high vitamin D supplementation was administered during the early phases of the disease, while a normal dose of vitamin D increased neurogenesis during the late phases. Conversely, an early hypovitaminosis D increased the number of amyloid plaques in AD mice while a late hypovitaminosis D impaired neurogenesis in AD and WT mice. The observed in vivo vitamin D-associated increased neurogenesis was partially substantiated by an augmented in vitro proliferation but not an increased differentiation of neural progenitors into neurons. Finally, a sexual dimorphism was observed. Vitamin D supplementation improved the working memory of males and females, when delivered during the pre-symptomatic and symptomatic phases, respectively. Our study establishes that (i) neurogenesis is improved by vitamin D in a male mouse model of AD, in a time-dependent manner, and (ii) cognition is enhanced in a gender-associated way. Additional pre-clinical studies are required to further understand the gender- and time-specific mechanisms of action of vitamin D in AD. This may lead to an adaptation of vitamin D supplementation in relation to patient's gender and age as well as to the stage of the disease

The influence of vitamin D on neurodegeneration and neurological disorders: A rationale for its physio-pathological actions

Vitamin D is a steroid hormone implicated in the regulation of neuronal integrity and many brain functions. Its influence, as a nutrient and a hormone, on the physiopathology of the most common neurodegenerative diseases is continuously emphasized by new studies. This review addresses what is currently known about the action of vitamin D on the nervous system and neurodegenerative diseases such as Multiple Sclerosis, Alzheimer's disease, Parkinson's disease and Amyotrophic Lateral Sclerosis. Further vitamin D research is necessary to understand how the action of this "neuroactive" steroid can help to optimize the prevention and treatment of several neurological diseases