Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden

Abstract Background It has traditionally been thought that the pathological accumulation of tau in Alzheimer's disease and other tauopathies facilitates neurodegeneration, which in turn leads to cognitive impairment. However, recent evidence suggests that tau tangles are not the entity responsible for memory loss, rather it is an intermediate tau species that disrupts neuronal function. Thus, efforts to discover therapeutics for tauopathies emphasize soluble tau reductions as well as neuroprotection. Results Here, we found that neuroprotection alone caused by methylene blue (MB), the parent compound of the anti-tau phenothiaziazine drug, Rember™, was insufficient to rescue cognition in a mouse model of the human tauopathy, progressive supranuclear palsy (PSP) and fronto-temporal dementia with parkinsonism linked to chromosome 17 (FTDP17): Only when levels of soluble tau protein were concomitantly reduced by a very high concentration of MB, was cognitive improvement observed. Thus, neurodegeneration can be decoupled from tau accumulation, but phenotypic improvement is only possible when soluble tau levels are also reduced. Conclusions Neuroprotection alone is not sufficient to rescue tau-induced memory loss in a transgenic mouse model. Development of neuroprotective agents is an area of intense investigation in the tauopathy drug discovery field. This may ultimately be an unsuccessful approach if soluble toxic tau intermediates are not also reduced. Thus, MB and related compounds, despite their pleiotropic nature, may be the proverbial "magic bullet" because they not only are neuroprotective, but are also able to facilitate soluble tau clearance. Moreover, this shows that neuroprotection is possible without reducing tau levels. This indicates that there is a definitive molecular link between tau and cell death cascades that can be disrupted.http://deepblue.lib.umich.edu/bitstream/2027.42/78314/1/1750-1326-5-45.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78314/2/1750-1326-5-45.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/78314/3/1750-1326-5-45-S1.PDFPeer Reviewe

Conscious monitoring and control (reinvestment) in surgical performance under pressure.

Research on intraoperative stressors has focused on external factors without considering individual differences in the ability to cope with stress. One individual difference that is implicated in adverse effects of stress on performance is "reinvestment," the propensity for conscious monitoring and control of movements. The aim of this study was to examine the impact of reinvestment on laparoscopic performance under time pressure

Ovine pedomics : the first study of the ovine foot 16S rRNA-based microbiome

We report the first study of the bacterial microbiome of ovine interdigital skin based on 16S rRNA by pyrosequencing and conventional cloning with Sanger-sequencing. Three flocks were selected, one a flock with no signs of footrot or interdigital dermatitis, a second flock with interdigital dermatitis alone and a third flock with both interdigital dermatitis and footrot. The sheep were classified as having either healthy interdigital skin (H), interdigital dermatitis (ID) or virulent footrot (VFR). The ovine interdigital skin bacterial community varied significantly by flock and clinical condition. The diversity and richness of operational taxonomic units was greater in tissue from sheep with ID than H or VFR affected sheep. Actinobacteria, Bacteriodetes, Firmicutes and Proteobacteria were the most abundant phyla comprising 25 genera. Peptostreptococcus, Corynebacterium and Staphylococcus were associated with H, ID and VFR respectively. Sequences of Dichelobacter nodosus, the causal agent of ovine footrot, were not amplified due to mismatches in the 16S rRNA universal forward primer (27F). A specific real time PCR assay was used to demonstrate the presence of D. nodosus which was detected in all samples including the flock with no signs of ID or VFR. Sheep with ID had significantly higher numbers of D. nodosus (104-109 cells/g tissue) than those with H or VFR feet

Le kyste hydatique du rein fistulisé dans les voies urinaires, prise en charge diagnostique et thérapeutique A propos de 14 cas

Objectif: l’hydatidose est une pathologie fréquente au Maroc et constitue un problème majeur de santé publique. La localisation rénale de cette parasitose est rare. Les formes s’accompagnant de plus d’une fistulisation dans les voies excrétrices présentent des particularités diagnostiques etthérapeutiques qui seront décrites dans cet article.Patients et méthodes: 14 patients présentant un kyste hydatique du rein fistulisé dans la voie excrétrice urinaire ont été inclus dans l’étude de 2002 à 2008. Les variables étudiées ont été : l’âge moyen, les antécédents, la symptomatologie clinique, l’imagerie, le traitement et l’évolution.Résultats: L’âge moyen était de 38 ans (21-54). La douleur lombaire a été retrouvée chez tous les patients et l’hydaturie chez 8 patients. L’échographie réalisée chez tous les patients a montré 6 cas de kyste hydatique de type III et 8 cas de type IV selon la classification de GHARBI. L’uroscanner a confirmé la nature hydatique de la masse et deux cas de rein non fonctionnel. L’hydaturie et la dilatation des cavités excrétrices ont été les principaux éléments orientant vers le diagnostic. Le traitement a consisté en une résection du dôme saillant et la fermeture de la fistule chez 12 patients; huit d’entre eux ont eu une néphrostomie per-opératoire après cure de la fistule et deux patients une montée de sonde urétérale double crosse en pré-opératoire, les deux autres n’ont pas été drainés. Les deux patients restant ont eu une néphrectomie. Les suites ont été marquées par une fistule stercorale colique chez un patient et deux cas d’infection de paroi.Conclusion: Tout kyste hydatique du rein doit avoir un bilan d’imagerie comportant un uroscanner avec des clichés tardifs à la recherche d’une fistulisation dans la voie excrétrice urinaire. Il est conseillé de mettre en place une sonde urétérale en préopératoire à visée diagnostique et thérapeutique.Mots clés : Rein, kyste hydatique, fistule dans les cavités excrétrices, drainage sonde urétérale double crosse, sutures en deux plan

Expression of Estrogen Alpha and Beta Receptors in Prostate Cancer and Hyperplasia: Immunohistochemical Analysis

Objectives: Estrogen receptors are believed to play a significant role in the pathogenesis of prostate carcinoma (PCa). The aim of this study is to evaluate the expression of ER-α and ER-β in human benign and malignant prostatic tissue.Patients and Methods: The archival materials of 100 prostatic specimens (65 PCa, 35 BPH) were collected from the Department of Pathology, King Abdul-Aziz University Hospital, Jeddah, Saudi Arabia. Seven PCa cases contained foci of high-grade prostate intraepithelial neoplasia (HGPIN). Immunohistochemistry was used to test the protein expression of ER-α and ER-β utilizing monoclonal mouse antihuman antibodies.Results: Among the 65 cases of PCa, ER-α was expressed in 3 cases (4.6%) in epithelial cells and 4 cases (6.1%) in stromal cells. ER-α was not expressed in any of the HGPIN foci. Additionally, ER-α was not expressed in either luminal or basal cells in any of the 35 BPH cases. However it was expressed in 4 cases (11.4%) in stromal cells of BPH. In PCa, ER-β was expressed in 61 cases (93.8%) and 35 cases (53.8%) in the epithelial and stromal cells respectively. ER-β was expressed only in 2 cases (28.5%) out of 7 HGPIN foci. It was expressed in 33 cases (94.3%) of epithelialand stromal cells of BPH. Conclusion: The majority of PCa and BPH exhibited nuclear immunoreactivity for ER-β in both tumor and stromal cells and they are usually negative for ER-α. There is probably partial loss of ER-β in HGPIN. ER-β may have a role in the process of prostatic hyperplasia and malignancy.Key Words: ER-α, ER-β, prostate, hyperplasia, premalignant, cancer,  immunohistochemistr

Exploring barriers to the use of formal maternal health services and priority areas for action in Sidama zone, southern Ethiopia.

In 2015 the maternal mortality ratio for Ethiopia was 353 per 100,000 live births. Large numbers of women do not use maternal health services. This study aimed to identify factors influencing the use of maternal health services at the primary health care unit (PHCU) level in rural communities in Sidama zone, south Ethiopia in order to design quality improvement interventions. We conducted a qualitative study in six woredas in 2013: 14 focus group discussions (FGDs) and 44 in-depth interviews with purposefully selected community members (women, male, traditional birth attendants, local kebele administrators), health professionals and health extension workers (HEWs) at PHCUs. We digitally recorded, transcribed and thematically analysed the interviews and FGDs using Nvivo. The 'three delay model' informed the analytical process and discussion of barriers to the use of maternal health services. Lack of knowledge on danger signs and benefits of maternal health services; cultural and traditional beliefs; trust in TBAs; lack of decision making power of women, previous negative experiences with health facilities; fear of going to an unfamiliar setting; lack of privacy and perceived costs of maternal health services were the main factors causing the first delay in deciding to seek care. Transport problems in inaccessible areas were the main contributing factor for the second delay on reaching care facilities. Lack of logistic supplies and equipment, insufficient knowledge and skills and unprofessional behaviour of health workers were key factors for the third delay in accessing quality care. Use of maternal health services at the PHCU level in Sidama zone is influenced by complex factors within the community and health system. PHCUs should continue to implement awareness creation activities to improve knowledge of the community on complications of pregnancy and benefits of maternal health services. The health system has to be responsive to community's cultural norms and practices. The mangers of the woreda health office and health centres should take into account the available budgets; work on ensuring the necessary logistics and supplies to be in place at PHCU

What is the value of orthodontic treatment?

Orthodontic treatment is as popular as ever. Orthodontists frequently have long lists of people wanting treatment and the cost to the NHS in England was £258m in 2010-2011 (approximately 10% of the NHS annual spend on dentistry). It is important that clinicians and healthcare commissioners constantly question the contribution of interventions towards improving the health of the population. In this article, the authors outline some of the evidence for and against the claims that people with a malocclusion are at a disadvantage compared with those without a malocclusion and that orthodontic treatment has significant health benefits. The authors would like to point out that this is not a comprehensive and systematic review of the entire scientific literature. Rather the evidence is presented in order to stimulate discussion and debate

A novel μCT analysis reveals different responses of bioerosion and secondary accretion to environmental variability

Corals build reefs through accretion of calcium carbonate (CaCO3) skeletons, but net reef growth also depends on bioerosion by grazers and borers and on secondary calcification by crustose coralline algae and other calcifying invertebrates. However, traditional field methods for quantifying secondary accretion and bioerosion confound both processes, do not measure them on the same time-scale, or are restricted to 2D methods. In a prior study, we compared multiple environmental drivers of net erosion using pre- and post-deployment micro-computed tomography scans (μCT; calculated as the % change in volume of experimental CaCO3 blocks) and found a shift from net accretion to net erosion with increasing ocean acidity. Here, we present a novel μCT method and detail a procedure that aligns and digitally subtracts pre- and post-deployment μCT scans and measures the simultaneous response of secondary accretion and bioerosion on blocks exposed to the same environmental variation over the same time-scale. We tested our method on a dataset from a prior study and show that it can be used to uncover information previously unattainable using traditional methods. We demonstrated that secondary accretion and bioerosion are driven by different environmental parameters, bioerosion is more sensitive to ocean acidity than secondary accretion, and net erosion is driven more by changes in bioerosion than secondary accretion

Forest landscape ecology and global change: an introduction

Forest landscape ecology examines broad-scale patterns and processes and their interactions in forested systems and informs the management of these ecosystems. Beyond being among the richest and the most complex terrestrial systems, forest landscapes serve society by providing an array of products and services and, if managed properly, can do so sustainably. In this chapter, we provide an overview of the field of forest landscape ecology, including major historical and present topics of research, approaches, scales, and applications, particularly those concerning edges, fragmentation, connectivity, disturbance, and biodiversity. In addition, we discuss causes of change in forest landscapes, particularly land-use and management changes, and the expected structural and functional consequences that may result from these drivers. This chapter is intended to set the context and provide an overview for the remainder of the book and poses a broad set of questions related to forest landscape ecology and global change that need answers

Post-mortem assessment in vascular dementia: advances and aspirations.

BACKGROUND: Cerebrovascular lesions are a frequent finding in the elderly population. However, the impact of these lesions on cognitive performance, the prevalence of vascular dementia, and the pathophysiology behind characteristic in vivo imaging findings are subject to controversy. Moreover, there are no standardised criteria for the neuropathological assessment of cerebrovascular disease or its related lesions in human post-mortem brains, and conventional histological techniques may indeed be insufficient to fully reflect the consequences of cerebrovascular disease. DISCUSSION: Here, we review and discuss both the neuropathological and in vivo imaging characteristics of cerebrovascular disease, prevalence rates of vascular dementia, and clinico-pathological correlations. We also discuss the frequent comorbidity of cerebrovascular pathology and Alzheimer's disease pathology, as well as the difficult and controversial issue of clinically differentiating between Alzheimer's disease, vascular dementia and mixed Alzheimer's disease/vascular dementia. Finally, we consider additional novel approaches to complement and enhance current post-mortem assessment of cerebral human tissue. CONCLUSION: Elucidation of the pathophysiology of cerebrovascular disease, clarification of characteristic findings of in vivo imaging and knowledge about the impact of combined pathologies are needed to improve the diagnostic accuracy of clinical diagnoses