Role of Presenilin-1 in Aggressive Human Melanoma.

Presenilin-1 (PS-1), a component of the gamma (γ)-secretase catalytic complex, has been implicated in Alzheimer's disease (AD) and in tumorigenesis. Interestingly, AD risk is inversely related to melanoma, suggesting that AD-related factors, such as PS-1, may affect melanomagenesis. PS-1 has been shown to reduce Wnt activity by promoting degradation of beta-catenin (ß-catenin), an important Wnt signaling partner. Since Wnt is known to enhance progression of different cancers, including melanoma, we hypothesized that PS-1 could affect Wnt-associated melanoma aggressiveness. Western blot results showed that aggressive melanoma cells expressed significantly lower levels of both PS-1 and phosphorylated-ß-catenin (P-ß-catenin) than nonaggressive melanoma cells. Immunohistochemistry of human melanoma samples showed significantly reduced staining for PS-1 in advanced stage melanoma compared with early stage melanoma. Furthermore, γ-secretase inhibitor (GSI) treatment of aggressive melanoma cells was followed by significant increases in PS-1 and P-ß-catenin levels, suggesting impaired Wnt signaling activity as PS-1 expression increased. Finally, a significant reduction in cell migration was associated with the higher levels of PS-1 and P-ß-catenin in the GSI-treated aggressive melanoma cells. We demonstrate for the first time that PS-1 levels can be used to assess melanoma aggressiveness and suggest that by enhancing PS-1 expression, Wnt-dependent melanoma progression may be reduced.

Vulnerability as practice in diagnosing multiple conditions.

The paper contributes to contemporary understandings of vulnerability by expanding their scope with an understanding of vulnerability as generated through institutionalised practices. The argument draws on experiential accounts of navigating the practices of diagnosis by people living with multiple conditions of ill-health and disability. Vulnerability as a concept is used widely across different domains and conveys a multitude of meanings. Contemporary biomedicine, and its associated health systems and services, understands vulnerability mostly as inherent to particular physical and mental bodily conditions that put people at risk of ill-health or emotionally fragility. This may combine with a more epidemiological understanding of vulnerability as the experience of certain population groups subject to entrenched structural inequalities. Philosophers and feminists have argued that vulnerability is a universal experience of being human while political commentators have explored its potential as a resource for resistance and action. Diagnosis within medicine and psychiatry has been the subject of extensive social analysis, critique and activism. The paper draws on first-hand experiential accounts collected through face-to-face interviews with people living with multiple conditions about their experiences of diagnosis, mostly at the primary care level. We identify five aspects to diagnostic practice that are harmful and exacerbate the experience of vulnerability: temporal sequencing; diagnostic authority; medical specialisation; strategic symptom selection; medical isolation. However, these diagnostic practices are not best understood only in terms of the power asymmetries inherent to the medical consultation, but are embedded into the very institution of diagnosis. The paper thus proposes a combined approach to vulnerability that recognises it as a universal condition of humanity but one that becomes animated or amplified for some bodies, through their own inherent incapacities or the external structures of inequality, and through the practices of medicine as situated in particular times and places.

Patient Activation Changes as a Potential Signal for Changes in Health Care Costs: Cohort Study of US High-Cost Patients.

BACKGROUND: Programs to improve quality of care and lower costs for the highest utilizers of health services are proliferating, yet such programs have difficulty demonstrating cost savings. OBJECTIVE: In this study, we explore the degree to which changes in Patient Activation Measure (PAM) levels predict health care costs among high-risk patients. PARTICIPANTS: De-identified claims, demographic data, and serial PAM scores were analyzed on 2155 patients from multiple medical groups engaged in an existing Center for Medicare and Medicaid Innovation-funded intervention over 3 years designed to activate and improve care coordination for high-risk patients. DESIGN: In this prospective cohort study, four levels of PAM (from low to high) were used as the main predictor variable. We fit mixed linear models for log10 of allowed charges in follow-up periods in relation to change in PAM, controlling for baseline PAM, baseline costs, age, sex, income, and baseline risk score. MAIN MEASURES: Total allowed charges were derived from claims data for the cohort. PAM scores were from a separate database managed by the local practices. KEY RESULTS: A single PAM level increase was associated with 8.3% lower follow-up costs (95% confidence interval 2.5-13.2%). CONCLUSIONS: These findings contribute to a growing evidence base that the change in PAM score could serve as an early signal indicating the impact of interventions designed for high-cost, high-needs patients.

Imagined futures in living with multiple conditions: Positivity, relationality and hopelessness.

Hope serves as an overarching concept for a range of engagements that demonstrate the benefits of a positive outlook for coping with chronic conditions of ill-health and disability. A dominant engagement through medicine has positioned hope as a desirable attribute and its opposite, hopelessness, as pathological. In this engagement hope is individual, internally located and largely cognitive and able to be learned. Attaining hope reflects a process of coming to terms with the losses associated with long-term conditions and of imagining new meanings and purposes for the future ahead. This process is characterised by a set of linear temporal stages, from loss and denial to acceptance and reappraising the life-course, by an emphasis on the morally desirable exercise of self-care and by a desired outcome that, in the absence of cure, is hope. Through interviews, we aim to unsettle the privileged status given to a positive outlook through examining the expressions, contexts and negotiations of hopelessness of people living with multiple conditions of ill-health and/or disability. These narratives of hopelessness disclose the ways in which realistic imagined possibilities for the future are constrained by external structures of time and function that demand complex negotiations with places, bodies and other people. As a situated and relational narrative, hopelessness draws our attention to the need to rebalance the exclusive attention to individual, internal resources with a renewed attention to contexts and settings. Moreover, hopelessness can be generative for those living with multiple conditions in shaping alternatively framed priorities with respect to their temporal and interpersonal relations.

Reoperation After Robotic and Vaginal Mesh Reconstructive Surgery: A Retrospective Cohort Study.

OBJECTIVES: Our primary objective was to compare reoperations after robotic-assisted sacrocolpopexy and transvaginal mesh for apical prolapse repair. Our secondary aim was to record perioperative complications after robotic and vaginal surgeries. METHODS: We reviewed medical records of women who underwent vaginal apical mesh support procedures or robotic sacrocolpopexy at Winthrop University Hospital between August 2009 and August 2013. We compared reoperations and perioperative complications between the 2 groups. RESULTS: There were 245 eligible cases during the 4-year study period. One hundred eighty-one women underwent robotic-assisted sacrocolpopexy and 64 women underwent transvaginal mesh. Women who underwent robotic surgery were younger and had decreased blood loss. Patients were followed up for a median of 3 months after robotic surgery and 11.5 months after transvaginal mesh. We found no difference in overall rate of reoperation between robotic and transvaginal mesh repair for apical prolapse. Specifically, there was no difference in the rate of reoperation for mesh exposure. CONCLUSIONS: Despite recent controversies, transvaginal mesh offers the benefit of an effective minimally invasive procedure with shorter operative times, and may not pose additional risk for reoperation when compared to robotic-assisted sacrocolpopexy.

Diagnosing FASD in adults: the development and operation of an adult FASD clinic in Ontario, Canada.

This paper describes the development and operation of an interdisciplinary Fetal Alcohol Spectrum Disorders (FASD) diagnostic clinic focussing specifically on adults. The clinic is embedded within a community-based interdisciplinary health agency specializing in intellectual and developmental disabilities. A review of the clinic's assessment process is presented describing the steps from intake to feedback and intervention. To date, the clinic has received 93 referrals and given 41 alcohol-related diagnoses including 10 completed using videoconferencing technology. Issues unique to adult diagnosis are discussed as well as some of the challenges, including high rates of cancellations/no-shows for appointments, obtaining background and historical information, establishing maternal alcohol history, working collaboratively with other support sectors such as children's protective services and the justice system, and finding appropriate follow-up and intervention services in the community. Recommendations for future work to support adults with FASD and their families are presented.

Brief Note: Response to Benatar.

In his response to my article entitled 'The Harm of Male-on-Female Rape: A Response to David Benatar', Benatar argues that I take his claims out of context, misrepresent them, and set up a straw man, which means, he claims, that I fail to respond to anything he has actually said. In this brief note, I respond to these allegations.

On the Horizon : New Oral Therapies for Type 2 Diabetes Mellitus : Review

The first documented case of diabetes mellitus occurred earlier than 4000 BC. Since then; many of the brightest minds in medicine have dedicated their time and effort toward developing treatments that can reverse the course of this deadly disease. As our understanding of the pathogenesis of diabetes increases; so does the availability of treatment options. The fight against diabetes once only had metformin and sulfonylureas as the cornerstone of oral treatment; but now; multiple classes have been added to this armamentarium including thiazolidenediones (TZDs) and dipeptidyl peptidase IV (DDP IV) inhibitors. These therapies provide reasonable durable glycemic control but are unable to arrest the natural progression of diabetes or the eventual need for insulin. By utilizing our growing knowledge on the pathogenesis of diabetes; a number of new therapeutic agents are in development to overcome the shortcomings of current therapies. Promising options on the horizon include sodium-coupled glucose co-transport 2 (SGLT2) inhibitors; ranolazine; salicylates; second-generation peroxisome proliferator-activator receptor agonists (PPARs); and 11-beta hydroxysteroid dehydrogenase type 1 inhibitors (11-beta HSD1 inhibitors). Various molecules; including some enzymes; are also in development; particularly to address beta-cell preservation and its sensitivity to glucose; while minimising hypoglycaemia. Most of these new classes of drugs consist of daily administration; simplifying the regimen for patients and likely increasing medication compliance. This article reviews the new agents that are advancing through clinical trials; their mechanism of actions; glucose lowering effect and possible side effects and limitations

Coexistence, niches and biodiversity effects on ecosystem functioning.

General principles from coexistence theory are often invoked to explain how and why mixtures of species outperform monocultures. However, the complementarity and selection effects commonly measured in biodiversity experiments do not precisely quantify the niche and relative fitness differences that govern species coexistence. Given this lack of direct correspondence, how can we know whether species-rich mixtures are stable and that the benefits of diversity will therefore persist? We develop a resource-based included-niche model in which plant species have asymmetric access to a nested set of belowground resource pools. We use the model to show that positive complementarity effects arise from stabilising niche differences, but do not necessarily lead to stable coexistence and hence can be transient. In addition, these transient complementarity effects occur in the model when there is no complementary resource use among species. Including a trade-off between uptake rates and the size of the resource pool stabilised interactions and led to persistent complementarity coupled with weak or negative selection effects, consistent with results from the longest-running field biodiversity experiments. We suggest that future progress requires a greater mechanistic understanding of the links between ecosystem functions and their underlying biological processes.

Outbreak of human trichinellosis in Northern California caused by Trichinella murrelli.

In October of 2008, an outbreak of trichinellosis occurred in northern California that sickened 30 of 38 attendees of an event at which meat from a black bear was served. Morphologic and molecular testing of muscle from the leftover portion of bear meat revealed that the bear was infected with Trichinella murrelli, a sylvatic species of Trichinella found in temperate North America. Clinical records revealed a high attack rate for this outbreak: 78% for persons consuming any bear meat and 100% for persons consuming raw or undercooked bear meat. To our knowledge, this report is the first published report of a human trichinellosis outbreak in the United States attributed to T. murrelli, and it is the second such outbreak reported worldwide.

Sirenomelia: four further cases with discussion of associated upper limb defects.

Sirenomelia, also known as the 'mermaid malformation/syndrome', is a rare, serious congenital anomaly characterized by variable degrees of fusion of the lower limbs and associated severe malformations of the lower vertebral and genitourinary systems. In this report, we describe a series of African patients with sirenomelia. We present the clinical and radiological features of four black South African patients and illustrate some of the rarer associated abnormalities, which include asymmetrical upper limb defects, not confined to the radial ray. The clinical phenotypic overlap between caudal dysgenesis, VACTERL association and sirenomelia in our patients is highlighted, lending support to the theory that these entities may be different manifestations of a single pathogenic process.

Planning for the North Carolina healthy homes initiative.

Substandard housing conditions have been linked to widespread childhood environmental health ailments, including two of the leading causes of childhood morbidity: lead poisoning and asthma. In 2009, the United States Surgeon General called for action around healthy homes. Improving home health environments can alleviate the cycle of childhood morbidity and mortality. The North Carolina (NC) Department of Environment and Natural Resources Children's Environmental Health Branch is working to build capacity at the State level to expand the childhood lead poisoning prevention program to respond to additional in-home environmental health issues. To achieve this objective, North Carolina must consider recommendations for assessment, management, and evaluation. This paper will situate healthy homes on the national public health agenda; discuss ways that healthy homes programs address children's environmental health disparities; introduce the NC Healthy Homes Initiative; explore current healthy housing efforts in North Carolina through an examination of the Guilford County Healthy Homes Initiative; and provide recommendations for the NC Healthy Homes Initiative to address children's environmental health disparities.

A restaurant-associated outbreak of Brainerd diarrhea in California.

In a rare outbreak of Brainerd diarrhea in California, we identified 23 patients, many of whom had diarrhea persisting for > or =6 months. Case-control studies revealed that illness was associated with 1 local restaurant but not with any specific food or beverage. A Campylobacter species was detected in some patients' stool specimens, but its role in the outbreak remains unclear.