The failure of suicide prevention in primary care: family and GP perspectives - a qualitative study

Background Although Primary care is crucial for suicide prevention, clinicians tend to report completed suicides in their care as non-preventable. We aimed to examine systemic inadequacies in suicide prevention from the perspectives of bereaved family members and GPs.Methods Qualitative study of 72 relatives or close friends bereaved by suicide and 19 General Practitioners who have experienced the suicide of patients.Results Relatives highlight failures in detecting symptoms and behavioral changes and the inability of GPs to understand the needs of patients and their social contexts. A perceived overreliance on anti-depressant treatment is a major source of criticism by family members. GPs tend to lack confidence in the recognition and management of suicidal patients, and report structural inadequacies in service provision.Conclusions Mental health and primary care services must find innovative and ethical ways to involve families in the decision-making process for patients at risk of suicide

Endothelium Derived Nitric Oxide Synthase Negatively Regulates the PDGF-Survivin Pathway during Flow-Dependent Vascular Remodeling

Chronic alterations in blood flow initiate structural changes in vessel lumen caliber to normalize shear stress. The loss of endothelial derived nitric oxide synthase (eNOS) in mice promotes abnormal flow dependent vascular remodeling, thus uncoupling mechanotransduction from adaptive vascular remodeling. However, the mechanisms of how the loss of eNOS promotes abnormal remodeling are not known. Here we show that abnormal flow-dependent remodeling in eNOS knockout mice (eNOS (−/−)) is associated with activation of the platelet derived growth factor (PDGF) signaling pathway leading to the induction of the inhibitor of apoptosis, survivin. Interfering with PDGF signaling or survivin function corrects the abnormal remodeling seen in eNOS (−/−) mice. Moreover, nitric oxide (NO) negatively regulates PDGF driven survivin expression and cellular proliferation in cultured vascular smooth muscle cells. Collectively, our data suggests that eNOS negatively regulates the PDGF-survivin axis to maintain proportional flow-dependent luminal remodeling and vascular quiescence

Multiple volcanic episodes of flood basalts caused by thermochemical mantle plumes

The hypothesis that a single mushroom-like mantle plume head can generate a large igneous province within a few million years has been widely accepted(1). The Siberian Traps at the Permian Triassic boundary(2) and the Deccan Traps at the Cretaceous Tertiary boundary(3) were probably erupted within one million years. These large eruptions have been linked to mass extinctions. But recent geochronological data(4-11) reveal more than one pulse of major eruptions with diverse magma flux within several flood basalts extending over tens of million years. This observation indicates that the processes leading to large igneous provinces are more complicated than the purely thermal, single-stage plume model suggests. Here we present numerical experiments to demonstrate that the entrainment of a dense eclogite-derived material at the base of the mantle by thermal plumes can develop secondary instabilities due to the interaction between thermal and compositional buoyancy forces. The characteristic timescales of the development of the secondary instabilities and the variation of the plume strength are compatible with the observations. Such a process may contribute to multiple episodes of large igneous provinces.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62705/1/nature03697.pd

Mechanical contributors to sex differences in idiopathic knee osteoarthritis

The occurrence of knee osteoarthritis (OA) increases with age and is more common in women compared with men, especially after the age of 50 years. Recent work suggests that contact stress in the knee cartilage is a significant predictor of the risk for developing knee OA. Significant gaps in knowledge remain, however, as to how changes in musculoskeletal traits disturb the normal mechanical environment of the knee and contribute to sex differences in the initiation and progression of idiopathic knee OA. To illustrate this knowledge deficit, we summarize what is known about the influence of limb alignment, muscle function, and obesity on sex differences in knee OA. Observational data suggest that limb alignment can predict the development of radiographic signs of knee OA, potentially due to increased stresses and strains within the joint. However, these data do not indicate how limb alignment could contribute to sex differences in either the development or worsening of knee OA. Similarly, the strength of the knee extensor muscles is compromised in women who develop radiographic and symptomatic signs of knee OA, but the extent to which the decline in muscle function precedes the development of the disease is uncertain. Even less is known about how changes in muscle function might contribute to the worsening of knee OA. Conversely, obesity is a stronger predictor of developing knee OA symptoms in women than in men. The influence of obesity on developing knee OA symptoms is not associated with deviation in limb alignment, but BMI predicts the worsening of the symptoms only in individuals with neutral and valgus (knockkneed) knees. It is more likely, however, that obesity modulates OA through a combination of systemic effects, particularly an increase in inflammatory cytokines, and mechanical factors within the joint. The absence of strong associations of these surrogate measures of the mechanical environment in the knee joint with sex differences in the development and progression of knee OA suggests that a more multifactorial and integrative approach in the study of this disease is needed. We identify gaps in knowledge related to mechanical influences on the sex differences in knee OA. © 2012 Nicolella et al.; licensee BioMed Central Ltd

Enhancing treatment decision-making: pilot study of a treatment decision aid in stage IV non-small cell lung cancer

We developed a decision aid (DA) for patients with metastatic non-small cell lung cancer (NSCLC), to better inform patients of their prognosis and treatment options, and facilitate involvement in decision-making. In a pilot study, 20 patients with metastatic NSCLC attending outpatient clinics at a major cancer centre, who had already made a treatment decision, reviewed acceptability of the DA. The median age of the patients was 61 years (range 37–77 years), 35% were male, 20% had a university education, and most (75%) had English as a first language. Most had received chemotherapy, with 65% currently on treatment. Patients were not anxious at baseline and had clear understanding of the goals and toxicity of chemotherapy in advanced NSCLC. After reviewing the DA, patients' anxiety decreased slightly (P=0.04) and knowledge scores improved by 25% (P<0.001). Most improvements in understanding were of prognosis with and without chemotherapy, although patients still believed advanced NSCLC to be curable. Patients rated the DA highly with respect to information clarity, usefulness and were positive about its use in practice, although 40% found the prognostic information slightly upsetting. The DA for advanced NSCLC is feasible, acceptable to patients and improves understanding of advanced NSCLC without increasing patient anxiety

Tradeoff between Stability and Maneuverability during Whole-Body Movements

Understanding how stability and/or maneuverability affects motor control strategies can provide insight on moving about safely in an unpredictable world. Stability in human movement has been well-studied while maneuverability has not. Further, a tradeoff between stability and maneuverability during movement seems apparent, yet has not been quantified. We proposed that greater maneuverability, the ability to rapidly and purposefully change movement direction and speed, is beneficial in uncertain environments. We also hypothesized that gaining maneuverability comes at the expense of stability and perhaps also corresponds with decreased muscle coactivation.We used a goal-directed forward lean movement task that integrated both stability and maneuverability. Subjects (n = 11) used their center of pressure to control a cursor on a computer monitor to reach a target. We added task uncertainty by shifting the target anterior-posterior position mid-movement. We used a balance board with a narrow beam that reduced the base of support in the medio-lateral direction and defined stability as the probability that subjects could keep the balance board level during the task.During the uncertainty condition, subjects were able to change direction of their anterior-posterior center of pressure more rapidly, indicating that subjects were more maneuverable. Furthermore, medio-lateral center of pressure excursions also approached the edges of the beam and reduced stability margins, implying that subjects were less stable (i.e. less able to keep the board level). On the narrow beam board, subjects increased muscle coactivation of lateral muscle pairs and had greater muscle activity in the left leg. However, there were no statistically significant differences in muscle activity amplitudes or coactivation with uncertainty.These results demonstrate that there is a tradeoff between stability and maneuverability during a goal-directed whole-body movement. Tasks with added uncertainty could help individuals learn to be more maneuverable yet sufficiently stable

Effects of Anti-VEGF on Predicted Antibody Biodistribution: Roles of Vascular Volume, Interstitial Volume, and Blood Flow

BACKGROUND: The identification of clinically meaningful and predictive models of disposition kinetics for cancer therapeutics is an ongoing pursuit in drug development. In particular, the growing interest in preclinical evaluation of anti-angiogenic agents alone or in combination with other drugs requires a complete understanding of the associated physiological consequences. METHODOLOGY/PRINCIPAL FINDINGS: Technescan™ PYP™, a clinically utilized radiopharmaceutical, was used to measure tissue vascular volumes in beige nude mice that were naïve or administered a single intravenous bolus dose of a murine anti-vascular endothelial growth factor (anti-VEGF) antibody (10 mg/kg) 24 h prior to assay. Anti-VEGF had no significant effect (p>0.05) on the fractional vascular volumes of any tissues studied; these findings were further supported by single photon emission computed tomographic imaging. In addition, apart from a borderline significant increase (p = 0.048) in mean hepatic blood flow, no significant anti-VEGF-induced differences were observed (p>0.05) in two additional physiological parameters, interstitial fluid volume and the organ blood flow rate, measured using indium-111-pentetate and rubidium-86 chloride, respectively. Areas under the concentration-time curves generated by a physiologically-based pharmacokinetic model changed substantially (>25%) in several tissues when model parameters describing compartmental volumes and blood flow rates were switched from literature to our experimentally derived values. However, negligible changes in predicted tissue exposure were observed when comparing simulations based on parameters measured in naïve versus anti-VEGF-administered mice. CONCLUSIONS/SIGNIFICANCE: These observations may foster an enhanced understanding of anti-VEGF effects in murine tissues and, in particular, may be useful in modeling antibody uptake alone or in combination with anti-VEGF

Visual Information Alone Changes Behavior and Physiology during Social Interactions in a Cichlid Fish (Astatotilapia burtoni)

Social behavior can influence physiological systems dramatically yet the sensory cues responsible are not well understood. Behavior of male African cichlid fish, Astatotilapia burtoni, in their natural habitat suggests that visual cues from conspecifics contribute significantly to regulation of social behavior. Using a novel paradigm, we asked whether visual cues alone from a larger conspecific male could influence behavior, reproductive physiology and the physiological stress response of a smaller male. Here we show that just seeing a larger, threatening male through a clear barrier can suppress dominant behavior of a smaller male for up to 7 days. Smaller dominant males being “attacked” visually by larger dominant males through a clear barrier also showed physiological changes for up to 3 days, including up-regulation of reproductive- and stress-related gene expression levels and lowered plasma 11-ketotestesterone concentrations as compared to control animals. The smaller males modified their appearance to match that of non-dominant males when exposed to a larger male but they maintained a physiological phenotype similar to that of a dominant male. After 7 days, reproductive- and stress- related gene expression, circulating hormone levels, and gonad size in the smaller males showed no difference from the control group suggesting that the smaller male habituated to the visual intruder. However, the smaller male continued to display subordinate behaviors and assumed the appearance of a subordinate male for a full week despite his dominant male physiology. These data suggest that seeing a larger male alone can regulate the behavior of a smaller male but that ongoing reproductive inhibition depends on additional sensory cues. Perhaps, while experiencing visual social stressors, the smaller male uses an opportunistic strategy, acting like a subordinate male while maintaining the physiology of a dominant male