Chronic excitotoxin-induced axon degeneration in a compartmented neuronal culture model

Glutamate excitotoxicity is a major pathogenic process implicated in many neurodegenerative conditions, including AD (Alzheimer's disease) and following traumatic brain injury. Occurring predominantly from over-stimulation of ionotropic glutamate receptors located along dendrites, excitotoxic axonal degeneration may also occur in white matter tracts. Recent identification of axonal glutamate receptor subunits within axonal nanocomplexes raises the possibility of direct excitotoxic effects on axons. Individual neuronal responses to excitotoxicity are highly dependent on the complement of glutamate receptors expressed by the cell, and the localization of the functional receptors. To enable isolation of distal axons and targeted excitotoxicity, murine cortical neuron cultures were prepared in compartmented microfluidic devices, such that distal axons were isolated from neuronal cell bodies. Within the compartmented culture system, cortical neurons developed to relative maturity at 11 DIV (days in vitro) as demonstrated by the formation of dendritic spines and clustering of the presynaptic protein synaptophysin. The isolated distal axons retained growth cone structures in the absence of synaptic targets, and expressed glutamate receptor subunits. Glutamate treatment (100 μM) to the cell body chamber resulted in widespread degeneration within this chamber and degeneration of distal axons in the other chamber. Glutamate application to the distal axon chamber triggered a lesser degree of axonal degeneration without degenerative changes in the untreated somal chamber. These data indicate that in addition to current mechanisms of indirect axonal excitotoxicity, the distal axon may be a primary target for excitotoxicity in neurodegenerative conditions

A Comparison of Administrative and Physiologic Predictive Models in Determining Risk Adjusted Mortality Rates in Critically Ill Patients

Hospitals are increasingly compared based on clinical outcomes adjusted for severity of illness. Multiple methods exist to adjust for differences between patients. The challenge for consumers of this information, both the public and healthcare providers, is interpreting differences in risk adjustment models particularly when models differ in their use of administrative and physiologic data. We set to examine how administrative and physiologic models compare to each when applied to critically ill patients.We prospectively abstracted variables for a physiologic and administrative model of mortality from two intensive care units in the United States. Predicted mortality was compared through the Pearsons Product coefficient and Bland-Altman analysis. A subgroup of patients admitted directly from the emergency department was analyzed to remove potential confounding changes in condition prior to ICU admission.We included 556 patients from two academic medical centers in this analysis. The administrative model and physiologic models predicted mortalities for the combined cohort were 15.3% (95% CI 13.7%, 16.8%) and 24.6% (95% CI 22.7%, 26.5%) (t-test p-value<0.001). The r(2) for these models was 0.297. The Bland-Atlman plot suggests that at low predicted mortality there was good agreement; however, as mortality increased the models diverged. Similar results were found when analyzing a subgroup of patients admitted directly from the emergency department. When comparing the two hospitals, there was a statistical difference when using the administrative model but not the physiologic model. Unexplained mortality, defined as those patients who died who had a predicted mortality less than 10%, was a rare event by either model.In conclusion, while it has been shown that administrative models provide estimates of mortality that are similar to physiologic models in non-critically ill patients with pneumonia, our results suggest this finding can not be applied globally to patients admitted to intensive care units. As patients and providers increasingly use publicly reported information in making health care decisions and referrals, it is critical that the provided information be understood. Our results suggest that severity of illness may influence the mortality index in administrative models. We suggest that when interpreting "report cards" or metrics, health care providers determine how the risk adjustment was made and compares to other risk adjustment models

Novel Cytochrome P450, cyp6a17, Is Required for Temperature Preference Behavior in Drosophila

Perception of temperature is an important brain function for organisms to survive. Evidence suggests that temperature preference behavior (TPB) in Drosophila melanogaster, one of poikilothermal animals, is regulated by cAMP-dependent protein kinase (PKA) signaling in mushroom bodies of the brain. However, downstream targets for the PKA signaling in this behavior have not been identified. From a genome-wide search for the genes regulated by PKA activity in the mushroom bodies, we identified the cyp6a17 Cytochrome P450 gene as a new target for PKA. Our detailed analysis of mutants by genetic, molecular and behavioral assays shows that cyp6a17 is essential for temperature preference behavior. cyp6a17 expression is enriched in the mushroom bodies of the adult brain. Tissue-specific knockdown and rescue experiments demonstrate that cyp6a17 is required in the mushroom bodies for normal temperature preference behavior. This is the first study, to our knowledge, to show PKA-dependent expression of a cytochrome P450 gene in the mushroom bodies and its role as a key factor for temperature preference behavior. Taken together, this study reveals a new PKA-Cytochrome P450 pathway that regulates the temperature preference behavior

Underlying Dimensions of DSM-5 Posttraumatic Stress Disorder and Major Depressive Disorder Symptoms

This study examined the relationship between the underlying latent factors of major depression symptoms and DSM-5 posttraumatic stress disorder (PTSD) symptoms (American Psychiatric Association, 2013). A nonclinical sample of 266 participants with a trauma history participated in the study. Confirmatory factor analyses were conducted to evaluate the fit of the DSM-5 PTSD model and dysphoria model, as well as a depression model comprised of somatic and nonsomatic factors. The DSM-5 PTSD model demonstrated somewhat better fit over the dysphoria model. Wald tests indicated that PTSD's negative alterations in cognitions and mood factor was more strongly related to depression's nonsomatic factor than its somatic factor. This study furthers a nascent line of research examining the relationship between PTSD and depression factors in order to better understand the nature of the high comorbidity rates between the two disorders. Moreover, this study provides an initial analysis of the new DSM-5 diagnostic criteria for PTSD

Monitoring and prevalence rates of metabolic syndrome in military veterans with serious mental illness

Background: Cardiovascular disease is the leading cause of mortality among patients with serious mental illness (SMI) and the prevalence of metabolic syndrome-a constellation of cardiovascular risk factors-is significantly higher in these patients than in the general population. Metabolic monitoring among patients using second generation antipsychotics (SGAs)-a risk factor for metabolic syndrome-has been shown to be inadequate despite the release of several guidelines. However, patients with SMI have several factors independent of medication use that predispose them to a higher prevalence of metabolic syndrome. Our study therefore examines monitoring and prevalence of metabolic syndrome in patients with SMI, including those not using SGAs. Methods and Findings: We retrospectively identified all patients treated at a Veterans Affairs Medical Center with diagnoses of schizophrenia, schizoaffective disorder or bipolar disorder during 2005-2006 and obtained demographic and clinical data. Incomplete monitoring of metabolic syndrome was defined as being unable to determine the status of at least one of the syndrome components. Of the 1,401 patients included (bipolar disorder: 822; schizophrenia: 222; and schizoaffective disorder: 357), 21.4% were incompletely monitored. Only 54.8% of patients who were not prescribed SGAs and did not have previous diagnoses of hypertension or hypercholesterolemia were monitored for all metabolic syndrome components compared to 92.4% of patients who had all three of these characteristics. Among patients monitored for metabolic syndrome completely, age-adjusted prevalence of the syndrome was 48.4%, with no significant difference between the three psychiatric groups. Conclusions: Only one half of patients with SMI not using SGAs or previously diagnosed with hypertension and hypercholesterolemia were completely monitored for metabolic syndrome components compared to greater than 90% of those with these characteristics. With the high prevalence of metabolic syndrome seen in this population, there appears to be a need to intensify efforts to reduce this monitoring gap

Costs and advance directives at the end of life: a case of the ‘Coaching Older Adults and Carers to have their preferences Heard (COACH)’ trial

Background Total costs associated with care for older people nearing the end of life and the cost variations related with end of life care decisions are not well documented in the literature. Healthcare utilisation and associated health care costs for a group of older Australians who entered Transition Care following an acute hospital admission were calculated. Costs were differentiated according to a number of health care decisions and outcomes including advance directives (ADs). Methods Study participants were drawn from the Coaching Older Adults and Carers to have their preferences Heard (COACH) trial funded by the Australian National Health and Medical Research Council. Data collected included total health care costs, the type of (and when) ADs were completed and the place of death. Two-step endogenous treatment-regression models were employed to test the relationship between costs and a number of variables including completion of ADs. Results The trial recruited 230 older adults with mean age 84 years. At the end of the trial, 53 had died and 80 had completed ADs. Total healthcare costs were higher for younger participants and those who had died. No statistically significant association was found between costs and completion of ADs. Conclusion For our frail study population, the completion of ADs did not have an effect on health care utilisation and costs. Further research is needed to substantiate these findings in larger and more diverse clinical cohorts of older people

Anti-inflammatory effects of nicotine in obesity and ulcerative colitis

Cigarette smoke is a major risk factor for a number of diseases including lung cancer and respiratory infections. Paradoxically, it also contains nicotine, an anti-inflammatory alkaloid. There is increasing evidence that smokers have a lower incidence of some inflammatory diseases, including ulcerative colitis, and the protective effect involves the activation of a cholinergic anti-inflammatory pathway that requires the α7 nicotinic acetylcholine receptor (α7nAChR) on immune cells. Obesity is characterized by chronic low-grade inflammation, which contributes to insulin resistance. Nicotine significantly improves glucose homeostasis and insulin sensitivity in genetically obese and diet-induced obese mice, which is associated with suppressed adipose tissue inflammation. Inflammation that results in disruption of the epithelial barrier is a hallmark of inflammatory bowel disease, and nicotine is protective in ulcerative colitis. This article summarizes current evidence for the anti-inflammatory effects of nicotine in obesity and ulcerative colitis. Selective agonists for the α7nAChR could represent a promising pharmacological strategy for the treatment of inflammation in obesity and ulcerative colitis. Nevertheless, we should keep in mind that the anti-inflammatory effects of nicotine could be mediated via the expression of several nAChRs on a particular target cell