Chronic glucolipotoxic conditions in pancreatic islets impair insulin secretion due to dysregulated calcium dynamics, glucose responsiveness and mitochondrial activity.

BACKGROUND: In the progression towards diabetes, glucolipotoxicity is one of the main causes of pancreatic beta cell pathology. The aim of this study was to examine the in vitro effects of chronic glucolipotoxic conditions on cellular responses in pancreatic islets, including glucose and fat metabolism, Calcium mobilization, insulin secretion and insulin content. RESULTS: Exposure of islets to chronic glucolipotoxic conditions decreased glucose stimulated insulin secretion in vitro. Reduced protein levels of Glut2/slc2a2, and decreased glucokinase and pyruvate carboxylase mRNA levels indicated a significant lowering in glucose sensing. Concomitantly, both fatty acid uptake and triglyceride accumulation increased significantly while fatty acid oxidation decreased. This general suppression in glucose metabolism correlated well with a decrease in mitochondrial number and activity, reduction in cellular ATP content and dampening of the TCA cycle. Further, we also observed a decrease in IP3 levels and lower Calcium mobilization in response to glucose. Importantly, chronic glucolipotoxic conditions in vitro decreased insulin gene expression, insulin content, insulin granule docking (to the plasma membrane) and insulin secretion. CONCLUSIONS: Our results present an integrated view of the effects of chronic glucolipotoxic conditions on known and novel signaling events, in vitro, that results in reduced glucose responsiveness and insulin secretion.

Communicating suicide risk to families of chronically suicidal borderline personality disorder patients to mitigate malpractice risk.

OBJECTIVE: The distinction between acute and chronic suicidality is important, because interventions designed to address acute suicidality can worsen chronic suicidality, resulting in an escalating cycle of suicide threats, suicide attempts, and futile hospitalizations. Though most chronically suicidal borderline personality disorder patients improve and do not complete suicide, the potential for suicide contributes to these hospitalizations and a paucity of outpatient services due to treaters' concern over malpractice lawsuits in case of suicide. Communicating with patients' families about the suicide risk has been suggested as a means to mitigate this malpractice risk, but the approach to such communication has not been described. METHOD: Once chronic suicidality is identified, a stepwise approach to communicating with the patient's family is described. RESULTS: The potential benefits of this risk communication are described, for patients, families, treaters, healthcare systems, and health and malpractice insurers. CONCLUSION: It helps to develop an alliance with families and patients around a shared understanding of outcomes in chronic suicidality - most eventually do better, but the risk of completed suicide is real. This enables patients and families to make a more fully informed choice about treatment, which in turn can reduce litigation risk in the minority of cases where the patient completes suicide.

The International Society for Bipolar Disorders (ISBD) consensus guidelines for the safety monitoring of bipolar disorder treatments.

OBJECTIVES: Safety monitoring is an important aspect of bipolar disorder treatment, as mood-stabilising medications have potentially serious side effects, some of which may also aggravate existing medical comorbidities. This paper sets out the International Society for Bipolar Disorders (ISBD) guidelines for the safety monitoring of widely used agents in the treatment of bipolar disorder. These guidelines aim to provide recommendations that take into consideration the balance between safety and cost-effectiveness, to highlight iatrogenic and preventive clinical issues, and to facilitate the broad implementation of therapeutic safety monitoring as a standard component of treatment for bipolar disorder. METHODS: These guidelines were developed by an ISBD workgroup, headed by the senior author (MB), through an iterative process of serial consensus-based revisions. After this, feedback from a multidisciplinary group of health professionals on the applicability of these guidelines was sought to develop the final recommendations. RESULTS: General safety monitoring recommendations for all bipolar disorder patients receiving treatment and specific monitoring recommendations for individual agents are outlined. CONCLUSIONS: These guidelines are derived from evolving and often indirect data, with minimal empirical cost-effectiveness data available to provide guidance. These guidelines will therefore need to be modified to adapt to different clinical settings and health resources. Clinical acumen and vigilance remain critical ingredients for safe treatment practice.

Effects of Blast Exposure on Subjective and Objective Sleep Measures in Combat Veterans with and without PTSD.

STUDY OBJECTIVES: This study examined the extent to which self-reported exposure to blast during deployment to Iraq and Afghanistan affects subjective and objective sleep measures in service members and veterans with and without posttraumatic stress disorder (PTSD). METHODS: Seventy-one medication-free service members and veterans (mean age = 29.47 ± 5.76 years old; 85% men) completed self-report sleep measures and overnight polysomnographic studies. Four multivariate analyses of variance (MANOVAs) were conducted to examine the impact of blast exposure and PTSD on subjective sleep measures, measures of sleep continuity, non-rapid eye movement (NREM) sleep parameters, and rapid eye movement (REM) sleep parameters. RESULTS: There was no significant Blast × PTSD interaction on subjective sleep measures. Rather, PTSD had a main effect on insomnia severity, sleep quality, and disruptive nocturnal behaviors. There was no significant Blast × PTSD interaction, nor were there main effects of PTSD or Blast on measures of sleep continuity and NREM sleep. A significant PTSD × Blast interaction effect was found for REM fragmentation. CONCLUSIONS: The results suggest that, although persistent concussive symptoms following blast exposure are associated with sleep disturbances, self-reported blast exposure without concurrent symptoms does not appear to contribute to poor sleep quality, insomnia, and disruptive nocturnal disturbances beyond the effects of PTSD. Reduced REM sleep fragmentation may be a sensitive index of the synergetic effects of both psychological and physical insults.

Anger attacks in bipolar depression: predictors and response to citalopram added to mood stabilizers.

BACKGROUND: Of the 2 reports in the literature on anger attacks in bipolar depression, one found them to be uncommon (12%) compared with the rate in bipolar mixed states and unipolar depression (40%-60%), whereas the other found them to be common (62%). We examined anger attacks among participants in an 8-week trial of open-label citalopram added to mood stabilizer for the treatment of bipolar depression. We also examined trait anger, hypomanic symptoms, and depressive symptoms as predictors of anger attacks. We hypothesized that if anger attacks were related to hypomanic symptoms they would respond unfavorably to citalopram, whereas if they were related to trait anger or depressive symptoms they would respond favorably. METHOD: In 45 participants with a DSM-IV diagnosis of bipolar I or II depression, anger attacks, hypomanic symptoms, and depressive symptoms were assessed using a modified Anger Attacks Questionnaire, Young Mania Rating Scale, and Hamilton Rating Scale for Depression, respectively. Trait anger was measured using the State-Trait Anger Inventory. Posttreatment data were collected at the end of 8 weeks of treatment with citalopram or at dropout from the trial. The first participant study visit was in November 1998, and the final participant study visit was in December 2000. RESULTS: Before treatment with citalopram, 17 (38.6%) of 44 participants reported anger attacks (data on anger attacks were missing for 1 participant before treatment and 4 after treatment). Significantly fewer participants reported anger attacks after treatment (6 of 41, 14.6%; McNemar test, p <.05, 2-tailed). At pretreatment and post-treatment, trait anger was the only significant predictor of anger attacks (p <.05). CONCLUSIONS: These findings suggest that in bipolar depression anger attacks are common, may respond favorably to acute treatment with citalopram added to mood stabilizer, and are better predicted by trait anger than hypomanic or depressive symptoms. Further studies are needed to clarify the diagnostic and treatment implications of anger attacks in bipolar depression.

Computerized adaptive measurement of depression: a simulation study.

BACKGROUND: Efficient, accurate instruments for measuring depression are increasingly important in clinical practice. We developed a computerized adaptive version of the Beck Depression Inventory (BDI). We examined its efficiency and its usefulness in identifying Major Depressive Episodes (MDE) and in measuring depression severity. METHODS: Subjects were 744 participants in research studies in which each subject completed both the BDI and the SCID. In addition, 285 patients completed the Hamilton Depression Rating Scale. RESULTS: The adaptive BDI had an AUC as an indicator of a SCID diagnosis of MDE of 88%, equivalent to the full BDI. The adaptive BDI asked fewer questions than the full BDI (5.6 versus 21 items). The adaptive latent depression score correlated r =.92 with the BDI total score and the latent depression score correlated more highly with the Hamilton (r =.74) than the BDI total score did (r =.70). CONCLUSIONS: Adaptive testing for depression may provide greatly increased efficiency without loss of accuracy in identifying MDE or in measuring depression severity.

Negative affect and parental aggression in child physical abuse.

OBJECTIVE: Parental negative affect is a risk factor for child physical abuse. As negative affect contributes to aggression, and because physical abuse involves an aggressive act directed at the child, we examined the relationship between negative affect and parent-to-child aggression (PTCA) in parents reported to Child Protective Services for physical abuse. METHOD: Baseline assessment data were retrospectively examined on 49 participants in a treatment study for child physical abuse. The negative affects studied were depression, anxiety, and hostility on the Beck Depression Inventory and the Brief Symptom Inventory. PTCA was assessed using the physical aggression subscales (Minor and Severe Physical Violence) of the Conflict Tactics Scale. The contribution of these negative affects to PTCA was examined after controlling individually for the effects of parental attributions and contextual variables widely regarded as etiological factors in child physical abuse. RESULTS: Contributions of negative affect to PTCA after individually controlling for other predictors were found for Minor Physical Violence but not Severe Physical Violence. Findings were strongest with depression on the Beck Depression Inventory and to a lesser extent with hostility on the Brief Symptom Inventory. CONCLUSIONS: Finding that negative affect contributed to PTCA in this sample suggests that it may be important to study the effects of emotion-focused treatments in physically abusive parents. These findings also suggest that PTCA may have qualities of impulsive aggression, a form of aggression that is conceptualized as driven by negative affect, occurs in response to aversive events, and is not planned.

Parental cognitions and satisfaction: relationship to aggressive parental behavior in child physical abuse.

There are limited data on cognitions and satisfaction with the child in parents who have physically abused their children. Therefore, we examined convergence among these constructs, and their relationships to parental aggression among participants in a treatment study for child physical abuse. Data were examined at two time points 12 weeks apart. The cognitions (unrealistic expectations of the child, perception of lack of control, and hostile attribution bias) and satisfaction with the child showed little convergence. Only parental satisfaction correlated significantly with aggressive parental behavior directed at the child, even after controlling for social desirability. Where there were significant correlations between externalizing child behavior and aggressive parental behavior and between parental depression and aggressive parental behavior, some limited support was found for an indirect path through parental satisfaction. If replicated, these findings suggest it may be useful to focus on parental satisfaction in research on child physical abuse.

Treatment for insomnia in combat-exposed OEF/OIF/OND military veterans: preliminary randomized controlled trial.

Chronic insomnia is highly prevalent among military personnel returning from Iraq and Afghanistan. We evaluated the effects of a military version of a brief behavioral treatment of insomnia (BBTI-MV) compared to an information only control (IC) condition in combat-exposed Veterans of Operations Enduring/Iraqi Freedom or Operation New Dawn (OEF/OIF/OND) on insomnia, sleep quality, and daytime symptoms of anxiety and depression. Forty OEF/OIF/OND Veterans (Mean age = 38.4 years old, s.d. = 11.69; 85% men; 77.5% white) were randomized to one of two conditions. BBTI-MV consisted of two in-person sessions and two telephone contacts delivered over four weeks, and included personalized recommendations to reduce insomnia. The IC condition also consisted of 2 in-person sessions two telephone contacts delivered over four weeks, and Veterans were encouraged to read written information about sleep-promoting behaviors. The Insomnia Severity Index, Pittsburgh Sleep Quality Index, PTSD Checklist, and Beck Depression and Anxiety Inventories were completed at baseline, post-treatment, and at the six-month follow-up. Both interventions were associated with clinically significant improvements in insomnia, although the magnitude of improvements in sleep and rates of treatment response and remission were greater for BBTI-MV compared to IC from pre- to post-treatment. Both BBTI-MV and the provision of information were associated with clinically significant improvements in insomnia among Veterans. Despite the preliminary nature of the findings and limitations inherent to small controlled trials, the findings suggest that both approaches may provide viable options in a stepped-care approach to the treatment of insomnia in retuning combat-exposed Veterans. Larger, confirmatory effectiveness trials are required. CLINICALTRIALSGOV IDENTIFIER: NCT00840255.

A window into the invisible wound of war: functional neuroimaging of REM sleep in returning combat veterans with PTSD.

Relative regional cerebral metabolic rate of glucose in rapid eye movement (REM) sleep and wakefulness was explored in combat veterans with and without posttraumatic stress disorder PTSD, using positron emission tomography. Hypermetabolism in brain regions involved in arousal regulation, fear responses, and reward processing persist during REM sleep in combat veterans with PTSD.

Sphingolipid metabolic pathway: an overview of major roles played in human diseases.

Sphingolipids, a family of membrane lipids, are bioactive molecules that participate in diverse functions controlling fundamental cellular processes such as cell division, differentiation, and cell death. Given that most of these cellular processes form the basis for several pathologies, it is not surprising that sphingolipids are key players in several pathological processes. This review discusses the role of the sphingolipid metabolic pathway in diabetes, Alzheimer's disease, and hepatocellular carcinoma, with a special emphasis on the changes in gene expression pattern in these disease conditions. For convenience, the sphingolipid metabolic pathway is divided into hypothetical compartments (modules) with each compartment representing a physiological process and changes in gene expression pattern are mapped to each of these modules. It appears that alterations in the gene expression pattern in these disease conditions are biased to manipulate the system in order to result in a particular disease.

Placebo-controlled comparison of prazosin and cognitive-behavioral treatments for sleep disturbances in US Military Veterans.

OBJECTIVE: Pharmacological and cognitive-behavioral treatments targeting insomnia and nightmares have been shown to be effective in the treatment of military veterans with sleep complaints comorbid with symptoms of stress-related disorders, including Post-Traumatic Stress Disorder (PTSD), but the two approaches have not been directly compared. This randomized controlled trial compared the effects of prazosin vs. a behavioral sleep intervention (BSI), targeting nightmares and insomnia against a placebo pill control condition on sleep and daytime symptoms. METHODS: Fifty United States military veterans (mean age 40.9years, SD=13.2years) with chronic sleep disturbances were randomized to prazosin (n=18), BSI (n=17), or placebo (n=15). Each intervention lasted 8weeks. Participants completed self-report measures of insomnia severity, sleep quality, and sleep disturbances. All kept a sleep diary throughout the intervention period. Polysomnographic studies were conducted pre- and post-intervention. RESULTS: Both active treatment groups showed greater reductions in insomnia severity and daytime PTSD symptom severity. Sleep improvements were found in 61.9% of those who completed the active treatments and 25% of those randomized to placebo. CONCLUSION: BSI and prazosin were both associated with significant sleep improvements and reductions in daytime PTSD symptoms in this sample of military veterans. Sleep-focused treatments may enhance the benefits of first-line PTSD treatments.