Focused Ultrasound Stimulates ER Localized Mechanosensitive PANNEXIN-1 to Mediate Intracellular Calcium Release in Invasive Cancer Cells.

Focused ultrasound (FUS) is a rapidly developing stimulus technology with the potential to uncover novel mechanosensory dependent cellular processes. Since it is non-invasive, it holds great promise for future therapeutic applications in patients used either alone or as a complement to boost existing treatments. For example, FUS stimulation causes invasive but not non-invasive cancer cell lines to exhibit marked activation of calcium signaling pathways. Here, we identify the membrane channel PANNEXIN1 (PANX1) as a mediator for activation of calcium signaling in invasive cancer cells. Knockdown of PANX1 decreases calcium signaling in invasive cells, while PANX1 overexpression enhances calcium elevations in non-invasive cancer cells. We demonstrate that FUS may directly stimulate mechanosensory PANX1 localized in endoplasmic reticulum to evoke calcium release from internal stores. This process does not depend on mechanosensory stimulus transduction through an intact cytoskeleton and does not depend on plasma membrane localized PANX1. Plasma membrane localized PANX1, however, plays a different role in mediating the spread of intercellular calcium waves via ATP release. Additionally, we show that FUS stimulation evokes cytokine/chemokine release from invasive cancer cells, suggesting that FUS could be an important new adjuvant treatment to improve cancer immunotherapy.

QTc Prolongation in Veterans With Heroin Dependence on Methadone Maintenance Treatment.

BACKGROUND: QTc prolongation and Torsade de Ppointes have been reported in patients on methadone maintenance. OBJECTIVES: In this study, QTc was compared before and after the veteran (n = 49) was on a stable dosage of methadone for 8.72 ± 4.50 years to treat heroin dependence. Risk factors were correlated with the QTc once the veteran was on a stable dose of methadone. Differences in the clinical risk factors in subgroups of veterans with below and above mean QTc change was compared. PATIENTS AND METHODS: ECG data was obtained from a 12-lead electrocardiogram (pre-methadone and on methadone) on 49 veterans. Data and risk factors were retrospectively collected from the medical records. RESULTS: The mean QTc at baseline (pre-methadone) was 426 ± 34 msec and after being on methadone for an average of 8.72 ± 4.50 years was significantly higher at 450 ± 35 msec. No significant relationships were found between QTc prolongation and risk factors except for calcium. The methadone dosage was significantly higher in veterans with a QTc change above the mean change of ≥ 24 msec (88.48 ± 27.20 mg v.s 68.96 ± 19.84 mg). None of the veterans experienced cardiac arrhythmias. CONCLUSIONS: The low complexity of medical co-morbidities may explain the lack of a significant correlation between any risk factor with the QTc except calcium and methadone dosage. The absence of TdP may be explained by the low prevalence of QTc values > 500 msec as well as the retrospective design of the study. During long-term methadone treatment, there was a slight increase in the QTc interval but we did not find evidence of increased cardiac toxicity as a reason for treatment termination.

Methadone, QTc interval prolongation and torsade de pointes: Case reports offer the best understanding of this problem.

We reviewed the literature and found 31 adult cases and 1 newborn case of methadone-associated QTc interval prolongation and/or torsade de pointes (TdP). Parametric statistics may not be useful in studying this issue because methadone-associated TdP is a very rare event and, hence, "an extreme outlier" consistent with scalable randomness. We may have to rely upon narrative medicine in the form of case reports with all its limitations and hazards to provide our best understanding. We report risk factors for methadone-associated QTc interval prolongation and TdP based on review of published case reports. We believe both drug manufacturers and the FDA would better serve our patients and inform clinicians if they more readily reported drug-induced outliers such as methadone-associated TdP using a case report format.

Selective serotonin reuptake inhibitors and torsade de pointes: new concepts and new directions derived from a systematic review of case reports.

OBJECTIVE: In the light of the recent United States Food and Drug Administration (FDA) warning to clinicians on using previously approved doses of citalopram because of the purported higher risk of torsade de pointes (TdP), we pursued the broader question: are selective serotonin reuptake inhibitor (SSRI) antidepressant agents as a group unsafe because they might induce QTc interval prolongation and TdP? METHOD: We reviewed the literature and found only 15 case reports (6 of fluoxetine, 1 of sertraline and 8 of citalopram) of SSRI-associated QTc interval prolongation linking to TdP. RESULTS: A total of 13 cases contained sufficient information for analysis. In the setting of TdP, QTc interval prolongation does not clearly relate to SSRI dose. CONCLUSION: Applying conventional statistics as the FDA does may not be the best tool to study this phenomenon because SSRI-associated TdP is a very rare event and hence best understood as an 'extreme outlier'. Despite the limitations inherent in case report material, case reports on drug-associated QTc interval prolongation and TdP provide valuable information that should be considered along with other sources of information for clinical guidance.

A roadmap for observership programs in psychiatry for international medical graduates.

OBJECTIVE: International medical graduates (IMGs) constitute a significant proportion of the psychiatric workforce in the United States. Observership programs serve an important role in preparing IMGs for U.S. residency positions; yet there are limited resources with information available on establishing these observerships, and none specific to psychiatry. In this article, authors present a roadmap for observership programs in psychiatry for IMGs. METHOD: This article draws on the experience of the IMG committee of the Group for Advancement of Psychiatry in establishing observership programs. RESULTS: Authors highlight the benefits of observership programs to IMGs, psychiatry departments, and the U.S. medical system as a whole. The different components of an observership program are presented, along with core competencies that need to be acquired. The authors discuss challenges that observership programs may encounter as well as recommendations for overcoming them. CONCLUSION: Observership programs provide a unique opportunity to integrate IMGs into the U.S. medical system. This article provides a framework for establishing such programs in a way that will optimize their benefits and avoid potential pitfalls.

Proarrhythmic risk with antipsychotic and antidepressant drugs: implications in the elderly.

The quinidine-like effects of some antidepressant drugs (particularly tricyclic antidepressants) and many antipsychotic drugs (particularly the phenothiazines) confound treatment of psychosis and depression in patients with major mental illness. This is especially true among elderly patients with existing risk factors for corrected QT (QTc) interval prolongation. We used PubMed, previously reported review articles and the extensive personal files of the authors to identify cases of subjects aged>or=60 years who developed QTc interval prolongation, polymorphic ventricular tachycardia (PVT)/torsade de pointes (TdP) and/or sudden cardiac death while taking antipsychotic or antidepressant drugs or a combination of these medications. We identified 37 patients who had taken, in total, 46 antipsychotic or antidepressant drugs. Our most striking finding was that almost four-fifths of our cases involved women. When the 14 critically ill subjects receiving haloperidol intravenously were excluded, 91.3% of our subjects were women. Almost three-quarters of our study subjects had cardiovascular disease. Intravenous administration of haloperidol in the critically ill and profoundly agitated elderly warrants particular comment. Of the 14 subjects in this category identified, six were men and eight were women. In 13 cases, the drug dose far exceeded the 2 mg necessary to produce an antipsychotic effect. These clinicians were using an agent to achieve sedation that usually requires very high doses in the critically ill and profoundly agitated elderly to achieve this effect. Inclusion criteria for our literature review required antipsychotic and/or antidepressant drug-induced QTc interval prolongation. Even so, our finding that 31 of our 37 subjects developed PVT is sobering. However, the reader should not conclude that drug-induced QTc interval prolongation is highly predictive of PVT or its TdP subtype. All of our study subjects had at least two risk factors for TdP, with age and sex being the most common. We included the rare case of a patient with congenital long QT syndrome who developed further lengthening of the QTc interval and TdP when prescribed an antidepressant drug well known to produce QTc interval prolongation. We conclude with recommendations for clinicians not expert in the specialty of cardiology to deal with the many questions raised in this review. Specifically, such clinicians treating elderly patients with antipsychotic and antidepressant drugs that may prolong the QTc interval should aggressively obtain a baseline ECG for elderly female patients with additional risk factors such as personal or family history of pre-syncope or syncope, electrolyte disturbances or cardiovascular disease. Elderly male patients are also subject to QTc interval prolongation when such risk factors are present. It is important that the clinicians themselves inspect ECGs. If the QT interval is more than half the RR interval, QTc interval prolongation is likely to be present. In such cases, a cardiology colleague interested in QTc interval issues and TdP should be asked to review the ECG. Finally, nothing in our recommendations replaces meticulous attention to US FDA guidelines in the package insert of each drug.

Pharmacological management of psychosis in elderly patients with parkinsonism.

Parkinsonism is a characteristic feature of Parkinson's disease and dementia with Lewy bodies and is commonly seen in Alzheimer's disease. Psychosis commonly appears during the course of these illnesses. Treatment of parkinsonism with antiparkinsonian medications constitutes an additional risk factor for the appearance or worsening of psychosis. Conversely, treatment of psychosis with antipsychotic drugs in patients with parkinsonism might worsen the underlying movement disorder, especially in the elderly. In this article, we review parkinsonian conditions in the elderly and offer guidelines to assess and manage comorbid psychosis. We focus on the pharmacologic management of psychosis with atypical antipsychotic medications and briefly review the role of acetylcholinesterase inhibitors.

Clinical monitoring and management of the metabolic syndrome in patients receiving atypical antipsychotic medications.

Individuals with major mental illness are a high-risk group for cardio-metabolic derangements due to genetic predisposition, developmental and environmental stressors, and lifestyle. This risk is compounded when they receive antipsychotic medications. Guidelines for screening, monitoring, and managing these patients for metabolic problems have been in place for several years. Despite this, recent reports document that this population continues to receive poor care in this regard. In this article, we review the metabolic profile of atypical antipsychotic medications and offer guidelines to reduce the metabolic complications of these agents.

Psychotropic drug considerations in depressed patients with metabolic disturbances.

Depression, obesity, diabetes mellitus, and the metabolic syndrome are conditions commonly treated in primary care. The prevalence of each condition separately does not explain the frequency of their co-occurrence. Depression may lead to or exacerbate these endocrine and metabolic conditions. Conversely, these medical conditions may lead to or exacerbate depression. Psychotropic drugs that treat depression may increase appetite with resultant weight gain. Rarely, such agents may be associated with weight loss. We review the potential for psychotropic drugs to alter body weight and provide a table as a guide to drug selection. Unless circumstances dictate otherwise, clinicians should select psychotropic drugs least likely to induce weight gain when treating depressed patients with obesity, diabetes mellitus, or the metabolic syndrome. Even drugs generally thought to be "weight neutral" may occasionally be associated with weight gain. Thus, alerting patients to this potential and due diligence form the cornerstone of weight management in the depressed patient.

The risk of overweight in children and adolescents with major mental illness.

OBJECTIVES: To survey the charts of youths with major mental illness who may constitute a high-risk group (HRG) for overweight. METHODS: We reviewed the charts of youths admitted to a public sector psychiatric hospital. For the 795 cases of patients 6 to 18 years old identified as the study cohort, we derived body mass index percentiles using the Centers for Disease Control Epi Info software. We defined a HRG as those youths who were "overweight" and "at risk for overweight" and compared them with national measurements. We also determined the frequency of psychiatric diagnoses and psychotropic drugs use. RESULTS: A total of 51.8% were in the HRG compared with the national average of 35.2% for the 6 to 19 years age group of the latest available National Health and Nutrition Examination Survey. We noted an increase in the prevalence of mood disorders and psychosis with increasing age. Many (45.3%) were discharged on medications that can potentially cause moderate-to-severe weight gain. CONCLUSIONS: Youths with major psychiatric illnesses constitute a HRG for overweight.

Cardiovascular side effects of newer antidepressants.

We review the cardiovascular effects of newer antidepressants. Although further studies are warranted, the safety of the selective serotonin reuptake inhibitors and the serotonin norepinephrine reuptake inhibitors on patients with comorbid cardiac conditions is impressive. Newer antidepressants should be considered as first-line agents for the treatment of depression in patients with and without cardiovascular disease.

Correlation between high risk obesity groups and low socioeconomic status in school children.

OBJECTIVE: Obesity is a major health problem among children and adolescents which is potentially affected by socioeconomic status (SES). The high risk group (HRG) comprises those youths with a body mass index (BMI) between the 85th and 95th percentile (at risk for overweight) and > or = 95th percentile (overweight). We sought a potential link between the HRG and SES. METHODS: Public schools in Chesterfield County, Virginia measured BMI among students in kindergarten and third, seventh, and tenth grades. We assessed SES based on eligibility for the National School Lunch Program and the percentage of the school-age population living in poverty based on per capita income from the 2000 Census. RESULTS: From 28 to 38% of children and adolescents were in the high risk group. Low SES had robust and highly significant correlations with HRG status with r-values ranging from 0.565 to 0.842, P < 0.0001. CONCLUSIONS: Low SES appears to be an important factor in childhood and adolescent obesity.

Toxicology findings in child and adolescent suicides in virginia: 1987-2003.

OBJECTIVE: In a follow-up report of child and adolescent suicides in Virginia, we describe postmortem toxicology findings in a subset of these youths. METHOD: We analyzed "unnatural" deaths from Virginia's Office of the Chief Medical Examiner for 1987 to 2003. There were 2818 unnatural deaths in children and adolescents. We grouped unnatural deaths as accidents, homicides, and suicides. Toxicology records were available for 753 cases, of which 732 were black or white youths. RESULTS: There were no age differences among suicide victims and accident or homicide victims. Whites were more likely than blacks to die by accident and suicide. White females were more likely than black females to commit suicide. Black males were more likely than white males to suffer homicide. For all unexpected deaths, antidepressants were more commonly found among whites than blacks. Suicide by poisoning occurred more commonly among whites. Recreational drugs were more commonly found among blacks than whites. Suicide by gun occurred more commonly among blacks. Antidepressants were found in 39 black and white suicide victims. Anti-depressants (all tricyclic antidepressants) were causally related in 17 cases of suicide by poisoning. No other antidepressants were found in lethal levels in suicide by poisoning. Selective serotonin reuptake inhibitors (SSRIs)/venlafaxine appeared more commonly in the suicides (p < .0001) than in accidents or homicides. For suicides, SSRIs appeared no more commonly in poisoning than in gun or hanging deaths (p = .695). CONCLUSIONS: Antidepressants appeared more commonly among youths committing suicide than those dying by accident or homicide. SSRIs did not appear more commonly among youths committing suicide by poisoning than those committing suicide by gun or hanging. Because our data are descriptive, they are subject to over-interpretation. Cause-effect inferences should not be drawn.

Posttraumatic stress disorder in male military veterans with comorbid overweight and obesity: psychotropic, antihypertensive, and metabolic medications.

UNLABELLED: Posttraumatic stress disorder (PTSD) is an important syndrome among military veterans. Little has been written about comorbid medical conditions of PTSD, particularly overweight and obesity. We focus on psychotropic and non-psychotropic drugs, their interactions, and metabolic issues most relevant to primary care physicians. METHOD: Data from the recently constituted PTSD program at the Department of Veterans Affairs Medical Center in Richmond, Va., were retrospectively reviewed to assess the prevalence and severity of comorbid overweight and obesity in male veterans with PTSD. Also, our database allowed us to correlate various drugs used to treat hypertension, diabetes mellitus, and dyslipidemia with body mass index (BMI). RESULTS: The mean BMI of 157 veterans with PTSD (DSM-IV criteria) in this sample was in the obese range (30.3 ± 5.6 kg/m²). The number of drugs a given patient was taking for treatment of hypertension, diabetes mellitus, and dyslipidemia correlated with BMI. Psychotropic drugs associated with weight gain did not explain our findings. CONCLUSIONS: Overweight and obesity among our male veterans with PTSD strikingly exceeded national findings. The administration of psychotropic drugs associated with weight gain did not explain these findings. The number of medications used to treat hypertension, diabetes mellitus, and dyslipidemia correlated significantly with BMI. Rather than these medications explaining the high prevalence of overweight and obesity in our study population, obesity probably worsened these components of the metabolic syndrome, necessitating more aggressive treatment reflected in the high number of drugs prescribed.

Treatment of depression in patients with coronary heart disease.

Depression and coronary heart disease are common conditions that often occur together. Evidence shows that the co-occurrence of these illnesses is not random but driven by depression as a risk factor for the occurrence and progression of coronary heart disease. This link is due, in part, to the impact that depression has on neuroendocrine pathways leading to increased platelet activation, cortisol and catecholamine excess, and altered autonomic nervous system function that influence the pathogenesis and progression of coronary atherosclerosis and subsequent heart disease. We know that treating depression in patients with coronary heart disease improves the symptoms and signs of depression. Evidence is less compelling that treating depression improves the morbidity and mortality of coronary heart disease. However, early findings suggest that some antidepressants may improve the course of coronary heart disease and improve patient compliance with various cardiac interventions. We outline a practical approach to the treatment of depression in patients with coronary heart disease. This approach includes education, counseling, antidepressant drugs, and referral when appropriate.

Posttraumatic stress disorder: clinical features, pathophysiology, and treatment.

Posttraumatic stress disorder (PSTD), classified as an anxiety disorder, has become increasingly important because of wars overseas, natural disasters, and domestic violence. After trauma exposes the victim to actual or threatened death or serious injury, 3 dimensions of PTSD unfold: (1) reexperiencing the event with distressing recollections, dreams, flashbacks, and/or psychologic and physical distress; (2) persistent avoidance of stimuli that might invite memories or experiences of the trauma; and (3) increased arousal. Traumatic events sufficient to produce PTSD in susceptible subjects may reach a lifetime prevalence of 50% to 90%. The actual lifetime prevalence of PTSD among US citizens is approximately 8%, with the clinical course driven by pathophysiologic changes in the amygdala and hippocampus. Comorbid depression and other anxiety disorders are common. General principles of treatment include the immediate management of PTSD symptoms and signs; management of any trauma-related comorbid conditions; nonpharmacologic interventions including cognitive behavioral treatment; and psychopharmacologic agents including antidepressants (selective serotonin reuptake inhibitors most commonly), antianxiety medications, mood stabilizing drugs, and antipsychotics. This review of PTSD will provide the reader with a clearer understanding of this condition, an increased capacity to recognize and treat this syndrome, and a greater appreciation for the role of the internist in PTSD.

Posttraumatic stress disorder and body mass index in military veterans. Preliminary findings.

INTRODUCTION: Current management of posttraumatic stress disorder (PTSD) focuses on the psychiatric parameters of this condition. Little has been written about co-morbid overweight and obesity in PTSD. METHODS: We used the database of the recently constituted PTSD program at the Hunter Holmes McGuire Veterans Affairs Medical Center in Richmond, Virginia to assess and better understand the prevalence and severity of overweight and obesity among military veterans with PTSD. Variables assessed included age, decade of life, height, weight, sex, race, and severity and chronicity of PTSD. We used PTSD CheckList-Military Version (PCL-M) to assess current complaints and service-connected disability (SCD) to estimate the long-term severity of PTSD. RESULTS: Of the 221 male veterans extracted from our PTSD database for purposes of this study, 144 (65.2%) were in the age range of 50 to 59 years consistent with Vietnam veterans dominating our study population. Their mean body mass index (BMI) was 30.2+/-5.8 kg/m(2) placing the typical veteran in the obese range. Far exceeding the current US population rate of 64.5%, 82.8% of our study population was either overweight or obese. Our sample had BMI measurements greater than those reported for non-PTSD veterans and also BMI measurements reported in the literature for veterans with PTSD. Current (PCL-M) and long-term (SCD) markers of PTSD did not relate to obesity. CONCLUSIONS: The prevalence of overweight and obesity among our veterans with PTSD far exceeded current US population findings and those of other veteran groups with and without PTSD. PTSD symptoms, whether assessed acutely or chronically, did not explain our findings. Prospective studies of PTSD and comorbidity are needed using larger study populations to better understand the relationships among PTSD, stress, and obesity.

Body mass index relates to males with posttraumatic stress disorder.

INTRODUCTION: We looked at the relationships among posttraumatic stress disorder (PTSD), body mass index (BMI) and socioeconomic status (SES) in a newly formed PTSD program at the Hunter Holmes McGuire Veterans Affairs Medical Center in Richmond, VA. METHODS: We reviewed 265 records and then selected only black and white male veterans (n=252) for study. Variables were: 1) age, 2) decade of life, 3) height, 4) weight, 5) sex, 6) race, and 7) SES (estimated using priority group status). Low income is an important variable determining priority group status. RESULTS: About two-thirds of the veterans were in the age range of 50-59 years (Vietnam veterans). Their mean BMI was 30.2 +/- 5.6 kg/m2, and this value did not separate by race. Far exceeding national numbers, 84.1% of our veterans were either overweight or obese. Veterans in the lower priority groups had greater (p=0.029) BMIs than their counterparts in higher priority groups. CONCLUSIONS: The pervasiveness of overweight and obesity in our PTSD population was profound. Our observations suggest that low SES is a likely contributor to veterans in lower priority groups having greater BMIs than veterans in higher priority groups.

Child and adolescent suicides in Virginia: 1987 to 2003.

OBJECTIVES: The aim of this study was to better understand suicides in children and adolescents using records from the Office of the Medical Examiner of Virginia from 1987 to 2003. MAIN FINDINGS, KEY DATA, AND STATISTICS: Suicide accounted for 16.8% of unnatural deaths. Suicide rates were highest for Caucasians. Guns were the most common method of death for suicides, followed by hanging and poisoning. Poisoning other than carbon monoxide accounted for 7.8% of suicides, with tricyclic antidepressants (TCAs) the most identifiable poison. Female youths were 10 times more likely to die from TCAs than male youths, after adjusting for race and age. CONCLUSIONS: Guns and hanging were the principal methods of suicide. Among the antidepressants, TCAs have been the most common poisons used in suicide. Increasing age was a powerful determinant of suicide. Some patients may have stockpiled their TCAs for a while before their TCA overdose. Other suicide victims may have used TCA supplies from family members. Hence, some of the suicide victims may not have taken TCAs on a regular basis before committing suicide. Further exploration of TCA-induced suicidal thoughts is needed. Conclusions cannot be made at the time about the precise role that TCAs played in TCA-induced suicide reported in our study.