High-resolution analysis of differential gene expression during skeletal muscle atrophy and programmed cell death.

Skeletal muscles can undergo atrophy and/or programmed cell death (PCD) during development or in response to a wide range of insults, including immobility, cachexia, and spinal cord injury. However, the protracted nature of atrophy and the presence of multiple cell types within the tissue complicate molecular analyses. One model that does not suffer from these limitations is the intersegmental muscle (ISM) of the tobacco hawkmoth Manduca sexta. Three days before the adult eclosion (emergence) at the end of metamorphosis, the ISMs initiate a nonpathological program of atrophy that results in a 40% loss of mass. The ISMs then generate the eclosion behavior and initiate a nonapoptotic PCD during the next 30 h. We have performed a comprehensive transcriptomics analysis of all mRNAs and microRNAs throughout ISM development to better understand the molecular mechanisms that mediate atrophy and death. Atrophy involves enhanced protein catabolism and reduced expression of the genes involved in respiration, adhesion, and the contractile apparatus. In contrast, PCD involves the induction of numerous proteases, DNA methylases, membrane transporters, ribosomes, and anaerobic metabolism. These changes in gene expression are largely repressed when insects are injected with the insect steroid hormone 20-hydroxyecdysone, which delays death. The expression of the death-associated proteins may be greatly enhanced by reductions in specific microRNAs that function to repress translation. This study not only provides fundamental new insights into basic developmental processes, it may also represent a powerful resource for identifying potential diagnostic markers and molecular targets for therapeutic intervention.

Acheron/Larp6 Is a Survival Protein That Protects Skeletal Muscle From Programmed Cell Death During Development.

The term programmed cell death (PCD) was coined in 1965 to describe the loss of the intersegmental muscles (ISMs) of moths at the end of metamorphosis. While it was subsequently demonstrated that this hormonally controlled death requires de novo gene expression, the signal transduction pathway that couples hormone action to cell death is largely unknown. Using the ISMs from the tobacco hawkmoth Manduca sexta, we have found that Acheron/LARP6 mRNA is induced ∼1,000-fold on the day the muscles become committed to die. Acheron functions as a survival protein that protects cells until cell death is initiated at eclosion (emergence), at which point it becomes phosphorylated and degraded in response to the peptide Eclosion Hormone (EH). Acheron binds to a novel BH3-only protein that we have named BBH1 (BAD/BNIP3 homology 1). BBH1 accumulates on the day the ISMs become committed to die and is presumably liberated when Acheron is degraded. This is correlated with the release and rapid degradation of cytochrome c and the subsequent demise of the cell. RNAi experiments in the fruit fly Drosophila confirmed that loss of Acheron results in precocious ecdysial muscle death while targeting BBH1 prevents death altogether. Acheron is highly expressed in neurons and muscles in humans and drives metastatic processes in some cancers, suggesting that it may represent a novel survival protein that protects terminally differentiated cells and some cancers from death.

Characteristics of Future Models of Integrated Outpatient Care.

Replacement of fee-for-service with capitation arrangements, forces physicians and institutions to minimize health care costs, while maintaining high-quality care. In this report we described how patients and their families (or caregivers) can work with members of the medical care team to achieve these twin goals of maintaining-and perhaps improving-high-quality care and minimizing costs. We described how increased self-management enables patients and their families/caregivers to provide electronic patient-reported outcomes (i.e., symptoms, events) (ePROs), as frequently as the patient or the medical care team consider appropriate. These capabilities also allow ongoing assessments of physiological measurements/phenomena (mHealth). Remote surveillance of these communications allows longer intervals between (fewer) patient visits to the medical-care team, when this is appropriate, or earlier interventions, when it is appropriate. Systems are now available that alert medical care providers to situations when interventions might be needed.

Timely Interventions for Children with ADHD through Web-Based Monitoring Algorithms.

The aim of this study was to evaluate an automated trigger algorithm designed to detect potentially adverse events in children with Attention-Deficit/Hyperactivity Disorder (ADHD), who were monitored remotely between visits. We embedded a trigger algorithm derived from parent-reported ADHD rating scales within an electronic patient monitoring system. We categorized clinicians' alert resolution outcomes and compared Vanderbilt ADHD rating scale scores between patients who did or did not have triggered alerts. A total of 146 out of 1738 parent reports (8%) triggered alerts for 98 patients. One hundred and eleven alerts (76%) required immediate clinician review. Nurses successfully contacted parents for 68 (61%) of actionable alerts; 46% (31/68) led to a change in care plan prior to the next scheduled appointment. Compared to patients without alerts, patients with alerts demonstrated worsened ADHD severity (ß = 5.8, 95% CI: 3.5⁻8.1 [p < 0.001] within 90 days prior to an alert. The trigger algorithm facilitated timely changes in the care plan in between face-to-face visits.

Caring electronically for young outpatients who have epilepsy.

PURPOSE: The purpose of this study was to review electronic tools that might improve the delivery of epilepsy care, reduce medical care costs, and empower families to improve self-management capability. METHOD: We reviewed the epilepsy-specific literature about self-management, electronic patient-reported or provider-reported outcomes, on-going remote surveillance, and alerting/warning systems. CONCLUSIONS: The improved care delivery system that we envision includes self-management, electronic patient (or provider)-reported outcomes, on-going remote surveillance, and alerting/warning systems. This system and variants have the potential to reduce seizure burden through improved management, keep children out of the emergency department and hospital, and even reduce the number of outpatient visits.

Mothers' vagal regulation during the Still-Face Paradigm: normative reactivity and impact of depression symptoms.

This study examined mothers' physiological reactivity in response to infant distress during the Still-Face Paradigm. We aimed to explore normative regulatory profiles and associated physiological and behavioral processes in order to further our understanding of what constitutes regulation in this dyadic context. We examined physiological patterns--vagal tone, indexed by respiratory sinus arrhythmia (RSA)--while mothers maintained a neutral expression over the course of the still face episode, as well as differential reactivity patterns in mothers with depression symptoms compared to non-depressed mothers. Behavioral and physiological data were collected from mothers of 5-month-old infants during the emotion suppression phase of the Still-Face Paradigm. We used Hierarchical Linear Modeling to examine changes in mothers' RSA during infant distress and explored maternal depression as a predictor of physiological profiles. Mothers were generally able to maintain a neutral expression and simultaneously demonstrated a mean-level increase in RSA during the still face episode compared to baseline, indicating an active regulatory response overall. A more detailed time-course examination of RSA trajectories revealed that an initial RSA increase was typically followed by a decrease in response to peak infant distress, suggesting a physiological mobilization response. However, this was not true of mothers with elevated depressive symptoms, who showed no change in RSA during infant distress. These distinct patterns of infant distress-related physiological activation may help to explain differences in maternal sensitivity and adaptive parenting.

The relationship of anxiety disorders, anxiety sensitivity and pulmonary dysfunction with dyspnea-related distress and avoidance.

Little is known about factors that mediate the relationship between anxiety and respiratory-related distress and disability. We hypothesized that elevations in anxiety sensitivity would be associated with greater severity of dyspnea, greater dyspnea-related avoidance, and poorer subjective assessment of health in patients with dyspnea referred for pulmonary function testing, regardless of objective evidence of pulmonary dysfunction. A total of 182 consecutive patients receiving pulmonary function tests to evaluate dyspnea were screened with a patient-rated Primary Care Evaluation of Mental Disorders and completed the Anxiety Sensitivity Index and questionnaires assessing symptom severity and avoidance. Anxiety Sensitivity Index score predicted more severe subjective dyspnea and greater dyspnea-related avoidance, even after adjustment for anxiety disorders and pulmonary dysfunction. Despite some limitations, these data provide preliminary support that strategies to identify, measure, and address high levels of anxiety sensitivity should be examined to reduce subjective distress and improve functioning for patients with dyspnea.

Olanzapine augmentation of fluoxetine for refractory generalized anxiety disorder: a placebo controlled study.

BACKGROUND: There has been little systematic study of "next-step" interventions for patients with generalized anxiety disorder (GAD) who remain symptomatic despite initial pharmacotherapy. We present one of the first randomized controlled trials for refractory GAD, comprising double blind augmentation with olanzapine or placebo for patients remaining symptomatic on fluoxetine. METHODS: Patients remaining symptomatic after 6 weeks of fluoxetine (20 mg/day) were randomized to 6 weeks of olanzapine (mean dose 8.7 +/- 7.1 mg/day) or placebo augmentation. RESULTS: Twenty-four of 46 fluoxetine-treated patients were randomized. Olanzapine resulted in a greater proportion of treatment responders based on a Clinical Global Impression-Severity Scale (CGI-S) end point score of 1 or 2 (Fisher's exact test [FET] p < .05) or a 50% reduction in Hamilton Anxiety Scale (HAMA-A) score (FET p < .05). There were no other statistically significant differences for olanzapine compared with placebo augmentation in outcome measures, though rates of remission (HAM-A

Fluoxetine for vestibular dysfunction and anxiety: a prospective pilot study.

Anxiety states and disorders amplify the symptoms and impairment associated with vestibular dysfunction. Five patients with inner ear vestibular dysfunction and anxiety were prospectively treated with fluoxetine, 20-60 mg/day, and received an extensive battery of assessments at baseline and after 12 weeks of treatment. Fluoxetine led to significant or near significant reductions in anxiety measures and in impairment due to dizziness; improvements in clinical balance function and vestibular function were less clear. The data add to the literature suggesting a role for selective serotonin reuptake inhibitors in the treatment of dizziness and anxiety.

Religion, spirituality, and chaplains in the biomedical literature: 1965-2000.

In recent years, several prominent medical journals have published articles addressing the relationship between religion/spirituality and medicine, and recognizing the importance of religion in the lives of most Americans, especially in times of illness. We hypothesized that the publication of these articles reflected a trend in the biomedical literature in which greater attention is being given to the role of religion and spirituality in health-care. A correlational design was used, based on an electronic survey of all articles in MEDLINE for the years 1965 through 2000. The search terms used were: 1) religion or religious; 2) spiritual; and 3) chaplain. The number of articles per 100,000 that mentioned religion (religion or religious), spirituality, or chaplains each year was determined. Statistically significant upward trends across years were found for the rates of articles addressing religion (r = .59, p < .001) and spirituality (r = .89, p < .001) and a non-significant trend was found for chaplains (r = .31). The rising rates of articles on religion and spirituality in biomedical journals suggest a growing recognition of the need to address spiritual and religious issues in health-care.

A systematic review on chaplains and community-based clergy in three palliative care journals: 1990-1999.

A systematic review of all articles appearing between 1990 and 1999 in the American Journal of Hospice and Palliative Care, the Hospice Journal, and the Journal of Palliative Care was conducted. Articles citing at least one reference were categorized as scholarly, included in the study, and divided into either research or nonresearch categories. Scholarly articles were classified as research if they contained clearly defined methods and results sections, even if these headings were not used. Research and nonresearch articles were subdivided into qualitative and quantitative research and general reviews or program descriptions, respectively. All scholarly articles were read to see if they mentioned clergy, including the terms rabbi, priest, minister, pastor, imam, chaplain, or other religious professionals. Of 838 scholarly articles published between 1990 and 1999 in the three journals, 348 (41.5 percent) were research articles, 417 (49.8 percent) were reviews, and 73 (8.7 percent) were program descriptions. Forty-seven (5.6 percent) of all 838 scholarly articles mentioned clergy or chaplains in some way. Clergy and chaplains were more likely to be an integral part of research articles, whereas mention of them in nonresearch articles tended to be incidental (chi-square = 16.8, p < .001). Moreover, quantitative articles were more likely to include clergy as an integral aspect of the article than were qualitative articles (Fischer's exact probability test, p = .088). The results are discussed with respect to the mutual roles hospice chaplains and community-based clergy play in providing spiritual care at the end of life.

An evaluation of the quantity and quality of empirical research in three pastoral care and counseling journals, 1990-1999: has anything changed?

This article summarizes a review of all articles published in Pastoral Psychology, The Journal of Rleigion and Health, and The Journal of Pastoral Care between 1900 and 1999, identifying a total of 737 scholarly articles, of which 165 (22.4%) were research studies. The proportion of research studies, especially quantitative studies, increased significantly between the first and second half of the study period (p < .05). There was a significant positive correlation between compliance with three out of four criteria of internal validity. Three of five criteria of external validity were also positively related to one another. Compared to previous research using identical criteria to assess quantitative studies in the same journals in 1980-1989, the 1990-1999 sample showed improved compliance with respect to specifying the sampling method (p < .001), reporting the response rate (p < .05), and discussing the limitations of research studies (p < .001). However, the overall findings suggest that many researchers in the field do not have a sophisticated knowledge of statistical sampling, statistical analysis, or research design. Several recommendations for increasing the quality of quantitative research are offered.