Hypothalamic subunit volumes and relations to violence and psychopathy in male offenders with or without a psychotic disorder.

The hypothalamus is key to body homeostasis, including regulating cortisol, testosterone, vasopressin, and oxytocin hormones, modulating aggressive behavior. Animal studies have linked the morphology and function of the hypothalamus to aggression and affiliation, with a subregional pattern reflecting the functional division between the hypothalamic nuclei. We explored the relationship between hypothalamic subunit volumes in violent offenders with (PSY-V) and without (NPV) a psychotic disorder, and the association with psychopathy traits. 3T MRI scans (n = 628, all male 18-70 years) were obtained from PSY-V, n = 38, NPV, n = 20, non-violent psychosis patients (PSY-NV), n = 134, and healthy controls (HC), n = 436. The total hypothalamus volume and its eleven nuclei were delineated into five subunits using Freesurfer v7.3. Psychopathy traits were assessed with Psychopathy Checklist-revised (PCL-R). ANCOVAs and linear regressions were used to analyze associations with subunit volumes. Both groups with a history of violence exhibited smaller anterior-superior subunit volumes than HC (NPV Cohen's d = 0.56, p = 0.01 and PSY-V d = 0.38, p = 0.01). There were no significant differences between HC and PSY-NV. PCL-R scores were positively associated with the inferior tubular subunit on a trend level (uncorrected p = 0.045, Cohen's d = 0.04). We found distinct hypothalamic subunit volume reductions in persons with a history of violence independent of concomitant psychotic disorder but not in persons with psychosis alone. The results provide further information about the involvement of the hypothalamus in aggression, which ultimately may lead to the development of targeted treatment for the clinical and societal challenge of aggression and violent behavior.

Quantifying KRAS G12C Covalent Drug Inhibitor Activity in Mouse Tumors Using Mass Spectrometry.

The growing opportunities recognized for covalent drug inhibitors, like KRAS G12C inhibitors, are driving the need for mass spectrometry methods that can quickly and robustly measure therapeutic drug activity in vivo for drug discovery research and development. Effective front-end sample preparation is critical for proteins extracted from tumors but is generally labor intensive and impractical for large sample numbers typical in pharmacodynamic (PD) studies. Herein, we describe an automated and integrated sample preparation method for the measurement of activity levels of KRAS G12C drug inhibitor alkylation from complex tumor samples involving high throughput detergent removal and preconcentration followed by quantitation using mass spectrometry. We introduce a robust assay with an average intra-assay coefficient of variation (CV) of 4% and an interassay CV of 6% obtained from seven studies, enabling us to understand the relationship between KRAS G12C target occupancy and the therapeutic PD effect from mouse tumor samples. Further, the data demonstrated that the drug candidate GDC-6036, a KRAS G12C covalent inhibitor, shows dose-dependent target inhibition (KRAS G12C alkylation) and MAPK pathway inhibition, which correlate with high antitumor potency in the MIA PaCa-2 pancreatic xenograft model.

Impulsivity across severe mental disorders: a cross-sectional study of immune markers and psychopharmacotherapy.

BACKGROUND: Impulsivity is a transdiagnostic feature linked to severe clinical expression and a potential target for psychopharmacological strategies. Biological underpinnings are largely unknown, but involvement of immune dysregulation has been indicated, and the effects of psychopharmacological agents vary. We investigated if impulsivity was associated with circulating immune marker levels and with a range of psychopharmacological treatment regimens in severe mental disorders. METHODS: Impulsivity was assessed in a sample (N = 657) of patients with schizophrenia or schizophreniform disorder (SCZ) (N = 116) or bipolar disorder (BD) (N = 159) and healthy participants (N = 382) using the Barratt Impulsiveness Scale (BIS-11) questionnaire. Plasma levels of systemic immune markers (RANTES, IL-1RA, IL-18, IL-18BP, sTNFR-1) were measured by enzyme immunoassays. Patients underwent thorough clinical assessment, including evaluation of psychotropic medication. Associations were assessed using linear regressions. RESULTS: Impulsivity  was positively associated with SCZ (p < 0.001) and BD (p < 0.001) diagnosis and negatively associated with age (p < 0.05), but not significantly associated with any of the circulating immune markers independently of diagnostic status. Among patients, impulsivity was negatively associated with lithium treatment (p = 0.003) and positively associated with antidepressant treatment (p = 0.011) after controlling for diagnosis, psychotropic co-medications, manic symptoms, and depressive symptoms. CONCLUSIONS: We report elevated impulsivity across SCZ and BD but no associations to systemic immune dysregulation based on the current immune marker selection. The present study reveals associations between impulsivity in severe mental disorders and treatment with lithium and antidepressants, with opposite directions. Future studies are warranted to determine the causal directionality of the observed associations with psychopharmacotherapy.

Psychopathy subdomains in violent offenders with and without a psychotic disorder.

BACKGROUND: Violence in psychosis has been linked to antisocial behavior and psychopathy traits. Psychopathy comprises aspects of interpersonal, affective, lifestyle, and antisocial traits which may be differently involved in violent offending by persons with psychotic disorders. We explored psychopathy subdomains among violent offenders with and without a psychotic disorder. METHODS: 46 males, with a history of severe violence, with (n = 26; age 35.85 ± 10.34 years) or without (n = 20; age 39.10 ± 11.63 years) a diagnosis of a psychotic disorder, were assessed with the Psychopathy Checklist-Revised (PCL-R). PCL-R was split into subdomains following the four-facet model. Group differences in total and subdomain scores were analyzed with a general linear model with covariates. RESULTS: Total PCL-R scores did not differ between the groups (p = 0.61, Cohen's d = 0.17). The violent offenders without psychotic disorders had higher facet 2 scores than the patient group with psychotic disorders (p = 0.029, Cohen's d = 0.77). Facet 1, 3, or 4 scores did not differ between the groups. Controlling for age did not alter the results. CONCLUSION: Patients with a psychotic disorder and a history of severe violence have lower affective psychopathy scores than violent offenders without psychotic disorders. This observation may point toward distinct underlying mechanisms for violence and may provide a target for focused treatment and prevention.

Hippocampal subfield and amygdala nuclei volumes in schizophrenia patients with a history of violence.

Schizophrenia (SCZ) is associated with an increased risk of violence compared to the general population. Previous studies have indicated smaller hippocampal and amygdala volumes in violent than non-violent psychotic patients. However, little is known about volumetric differences at the subdivision level of these structures. In the present study, hippocampal subfields and amygdala nuclei volumes were estimated with FreeSurfer from 3 T MRI of SCZ patients with (SCZ-V, n = 24) and without (SCZ-NV, n = 51) a history of severe violence and 90 healthy controls (HC). Volumetric differences between groups were explored with a general linear model covarying for confounders, in addition to follow-up analyses in patient groups controlling for clinical characteristics such as antipsychotic medication, duration of illness and illicit substance use. SCZ-V had smaller total hippocampal volume and smaller CA1, HATA, fimbria, and molecular layer of DG volumes compared to HC. Total amygdala volume together with basal nucleus, accessory basal nucleus, CTA, and paralaminar nucleus volumes were smaller in SCZ-V compared to HC. In SCZ-NV, compared to HC, the observed smaller volumes were limited to basal and paralaminar nucleus. There were no significant differences in hippocampal subfield and amygdala nuclei volumes between SCZ-V and SCZ-NV. Follow-up analyses showed that the results in patient groups were not affected by clinical characteristics. The results suggest that smaller hippocampal subfield and amygdala nuclei volumes may be relevant to violence risk in SCZ. However, the neurobiological signature of violence in SCZ should be further investigated in larger cohorts.

Ryanodine channel complex stabilizer compound S48168/ARM210 as a disease modifier in dystrophin-deficient mdx mice: proof-of-concept study and independent validation of efficacy.

Muscle fibers lacking dystrophin undergo a long-term alteration of Ca2+ homeostasis, partially caused by a leaky Ca2+ release ryanodine (RyR) channel. S48168/ARM210, an RyR calcium release channel stabilizer (a Rycal compound), is expected to enhance the rebinding of calstabin to the RyR channel complex and possibly alleviate the pathologic Ca2+ leakage in dystrophin-deficient skeletal and cardiac muscle. This study systematically investigated the effect of S48168/ARM210 on the phenotype of mdx mice by means of a first proof-of-concept, short (4 wk), phase 1 treatment, followed by a 12-wk treatment (phase 2) performed in parallel by 2 independent laboratories. The mdx mice were treated with S48168/ARM210 at two different concentrations (50 or 10 mg/kg/d) in their drinking water for 4 and 12 wk, respectively. The mice were subjected to treadmill sessions twice per week (12 m/min for 30 min) to unmask the mild disease. This testing was followed by in vivo forelimb and hindlimb grip strength and fatigability measurement, ex vivo extensor digitorum longus (EDL) and diaphragm (DIA) force contraction measurement and histologic and biochemical analysis. The treatments resulted in functional (grip strength, ex vivo force production in DIA and EDL muscles) as well as histologic improvement after 4 and 12 wk, with no adverse effects. Furthermore, levels of cellular biomarkers of calcium homeostasis increased. Therefore, these data suggest that S48168/ARM210 may be a safe therapeutic option, at the dose levels tested, for the treatment of Duchenne muscular dystrophy (DMD).-Capogrosso, R. F., Mantuano, P., Uaesoontrachoon, K., Cozzoli, A., Giustino, A., Dow, T., Srinivassane, S., Filipovic, M., Bell, C., Vandermeulen, J., Massari, A. M., De Bellis, M., Conte, E., Pierno, S., Camerino, G. M., Liantonio, A., Nagaraju, K., De Luca, A. Ryanodine channel complex stabilizer compound S48168/ARM210 as a disease modifier in dystrophin-deficient mdx mice: proof-of-concept study and independent validation of efficacy.

Malnutrition in the nursing home.

PURPOSE OF REVIEW: Malnutrition in the nursing home is increasingly recognized as a major international research priority, given the expanding geriatric populations, serious consequences, and challenges conducting research in nursing homes. This review examines the recent literature and suggests implications for research and practice. RECENT FINDINGS: Across the recent studies, approximately 20% of nursing home residents had some form of malnutrition. However, malnutrition definitions were variable and prevalence ranged from 1.5 to 66.5%. Depression, cognitive impairment, functional impairment, and swallowing difficulty were consistently associated with malnutrition. Mortality was the major consequence of malnutrition among nursing home residents, whereas higher BMIs had lower risks of mortality. Beneficial interventions to reduce malnutrition in the nursing home included dietary supplements, greater resident role in food choice, and staff training programs. SUMMARY: To truly tackle the issue of malnutrition in the nursing home setting, a consistent definition is needed. We strongly recommend that an expert consensus panel identify a standard set of measures to more accurately compare the prevalence across countries. Given the mortality consequences of malnutrition and the paucity of intervention studies, research on interventions for malnutrition in the nursing home needs to be a higher priority for facilities, researchers, and funding agencies.

Mid-life proteinuria and late-life cognitive function and dementia in elderly men: the Honolulu-Asia Aging Study.

BACKGROUND: Impaired renal function has been linked to cognitive impairment. We assessed mid-life proteinuria and late-life cognitive function in elderly Asian men. METHODS: The Honolulu Heart Program is a prospective study that began in 1965 with 8006 Japanese-American men aged 45 to 68 years. Mid-life proteinuria was detected by urine dipstick in 1971 to 1974. The Honolulu-Asia Aging Study began 20 years later, with cognitive assessment by the Cognitive Abilities Screening Instrument (CASI) in 3734 men. Standard criteria were used to classify 8-year incident dementia and subtypes. RESULTS: The age-adjusted incidence of dementia increased significantly from 13.8, to 22.8, to 39.7 per 1000 person years follow-up, among those with no, trace, and positive mid-life proteinuria (P=0.004). Using linear regression adjusting for age, education, APOEε4, stroke, hypertension, systolic blood pressure, diabetes, fasting blood glucose, physical activity, and baseline CASI, those with positive proteinuria had significantly higher annual change in CASI over 8 years follow-up (-1.24, P=0.02) (reference=no proteinuria). Multivariate Cox regression found that positive proteinuria had a significant association with incident all-cause dementia (RR=2.66; 95%CI, 1.09-6.53; P=0.03), but no significant associations with incident Alzheimer disease or vascular dementia. CONCLUSION: Mid-life proteinuria was an independent predictor for late-life incident all-cause dementia and cognitive decline over 8 years.

Quantitative proteomics reveals the induction of mitophagy in tumor necrosis factor-α-activated (TNFα) macrophages.

Macrophages play an important role in innate and adaptive immunity as professional phagocytes capable of internalizing and degrading pathogens to derive antigens for presentation to T cells. They also produce pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) that mediate local and systemic responses and direct the development of adaptive immunity. The present work describes the use of label-free quantitative proteomics to profile the dynamic changes of proteins from resting and TNF-α-activated mouse macrophages. These analyses revealed that TNF-α activation of macrophages led to the down-regulation of mitochondrial proteins and the differential regulation of several proteins involved in vesicle trafficking and immune response. Importantly, we found that the down-regulation of mitochondria proteins occurred through mitophagy and was specific to TNF-α, as other cytokines such as IL-1ß and IFN-γ had no effect on mitochondria degradation. Furthermore, using a novel antigen presentation system, we observed that the induction of mitophagy by TNF-α enabled the processing and presentation of mitochondrial antigens at the cell surface by MHC class I molecules. These findings highlight an unsuspected role of TNF-α in mitophagy and expanded our understanding of the mechanisms responsible for MHC presentation of self-antigens.

Factors Associated with Nursing Home Admission after Stroke in Older Women.

BACKGROUND: We examined the social and economic factors associated with nursing home (NH) admission in older women, overall and poststroke. METHODS: The Women's Health Initiative (WHI) included women aged 50-79 years at enrollment (1993-1998). In the WHI Extension Study (2005-2010), participants annually reported any NH admission in the preceding year. Separate multivariate logistic regression models analyzed social and economic factors associated with long-term NH admission, defined as an admission on 2 or more questionnaires, overall and poststroke. RESULTS: Of 103,237 participants, 8904 (8.6%) reported NH admission (2005-2010); 534 of 2225 (24.0%) women with incident stroke reported poststroke NH admission. Decreased likelihoods of NH admission overall were demonstrated for Asian, Black, and Hispanic women (versus whites, adjusted odds ratio [aOR] = .35-.44, P < .001) and women with higher income (aOR = .75, 95% confidence interval [CI] = .63-.90), whereas increased likelihoods of NH admission overall were seen for women with lower social support (aOR = 1.34, 95% CI = 1.16-1.54) and with incident stroke (aOR = 2.59, 95% CI = 2.15-3.12). Increased odds of NH admission after stroke were demonstrated for women with moderate disability after stroke (aOR = 2.76, 95% CI = 1.73-4.42). Further adjustment for stroke severity eliminated the association found for race/ethnicity, income, and social support. CONCLUSIONS: The level of care needed after a disabling stroke may overwhelm social and economic structures in place that might otherwise enable avoidance of NH admission. We need to identify ways to provide care consistent with patients' preferences, even after a disabling stroke.

Low dietary vitamin D in mid-life predicts total mortality in men with hypertension: the Honolulu heart program.

BACKGROUND: Vitamin D deficiency was associated with total mortality in previous epidemiological studies. Little is known about the effects of dietary vitamin D intake on mortality. We examined the association between mid-life dietary vitamin D intake and 45-year total mortality. METHODS: The Honolulu Heart Program is a longitudinal cohort study of 8006 Japanese American men in Hawaii aged 45 to 68 at baseline (1965-1968). Mid-life dietary vitamin D intake was calculated from 24-hour dietary recall using Nutritionist IV v3 software. We divided subjects into quartiles of dietary vitamin D. Total mortality data were available over 45 years through 2010. RESULTS: Age-adjusted total mortality rates were higher in the lower quartiles of dietary vitamin D intake compared to the highest (p for trend = 0.011). Using Cox regression, low dietary vitamin D was significantly associated with total mortality; quartile (Q) 1 hazard ratio (HR) = 1.14, 95% confidence interval (95% CI) = 1.07-1.22, p < 0.001; Q2 HR = 1.11, 95% CI = 1.04-1.18, p = 0.002; and Q3 HR = 1.08, 95% CI = 1.01-1.15, p = 0.027; Q4 = reference. After adjusting for age, kilocalories, cardiovascular risk factors, and prevalent chronic diseases, only Q2 remained significant (HR = 1.08, 95% CI = 1.00-1.15, p = 0.037). Among hypertensive subjects only, those in the lower 2 quartiles had higher total mortality; Q1 HR = 1.12, 95% CI = 1.01-1.25, p = 0.039, and Q2 HR = 1.13, 95% CI = 1.02-1.26, p = 0.025, compared to Q4. There was no significant relationship in subjects without hypertension. CONCLUSIONS: Low dietary vitamin D intake in mid-life was a weak predictor of total mortality over 45 years of follow-up. We found a significant association between low dietary vitamin D intake and higher total mortality only among hypertensive subjects. Vitamin D may have cardioprotective effects.

Quantitative proteomics reveals that only a subset of the endoplasmic reticulum contributes to the phagosome.

Phagosomes, by killing and degrading pathogens for antigen presentation, are organelles implicated in key aspects of innate and adaptive immunity. Although it has been well established that phagosomes consist of membranes from the plasma membrane, endosomes, and lysosomes, the notion that the endoplasmic reticulum (ER) membrane could play an important role in the formation of the phagosome is debated. However, a method to accurately estimate the contribution of potential source organelles and contaminants to the phagosome proteome has been lacking. Herein, we have developed a proteomic approach for objectively quantifying the contribution of various organelles to the early and late phagosomes by comparing these fractions to their total membrane and postnuclear supernatant of origin in the J774A.1 murine macrophage cell line. Using quantitative label-free mass spectrometry, the abundance of peptides corresponding to hundreds of proteins was estimated and attributed to one of five organelles (e.g. plasma membrane, endosomes/lysosomes, ER, Golgi, and mitochondria). These data in combination with a stable isotope labeling in cell culture method designed to detect potential contaminant sources revealed that the ER is part of the phagosomal membrane and contributes ≈ 20% of the early phagosome proteome. In addition, only a subset of ER proteins is recruited to the phagosome, suggesting that a specific subdomain(s) of the ER might be involved in phagocytosis. Western blotting and immunofluorescence substantially validated this conclusion; we were able to demonstrate that the fraction of the ER in which the ER marker GFP-KDEL accumulates is excluded from the phagosomes, whereas that containing the mVenus-Syntaxin 18 is recruited. These results highlight promising new avenues for the description of the pathogenic mechanisms used by Leishmania, Brucella, and Legionella spp., which thrive in ER-rich phagosomes.

Prestroke weight loss is associated with poststroke mortality among men in the Honolulu-Asia Aging Study.

OBJECTIVE: To examine baseline prestroke weight loss and poststroke mortality among men. DESIGN: Longitudinal study of late-life prestroke body mass index (BMI), weight loss, and BMI change (midlife to late life) with up to 8-year incident stroke and mortality follow-up. SETTING: Community-based aging study data. PARTICIPANTS: Japanese-American men (N=3581; age range, 71-93y) who were stroke free at baseline. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Poststroke mortality: 30 days poststroke, analyzed with stepwise multivariable logistic regression; and long-term poststroke (up to 8y), analyzed with stepwise multivariable Cox regression. RESULTS: Weight loss (4.5kg decrements) was associated with increased 30-day poststroke mortality (adjusted odds ratio=1.48; 95% confidence interval [CI], 1.14-1.92), long-term mortality after incident stroke (all types, n=225; adjusted hazards ratio (aHR)=1.25; 95% CI, 1.09-1.44), and long-term mortality after incident thromboembolic stroke (n=153; aHR=1.19; 95% CI, 1.01 to 1.40). Men with overweight/obese late-life BMI (≥25kg/m(2), compared with healthy/underweight BMI) had increased long-term mortality after incident hemorrhagic stroke (n=54; aHR=2.27; 95% CI, 1.07-4.82). Neither desirable nor excessive BMI reductions (vs no change/increased BMI) were associated with poststroke mortality. In the overall sample (N=3581), nutrition factors associated with increased long-term mortality included the following: (1) weight loss (10lb decrements; aHR=1.15; 95% CI, 1.09-1.21), (2) underweight BMI (vs healthy BMI; aHR=1.76; 95% CI, 1.40-2.20), and (3) both desirable and excessive BMI reductions (vs no change or gain, separate model from weight loss and BMI; aHR range, 1.36-1.97; P<.001). CONCLUSIONS: Although obesity is a risk factor for stroke incidence, prestroke weight loss was associated with increased poststroke (all types and thromboembolic) mortality. Overweight/obese late-life BMI was associated with increased posthemorrhagic stroke mortality. Desirable and excessive BMI reductions were not associated with poststroke mortality. Weight loss, underweight late-life BMI, and any BMI reduction were all associated with increased long-term mortality in the overall sample.

Combining quality improvement and geriatrics training: the nursing home polypharmacy outcomes project.

To examine sustained effects of an educational intervention, the authors repeated a successful quality improvement (QI) project on medication safety and cost effectiveness. In October 2007 and August 2008, the facility leadership and geriatrics faculty identified all patients receiving nine or more medications (polypharmacy cohort) in a 170-bed teaching nursing home. They then taught Geriatric Medicine fellows (n = 12 in 2007, 11 in 2008) to (a) systematically collect medication data; (b) generate medication recommendations (stop, taper, or continue) based on expert criteria (Beers criteria) or drug-drug interaction programs; (c) discuss recommendations with patients' attending physicians; and (d) implement approved recommendations. Over the two projects, the polypharmacy cohorts demonstrated decreased potentially inappropriate medications (odds ratio [OR] = .78, 95% confidence interval [95% CI] [0.69, 0.88], p < .001), contraindicated medications (OR = .63, 95% CI [0.47, 0.85], p = .002) and medication costs (OR = .97, 95% CI [0.96, 0.99], p < .001). Findings suggest that programs planning educational QI projects for trainees may benefit from a multiyear approach to maximize clinical and educational benefits.

Adaptive Care Planning: A paradigm shift.

A key challenge of implementing advance care planning lies in the fact that decisions made in advance require patients and their family members to imagine what their clinical picture will look like rather than knowing or experiencing the clinical circumstances as they unfold. Even more important is the acknowledgment of the unpredictability of a given clinical course. This type of situation requires adaptiveness and flexibility in decision-making that frequently occurs in the moment(s) triggered by changes in health state(s). We describe an alternative frameshifting approach called "Adaptive Care Planning (AdaptCP)," which features an evolving communication between physicians and patients/families with ongoing incorporation of the patient's/family's perspective. This process continues iteratively until each decision can be reached in a way that is both harmonious with the patient's/family's perspective and is consistent with medical treatment options that are actionable for the healthcare team. We include a table of tools drawn from the literature that can help clinicians when implementing AdaptCP.

Pregnancy outcomes for women with pre-existing renal disease and the role of a dedicated joint maternal medicine and renal clinic: A retrospective cohort study.

OBJECTIVE: To reaffirm the value of a joint obstetric and renal clinic on obstetric outcomes in patients with high-risk pregnancies due to chronic kidney disease (CKD). METHODS: This was a retrospective cohort study of patients who attended the clinic between 2005 and December 2021. The hospital is a regional tertiary unit for renal medicine and a maternal medicine hub. The data included all women with pre-existing renal conditions who were cared for in a dedicated renal and obstetric clinic. Datasets were extracted from hospital notes, the renal database, clinical data and maternity electronic health records. The data analyzed included pre-existing renal conditions, biochemical parameters related to the renal condition, pregnancy outcomes included miscarriages, gestation, mode of delivery, postpartum hemorrhage (PPH), loss, birth weight and neonatal admission. RESULTS: The results were as follows: Lupus nephritis: four term deliveries; three had pre-eclampsia; two PPH and two miscarriages. Four estimated glomerular filtration rates (eGFRs) returned to baseline levels within 12 months. With regard to IgA nephropathy there were five live births, four term deliveries, two pre-eclampsia (PE) and five cesarean sections (CS). All eGFRs returned to baseline within 12 months. With regard to patients with adult polycystic kidney disease (APKD), there were six live births, two had pre-eclampsia and there were five term vaginal deliveries. CONCLUSION: Patients with lupus nephritis, APKD, and IgA demonstrated a higher incidence of adverse pregnancy outcomes as compared with our local pregnant population. Our findings reflect those of larger studies and support the role of combined renal/obstetric clinics. More research and larger scale studies are needed into specific CKD conditions and their outcomes.

A comprehensive characterization of membrane vesicles released by autophagic human endothelial cells.

The stress status of the apoptotic cell can promote phenotypic changes that have important consequences on the immunogenicity of the dying cell. Autophagy is one of the biological processes activated in response to a stressful condition. It is an important mediator of intercellular communications, both by regulating the unconventional secretion of molecules, including interleukin 1ß, and by regulating the extracellular release of ATP from early stage apoptotic cells. Additionally, autophagic components can be released in a caspase-dependent manner by serum-starved human endothelial cells that have engaged apoptotic and autophagic processes. The nature and the components of the extracellular vesicles released by dying autophagic cells are not known. In this study, we have identified extracellular membrane vesicles that are released by human endothelial cells undergoing apoptosis and autophagy, and characterized their biochemical, ultrastructural, morphological properties as well as their proteome. These extracellular vesicles differ from classical apoptotic bodies because they do not contain nucleus components and are released independently of Rho-associated, coiled-coil containing protein kinase 1 activation. Instead, they are enriched with autophagosomes and mitochondria and convey various danger signals, including ATP, suggesting that they could be involved in the modulation of innate immunity.

Proteomics analysis of herpes simplex virus type 1-infected cells reveals dynamic changes of viral protein expression, ubiquitylation, and phosphorylation.

Herpesviruses are among the most complex and widespread human viruses and cause a number of diseases ranging from cold sores to genital infections and encephalitis. While the composition of viral particles has been studied, less is known about the expression of the whole viral proteome in infected cells. Here, we analyzed the proteome of the prototypical Herpes Simplex Virus type 1 (HSV1) in infected cells by mass spectrometry. Using a high sensitivity LTQ-Orbitrap, we achieved a very high level of protein coverage and identified a total of 67 structural and nonstructural viral proteins. We also identified 90 novel phosphorylation sites and 10 novel ubiquitylation sites on different viral proteins. Ubiquitylation was observed on nine HSV1 proteins. We identified phosphorylation sites on about half of the detected viral proteins; many of the highly phosphorylated ones are known to regulate gene expression. Treatment with inhibitors of DNA replication induced changes of both viral protein abundance and modifications, highlighting the interdependence of viral proteins during the life cycle. Given the importance of expression dynamics, ubiquitylation, and phosphorylation for protein function, these findings will serve as important tools for future studies on herpesvirus biology.

Aging and caregiving in the Republic of Palau.

Aging has been an important population trend of the twentieth century, with most elderly people living in developing countries. Little has been published on the healthcare needs of elderly in the Pacific Islands. The Pacific Islands Geriatric Education Center, at the University of Hawaii, has a mission to promote training in geriatric education in the Pacific Islands to improve healthcare to the elderly. The aim of this project was to develop and test a family caregiver training program for Palau and was achieved in two phases: (1) assessing needs by interviewing key informants and surveying elders and (2) evaluating the caregiver training program that was designed based on findings from the assessment. The Ecological Systems Theory provided the theoretical framework for this study. The needs assessment identified training and education of family caregivers as a top priority, with the Palauan culture of family caring for seniors presently threatened by caregiver burnout. Nearly all of the long-term care in Palau is provided by families, and elders have high prevalence of geriatric syndromes. A family caregiver train-the-trainer workshop was subsequently conducted in February 2011. Forty-four trainers, including 12 from other Pacific Islands, attended the workshop. To assess changes in knowledge and confidence to teach, we compared scores on pre- and post-questionnaires using paired t tests. The train-the-trainer workshop resulted in significantly improved self-assessed competence and confidence to teach in all geriatric syndromes, including dealing with difficult behaviors, gait and transfer training, caregiver stress relief, and resources for caregivers (p < 0.0001). This successful intervention identified geriatric care needs in Palau and successfully trained family caregivers to meet these needs, and may be used as a model for similar interventions in other Pacific Islands.

Violent Offending in Males With or Without Schizophrenia: A Role for Social Cognition?

BACKGROUND AND HYPOTHESIS: Reduced social cognition has been reported in individuals who have committed interpersonal violence. It is unclear if individuals with schizophrenia and a history of violence have larger impairments than violent individuals without psychosis and non-violent individuals with schizophrenia. We examined social cognition in two groups with violent offenses, comparing their performance to non-violent individuals with schizophrenia and healthy controls. STUDY DESIGN: Two social cognitive domains were assessed in four groups: men with a schizophrenia spectrum disorder with (SSD-V, n = 27) or without (SSD-NV, n = 42) a history of violence, incarcerated men serving preventive detention sentences (V, n = 22), and healthy male controls (HC, n = 76). Theory of mind (ToM) was measured with the Movie for the Assessment of Social Cognition (MASC), body emotion perception with Emotion in Biological Motion (EmoBio) test. STUDY RESULTS: Kruskal-Wallis H-tests revealed overall group differences for social cognition. SSD-V had a global and clinically significant social cognitive impairment. V had a specific impairment, for ToM. Binary logistic regressions predicting violence category membership from social cognition and psychosis (SSD status) were conducted. The model with best fit, explaining 18%-25% of the variance, had ToM as the only predictor. CONCLUSIONS: Social cognitive impairment was present in individuals with a history of violence, with larger and more widespread impairment seen in schizophrenia. ToM predicted violence category membership, psychosis did not. The results suggest a role for social cognition in understanding interpersonal violence.