Interferon alpha promotes caspase-8 dependent ultraviolet light-mediated keratinocyte apoptosis via interferon regulatory factor 1.

Introduction: Ultraviolet (UV) light is a known trigger of both cutaneous and systemic disease manifestations in lupus patients. Lupus skin has elevated expression of type I interferons (IFNs) that promote increased keratinocyte (KC) death after UV exposure. The mechanisms by which KC cell death is increased by type I IFNs are unknown. Methods: Here, we examine the specific cell death pathways that are activated in KCs by type I IFN priming and UVB exposure using a variety of pharmacological and genetic approaches. Mice that overexpress Ifnk in the epidermis were exposed to UVB light and cell death was measured. RNA-sequencing from IFN-treated KCs was analyzed to identify candidate genes for further analysis that could drive enhanced cell death responses after UVB exposure. Results: We identify enhanced activation of caspase-8 dependent apoptosis, but not other cell death pathways, in type I IFN and UVB-exposed KCs. In vivo, overexpression of epidermal Ifnk resulted in increased apoptosis in murine skin after UVB treatment. This increase in KC apoptosis was not dependent on known death ligands but rather dependent on type I IFN-upregulation of interferon regulatory factor 1 (IRF1). Discussion: These data suggest that enhanced sensitivity to UV light exhibited by lupus patients results from type I IFN priming of KCs that drives IRF1 expression resulting in caspase-8 activation and increased apoptosis after minimal exposures to UVB.

Infraslow closed-loop brain training for anxiety and depression (ISAD): a protocol for a randomized, double-blind, sham-controlled pilot trial in adult females with internalizing disorders.

BACKGROUND: The core intrinsic connectivity networks (core-ICNs), encompassing the default-mode network (DMN), salience network (SN) and central executive network (CEN), have been shown to be dysfunctional in individuals with internalizing disorders (IDs, e.g. major depressive disorder, MDD; generalized anxiety disorder, GAD; social anxiety disorder, SOC). As such, source-localized, closed-loop brain training of electrophysiological signals, also known as standardized low-resolution electromagnetic tomography (sLORETA) neurofeedback (NFB), targeting key cortical nodes within these networks has the potential to reduce symptoms associated with IDs and restore normal core ICN function. We intend to conduct a randomized, double-blind (participant and assessor), sham-controlled, parallel-group (3-arm) trial of sLORETA infraslow (<0.1 Hz) fluctuation neurofeedback (sLORETA ISF-NFB) 3 times per week over 4 weeks in participants (n=60) with IDs. Our primary objectives will be to examine patient-reported outcomes (PROs) and neurophysiological measures to (1) compare the potential effects of sham ISF-NFB to either genuine 1-region ISF-NFB or genuine 2-region ISF-NFB, and (2) assess for potential associations between changes in PRO scores and modifications of electroencephalographic (EEG) activity/connectivity within/between the trained regions of interest (ROIs). As part of an exploratory analysis, we will investigate the effects of additional training sessions and the potential for the potentiation of the effects over time. METHODS: We will randomly assign participants who meet the criteria for MDD, GAD, and/or SOC per the MINI (Mini International Neuropsychiatric Interview for DSM-5) to one of three groups: (1) 12 sessions of posterior cingulate cortex (PCC) ISF-NFB up-training (n=15), (2) 12 sessions of concurrent PCC ISF up-training and dorsal anterior cingulate cortex (dACC) ISF-NFB down-training (n=15), or (3) 6 sessions of yoked-sham training followed by 6 sessions genuine ISF-NFB (n=30). Transdiagnostic PROs (Hospital Anxiety and Depression Scale, HADS; Inventory of Depression and Anxiety Symptoms - Second Version, IDAS-II; Multidimensional Emotional Disorder Inventory, MEDI; Intolerance of Uncertainty Scale - Short Form, IUS-12; Repetitive Thinking Questionnaire, RTQ-10) as well as resting-state neurophysiological measures (full-band EEG and ECG) will be collected from all subjects during two baseline sessions (approximately 1 week apart) then at post 6 sessions, post 12 sessions, and follow-up (1 month later). We will employ Bayesian methods in R and advanced source-localisation software (i.e. exact low-resolution brain electromagnetic tomography; eLORETA) in our analysis. DISCUSSION: This protocol will outline the rationale and research methodology for a clinical pilot trial of sLORETA ISF-NFB targeting key nodes within the core-ICNs in a female ID population with the primary aims being to assess its potential efficacy via transdiagnostic PROs and relevant neurophysiological measures. TRIAL REGISTRATION: Our study was prospectively registered with the Australia New Zealand Clinical Trials Registry (ANZCTR; Trial ID: ACTRN12619001428156). Registered on October 15, 2019.

Implementation of a youth-adult partnership model in youth mental health systems research: Challenges and successes.

BACKGROUND: By integrating Youth-Adult Partnerships (Y-APs) in organizational decision making and programming in health-care settings, youth can be engaged in decisions that affect them in a way that draws on their unique skills and expertise. Despite challenges, Y-APs can have many benefits for youth and adults alike, as well as for the programmes and initiatives that they undertake together. OBJECTIVE: This article describes the development, implementation and success of a Y-AP initiative at the McCain Centre at the Centre for Addiction and Mental Health, a large urban hospital. METHOD: The McCain Y-AP implementation model was developed based on the existing literature, guided by the team's progressive experience. The development and implementation procedure is described, with indicators of the model's success and recommendations for organizations interested integrating youth engagement. RESULTS: The McCain Y-AP has integrated youth into a wide range of mental health and substance use-related initiatives, including research projects, conferences and educational presentations. The model of youth engagement is flexible to include varying degrees of involvement, allowing youth to contribute in ways that fit their availability, interest and skills. Youth satisfaction has been strong and both the youth and adult partners have learned from the experience. DISCUSSION: Through the McCain Y-AP initiative, youth engagement has helped advance numerous initiatives in a variety of ways. Flexible engagement, multifaceted mentorship, reciprocal learning and authentic decision making have led to a successful partnership that has provided opportunities for growth for all those involved. Health-care organizations interested in engaging youth can learn from the McCain Y-AP experience to guide their engagement initiatives and maximize success.

Laparoendoscopic single-site surgery, minilaparoscopy and natural orifice transluminal endoscopic surgery in urology.

This article reviews the development of laparo-endoscopic single-site surgery (LESS), minilaparoscopy (MiniLap), and natural orifice transluminal endoscopic surgery (NOTES) with a particular focus on the applications in urologic surgery. We also provide the reader with a focused summary of the relevant nomenclature, history, and comparative outcomes. A literature search was conducted on LESS, MiniLap, needlescopy, microlaparoscopy and NOTES procedures in urology which is current through January 2013. The most relevant contemporary publications were selected and the pertinent findings were reviewed. Over the last few decades, we note that many innovative surgeons have performed a myriad of urologic procedures using LESS, MiniLap and NOTES techniques. These techniques are beginning to garner interest throughout the world; however, the enthusiasm for said techniques, while high, has not yet been met with high level scientific data clearly demonstrating the advantages of these approaches over conventional laparoscopy. In this review, we outline the history and clinical implementation of these techniques while also reviewing the comparative data where it exists. We attempt to provide the reader with a balanced overview of these techniques, their origins and lay the groundwork for future research and development.

Construction of an inducible system for the analysis of essential genes in Yersinia pestis.

Yersinia pestis, a Gram negative bacterium, causes bubonic and pneumonic plague. Emerging antibiotic resistance in clinical isolates is driving a need to develop novel antibiotics to treat infection by this transmissible and highly virulent pathogen. Proteins required for viability, so called essential genes, are attractive potential therapeutic targets, however, confirmation of essentiality is problematic. For the first time, we report the development of a system that allows the rapid determination of Y. pestis gene essentiality through mutagenesis and inducible expression of a plasmid borne copy of the target gene. Using this approach, we have confirmed the uridine monophosphate kinase PyrH as an essential protein in Y. pestis. This methodology and the tools we have developed will allow the confirmation of other putative essential genes in this dangerous pathogen, and facilitate the identification of novel targets for antimicrobial development.

The current status of infrastructure for monitoring the efficacy of antimalarial therapeutics in Zambia.

Background: Sub-Saharan countries have experienced centuries of high morbidity and mortality due to malaria. In addition to insecticide-treated mosquito nets and indoor residual spraying, modern antimalarial medicines have been developed to reduce disease prevalence, although the emergence of drug-resistant strains has compromised their efficacy. The purpose of this study was to evaluate the current status of malaria diagnosis and treatment, and to monitor the therapeutic efficacy of antimalarial drugs. Materials and Methods: A descriptive cross-sectional survey was conducted from 2011 to 2013 at 10 district hospitals in Zambia designated as malaria sentinel sites as well as at the National Malaria Control Centre. District medical officers at each site completed interview questionnaires. Results: Although basic infrastructure necessary for monitoring antimalarial drug resistance (such as laboratory, dispensary, admission ward, database unit, administration offices, bed space, examination and emergency rooms) was present at all sites, there was a shortage of licensed healthcare personnel. At some sites, antimalarial drugs were prescribed for malaria-like symptoms without diagnostic confirmation by blood smear. There was no regular monitoring of antimalarial drug resistance: only one trial was conducted among all sites in the previous 24 months. Conclusion: A lack of antimalarial drug resistance monitoring might be associated with personnel and funding shortages. Additional financial support would be necessary to avoid the development and spread of drug-resistant malaria in Zambia.

Effective strategies to improve the management of diabetes: case illustration from the diabetes health and wellness institute.

Many patients with diabetes do not have access to clinical care or medications, resulting in cases of undiagnosed diabetes or uncontrolled diabetes, especially in patients of low socioeconomic status. Given these considerations, new strategies are needed to control the rampant growth of diabetes and prevent new cases. This article discusses effective strategies for improving the management of diabetes in underserved populations, with special reference to the Juanita J. Craft Diabetes Health and Wellness Institute, a unique partnership between a large, urban integrated health care system, the City of Dallas, and a South Dallas community.

Assessing digital literacy in web-based physical activity surveillance: the WIN study.

PURPOSE. Investigate relations between demographic characteristics and submission method, Internet or paper, when physical activity behaviors are reported. DESIGN. Observational. SETTING . Metropolitan. SUBJECTS. Adult women (N  =  918) observed weekly for 2 years (total number of weekly reports, 44,963). MEASURES. Independent variables included age, race, education, income, employment status, and Internet skills. Dependent variables were method of submission (Internet or paper) and adherence. ANALYSIS . Logistic regression to analyze weekly odds of submitting data online and meeting study adherence criteria. Model 1 investigated method of submission, model 2 analyzed meeting study's Internet adherence, and model 3 analyzed meeting total adherence regardless of submission method. RESULTS. Whites, those with good Internet skills, and those reporting higher incomes were more likely to log online. Those who were white, older, and reported good Internet skills were more likely to be at least 75% adherent online. Older women were more likely to be adherent regardless of method. Employed women were less likely to log online or be adherent. CONCLUSION . Providing participants with multiple submission methods may reduce potential bias and provide more generalizable results relevant for future Internet-based research.

Long-term tracking of physical activity behaviors in women: the WIN Study.

PURPOSE: Interest lies in the prevalence of community-living women meeting the 2008 Department of Health and Human Services physical activity guidelines across time. The purpose was to report prevalence and stability of long-term (up to 125 wk) tracking of physical activity behaviors and to compare self-reported physical activity behaviors using different measures. METHODS: The WIN study tracks nearly real-time physical activity behaviors in community-living women. At baseline, 918 women began weekly Internet reporting of physical activity behaviors, accessing a secure Internet site and answering eight questions about physical activity behaviors for the previous week. Measures included days and minutes of moderate, vigorous, walking, and strengthening activities, and pedometer steps were recorded weekly. RESULTS: Prevalence of meeting physical activity guidelines depended on the criterion used. Weekly averages across the surveillance period indicated 25% reported ≥150 min of moderate physical activity, 47% reported ≥75 min of vigorous physical activity, 57% reported ≥150 min of moderate-to-vigorous physical activity, 63% conducted ≥500 MET·min of physical activity, 15% reported ≥2 d of strengthening activities per week, and 39% reported ≥7500 steps per week. Alpha coefficients (≥0.97) indicated stable physical activity behaviors across all measures. CONCLUSIONS: Across reporting methods, it is estimated that approximately 50% or more of these community-living women engage in sufficient physical activity for health benefits weekly across long-term follow-up. Self-report physical activity behaviors are stable across long periods in these community-living women not participating in a specific physical activity intervention.

Spatially addressed combinatorial protein libraries for recombinant antibody discovery and optimization.

Antibody discovery typically uses hybridoma- or display-based selection approaches, which lack the advantages of directly screening spatially addressed compound libraries as in small-molecule discovery. Here we apply the latter strategy to antibody discovery, using a library of ∼10,000 human germline antibody Fabs created by de novo DNA synthesis and automated protein expression and purification. In multiplexed screening assays, we obtained specific hits against seven of nine antigens. Using sequence-activity relationships and iterative mutagenesis, we optimized the binding affinities of two hits to the low nanomolar range. The matured Fabs showed full and partial antagonism activities in cell-based assays. Thus, protein drug leads can be discovered using surprisingly small libraries of proteins with known sequences, questioning the requirement for billions of members in an antibody discovery library. This methodology also provides sequence, expression and specificity information at the first step of the discovery process, and could enable novel antibody discovery in functional screens.

Internet reporting of weekly physical activity behaviors: the WIN Study.

BACKGROUND: Self-report measures have been validated and are widely used. Interest currently lies in the development of simple, valid methods that can be used in any location to determine level of PA in large populations/samples. The purpose of this report is to illustrate tracking of physical activity behaviors and musculoskeletal injury reports on a weekly basis via the Internet. METHODS: The Women's Injury Study (WIN) methodology includes use of BRFSS-related physical activity items that are completed online by more than 900 women weekly for an average of 3 years. RESULTS: With more than 45,000 weekly physical activity and injury logs, the percentage of total logs submitted via online records is 91%. Self-reported pedometer steps are consistent with similar, smaller research samples. CONCLUSIONS: This report suggests that Internet tracking is a viable means of assessing nearly real-time physical activity, describes the process of developing and monitoring self-reported physical activity behaviors via the Internet, and provides recommendations for others considering such methods.

Polysaccharides and virulence of Burkholderia pseudomallei.

Burkholderia pseudomallei is the causative agent of melioidosis, an infectious disease of humans and animals. Gene clusters which encode capsular polysaccharide (type I O-PS) and LPS (type II O-PS), both of which play roles in virulence, have previously been identified. Here, the identification of two further putative clusters, type III O-PS and type IV O-PS, is reported. Mice challenged with type III O-PS or type IV O-PS mutants showed increased mean times to death (7.8 and 11.6 days) compared to those challenged with wild-type B. pseudomallei (3 days). To investigate the possible roles of polysaccharides in protection, mice were immunized with killed cells of wild-type B. pseudomallei or killed cells of B. pseudomallei with mutations in the O antigen, capsular polysaccharide, type III O-PS or type IV O-PS gene clusters. Immunization with all polysaccharide mutant strains resulted in delayed time to death compared to the naïve controls, following challenge with wild-type B. pseudomallei strain K96243. However, immunization with killed polysaccharide mutant strains conferred different degrees of protection, demonstrating the immunological importance of the polysaccharide clusters on the surface of B. pseudomallei.

Synthesis and evaluation of antitumor activity of novel N-acyllavendamycin analogues and quinoline-5,8-diones.

A series of 7-N-acyllavendamycins with zero, one or two substituents at the C-2', C-3', and C-11' were synthesized through short and efficient methods. Pictet-Spengler condensation of 7-N-acylamino-2-formylquinoline-5,8-diones with tryptamine or tryptophans produced the desired lavendamycins. Screening data on a panel of three ras oncogene-transformed cell lines and the non-transformed parent cell line showed that a significant number of these analogues are potent antitumor agents and appear to be particularly active against K-ras transformed cells. Compared with the corresponding quinolinediones, these novel lavendamycins are much more inhibitory toward the transformed cells indicating that the beta-carboline moiety of the lavendamycin analogues plays an important role in its potency and selective toxicity.

Alexithymia: its prevalence and correlates in a British undergraduate sample.

INTRODUCTION: Alexithymia is characterized by a difficulty identifying and describing emotional states, as well as an externally oriented thinking style. This study investigated the prevalence of alexithymia in a British undergraduate sample and assesses its relationship to both parental bonding and dissociation. METHOD: The Toronto alexithymia scale (TAS-20), the Parental Bonding Instrument (PBI), and the Dissociative Experience Scale (DES) were administered to a sample of 181 male and 190 female undergraduate students from both arts and science subjects. RESULTS: Rates of alexithymia were comparable with those observed in some other countries. Contrary to predictions, females were found to have higher rates than males, and the highest presence of alexithymia was in female science students. As in previous studies, alexithymia was linked to both dissociation and perceptions of a lack of maternal care, though the degree of association to the latter was small. Dissociative experiences were predicted by both maternal overprotection and difficulties identifying feelings. DISCUSSION: Some qualified support was found for the relevance of early maternal bonding to later difficulties processing emotions. The presence of greater alexithymia in females, and female science students in particular, was discussed in reference to similar observations elsewhere. There was also an understandable relationship between 'difficulty identifying feelings' (TAS) and both depersonalization/derealization and absorption (DES).

Self-blood-pressure monitoring--a questionnaire study: response, requirement, training, support-group popularity and recommendations.

The objective of this study was to survey hypertensive patients' response to, requirement for and training in self-blood pressure monitoring (SBPM). A total of 222 hypertensives were invited to complete a questionnaire even when not participating in the project. Questions supplied information on demographics, monitoring frequency, convenience of attending the surgery, monitor ownership and preference for and ease of self-monitoring. Comments supplied qualitative data. Training group questionnaires supplied similar data as well as SBPM data before and after training. Of 133 respondents, a higher educated, younger, wider age range wanted to participate (76; 57.2%) and tended to self-monitor. However, only an increase in further education (FE) was associated with an increased probability of participation and inclination to self-monitor in the multivariate analyses. A positive relationship exists between age and frequency in both groups. About a sixth of respondents own monitors and ownership is correlated to FE. Although most patients found it convenient to visit the surgery, the percentage finding it convenient was lower in patients attending training sessions than in the original survey, possibly indicating that independence is important for SBPM. Younger, higher-educated patients tended to self-monitor although FE was again the significant factor. Training increased preference for the idea of SBPM, prospective monitor ownership (64.8% of non-owners) and self-monitoring intention (76.1%). Patients found recording card listed cardiovascular disease (CVD) risks valuable and 69.6% (32) wanted to establish a support group. Comments and interviews indicated haphazard knowledge, routines and uncertainty about SBPM. A standardised procedure including patient assessment, SBPM protocol and lifestyle education is needed for SBPM to be successful.

Reported sexual abuse and subsequent psychopathology among women attending psychology clinics: the mediating role of dissociation.

OBJECTIVE: While there is now a good clinical research base that outlines the links between reported sexual abuse and psychological symptoms and disorders, there is less of an understanding of the psychological processes mediating that relationship. This study assessed the role of dissociation as a mediator between reported sexual abuse and a range of psychopathological characteristics. DESIGN: A patient-series design was used. METHOD: Participants were an unselected sample of 45 women attending clinical psychology services. Each woman was interviewed regarding a reported history of sexual abuse, and completed standardized measures of general psychopathology, borderline personality disorder characteristics and dissociation. RESULTS: Sexual abuse per se was associated with the extent of depression, somatization, compulsive behaviour, phobic symptoms and borderline personality disorder characteristics. In each case, dissociation served as a complete mediator in that link. However, the same mediating relationship was not found when attempting to explain the greater psychopathological impact of more 'severe' forms of abuse (childhood experiences; intra-familial abuse). CONCLUSION: These findings suggest that the effective of clinical work with these psychopathological features would be enhanced if dissociation symptoms were addressed in women with a reported history of sexual abuse. However, the importance of that therapeutic target may be unrelated to the severity of the psychological disturbance.

Evaluation of a summer enrichment physiology course for matriculating medical students.

A summer enrichment physiology course for matriculating medical students has met a number of short-term goals, including bringing the students to the level of average medical student performance by the end of the summer. The long-term benefit of the program was evaluated by constructing a prospective expectation for each member of the medical class. Physiology grades obtained by past medical students were regressed on their undergraduate grades and MCAT scores. This regression model was used in a prospective manner to predict a physiology course grade for the entering class. Six of the seven summer program participants achieved scores equal to or higher than their predicted scores. Additionally, the regression model identified prospectively four of the six medical students who scored below 70% for the medical physiology course. This study suggests that a summer enrichment program can benefit participants.