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The environmental surveys following the 2010 Deepwater Horizon (DWH) spill identified a variety of hydrocarbon-degrading microorganisms, and laboratory studies with field-collected water samples then demonstrated faster-than-expected hydrocarbon biodegradation rates at 5°C. Knowledge about microbial community composition, diversity, and functional metabolic capabilities aids in understanding and predicting petroleum biodegradation by microbial communities in situ and is therefore an important component of the petroleum spill response decision-making process. This study investigates the taxonomic composition of microbial communities in six different global basins where petroleum and gas activities occur. Shallow-water communities were strikingly similar across basins, while deep-water communities tended to show subclusters by basin, with communities from the epipelagic, mesopelagic, and bathypelagic zones sometimes appearing within the same cluster. Microbial taxa that were enriched in the water column in the Gulf of Mexico following the DWH spill were found across marine basins. Several hydrocarbon-degrading genera (e.g., Actinobacteria, Pseudomonas , and Rhodobacteriacea ) were common across all basins. Other genera such as Pseudoalteromonas and Oleibacter were highly enriched in specific basins. IMPORTANCE Marine microbial communities are a vital component of global carbon cycling, and numerous studies have shown that populations of petroleum-degrading bacteria are ubiquitous in the oceans. Few studies have attempted to distinguish all of the taxa that might contribute to petroleum biodegradation (including, e.g., heterotrophic and nondesignated microbes that respond positively to petroleum and microbes that grow on petroleum as the sole carbon source). This study quantifies the subpopulations of microorganisms that are expected to be involved in petroleum hydrocarbon biodegradation, which is important information during the decision-making process in the event of a petroleum spill accident., (Copyright © 2020 Miller et al.)

For patients participating in trauma-focused psychotherapies for posttraumatic stress disorder (PTSD), such as cognitive processing therapy (CPT), pretreatment characteristics may moderate treatment effectiveness. For instance, preexisting supportive relationships may encourage skill utilization or provide contrasts to maladaptive cognitive biases highlighted in trauma-focused treatments for PTSD. Such pretreatment characteristics are important to study in rural individuals, who may experience barriers to initiating and completing treatment. The aim of this study was to examine whether pretreatment social support, measured using the Medical Outcomes Study Social Support Survey, would moderate the association between CPT duration (i.e., number of sessions attended) and change in PTSD symptoms, using data from a pragmatic randomized controlled trial of a telemedicine-based collaborative care intervention for rural veterans (N = 225). Social support moderated the association between CPT duration and PTSD symptom change, B = -0.016, SE = -.006; 95% CI [-0.028, -0.005], such that increased duration was associated with more PTSD symptom change only at average or higher levels of support. This effect was found for overall and emotional support but not tangible support. Additionally, on average, among participants who attended eight or more CPT sessions, only those at or above 1 standard deviation above the mean social support score demonstrated a reliable change in PTSD symptoms. The results indicate that the link between CPT treatment duration and treatment outcomes may be stronger for veterans with higher levels of pretreatment social support., (Published 2020. This article is a U.S. Government work and is in the public domain in the USA.)

Background: Minimally invasive hysterectomy for fibroids decreases recovery time and risk of postoperative complications compared with abdominal hysterectomy. Within Veterans Affair (VA), black women with uterine fibroids are less likely to receive a minimally invasive hysterectomy than white women., Objective: To quantify the contributions of patient, facility, temporal and geographic factors to VA black-white disparity in minimally invasive hysterectomy., Research Design: A cross-sectional study., Subjects: Veterans with fibroids and hysterectomy performed in VA between October 1, 2012 and September 30, 2015., Measures: Hysterectomy mode was defined using ICD-9 codes as minimally invasive (laparoscopic, vaginal, or robotic-assisted) versus abdominal. The authors estimated a logistic regression model with minimally invasive hysterectomy modeled as a function of 4 sets of factors: sociodemographic characteristics other than race, health risk factors, facility, and temporal and geographic factors. Using decomposition techniques, systematically substituting each white woman's characteristics for each black woman's characteristics, then recalculating the predicted probability of minimally invasive hysterectomy for black women for each possible combination of factors, we quantified the contribution of each set of factors to observed disparities in minimally invasive hysterectomy., Results: Among 1255 veterans with fibroids who had a hysterectomy at a VA, 61% of black women and 39% of white women had an abdominal hysterectomy. Our models indicated there were 99 excess abdominal hysterectomies among black women. The majority (n=77) of excess abdominal hysterectomies were unexplained by measured sociodemographic factors beyond race, health risk factors, facility, and temporal or geographic trends., Conclusion: Closer examination of the equity of VA gynecology care and ways in which the VA can work to ensure equitable care for all women veterans is necessary.

Objective: Lack of social support predicts the development, maintenance, and exacerbation of posttraumatic stress disorder (PTSD). Moreover, social dysfunction is associated with recurrent episodes of PTSD care, and detachment/estrangement from others is a strong predictor of suicidal ideation among those with PTSD. Thus, treatments to improve social functioning among those with PTSD are needed., Method: Eighty veterans of recent operations in Iraq and Afghanistan participated in a randomized controlled trial comparing treatment as usual to behavioral activation (BA) for PTSD, a treatment that focuses on reducing avoidance behaviors and increasing engagement in valued goals rather than explicitly confronting trauma memories., Results: Mixed-model regression analyses revealed that, accounting for gender, baseline PTSD, and marital status, participants who received BA experienced greater improvements in the number of social supports from baseline to posttreatment compared with those in treatment as usual (F1,96 = 6.29, p = .014). Gains were not maintained at 3-month follow-up, and significant results were not found for satisfaction with social supports., Conclusions: BA may facilitate an increase in the perceived number of social supports available to veterans with PTSD, but treatment adaptation may be necessary to maintain these gains and to increase satisfaction with social support. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Background: For people living with HIV (PLWH), alcohol use is harmful and may be influenced by unique challenges faced by PLWH living in rural areas. We describe patterns of alcohol use across rurality among PLWH., Methods: Veterans Aging Cohort Study electronic health record data were used to identify patients with HIV (ICD-9 codes for HIV or AIDS) who completed AUDIT-C alcohol screening between February 1, 2008, and September 30, 2014. Regression models estimated and compared 4 alcohol use outcomes (any use [AUDIT-C > 0] and alcohol use disorder [AUD; ICD-9 codes for abuse or dependence] diagnoses among all PLWH, and AUDIT-C risk categories: lower- [1-3 men/1-2 women], moderate- [4-5 men/3-5 women], higher- 6-7]), and severe-risk [8-12], and heavy episodic drinking (HED; ≥1 past-year occasion) among PLWH reporting use) across rurality (urban, large rural, small rural) and census-defined region., Findings: Among 32,699 PLWH (29,540 urban, 1,301 large rural, and 1,828 small rural), both any alcohol use and AUD were highest in urban areas, although this varied across region. Predicted prevalence of any alcohol use was 54.1% (53.5%-54.7%) in urban, 49.6% (46.9%-52.3%) in large rural, and 50.6% (48.3%-52.9%) in small rural areas (P < .01). Predicted prevalence of AUD was 14.4% (14.0%-14.8%) in urban, 11.8% (10.0%-13.5%) in large rural, and 12.3% (10.8%-13.8%) in small rural areas (P < .01). Approximately 12% and 25% had higher- or severe-risk drinking and HED, respectively, but neither differed across rurality., Conclusion: Though some variation across rurality and region was observed, alcohol-related interventions are needed for PLWH across all geographic locations., (© 2018 National Rural Health Association.)

Purpose: It is unknown whether receipt of evidence-based alcohol-related care varies by rurality among people living with HIV (PLWH) with unhealthy alcohol use-a population for whom such care is particularly important., Methods: All positive screens for unhealthy alcohol use (AUDIT-C ≥ 5) among PLWH were identified using Veterans Health Administration electronic health record data (10/1/09-5/30/13). Three domains of alcohol-related care were assessed: brief intervention (BI) within 14 days, and specialty addictions treatment or alcohol use disorder (AUD) medications (filled prescription for naltrexone, disulfiram, acamprosate, or topiramate) within 1 year of positive screen. Adjusted Poisson models and recycled predictions were used to estimate predicted prevalence of outcomes across rurality (urban, large rural, small rural), clustered on facility. Secondary analyses assessed outcomes in the subsample with documented AUD., Findings: 4,581 positive screens representing 3,458 PLWH (3,112 urban, 130 large rural, and 216 small rural) were included; 49.1% had diagnosed AUD. PLWH in large rural areas had highest receipt of BI (urban 56.6%, 95% CI: 55.0-58.2; large rural 66.0%, CI: 58.6-73.5; small rural 60.7%, CI: 54.6-67.0). PLWH in urban areas had highest receipt of specialty addictions treatment (urban 28.2%, CI: 26.7-29.8; large rural 19.7%, CI: 13.1-26.2; small rural 19.6%, CI: 14.1-25.0). There was no difference in receipt of AUD medications, although overall receipt was low (3%-4%). Results were similar in the subsample with AUD., Conclusion: Among PLWH with unhealthy alcohol use, those in rural areas may be vulnerable to under-receipt of specialty addictions treatment. Targeted interventions may help ensure PLWH receive recommended care regardless of rurality., (© 2019 National Rural Health Association.)

The Caspian Sea, which is the largest landlocked body of water on the planet, receives substantial annual hydrocarbon input from anthropogenic sources (e.g., industry, agriculture, oil exploration, and extraction) and natural sources (e.g., mud volcanoes and oil seeps). The Caspian Sea also receives substantial amounts of runoff from agricultural and municipal sources, containing nutrients that have caused eutrophication and subsequent hypoxia in the deep, cold waters. The effect of decreasing oxygen saturation and cold temperatures on oil hydrocarbon biodegradation by a microbial community is not well characterized. The purpose of this study was to investigate the effect of oxic and anoxic conditions on oil hydrocarbon biodegradation at cold temperatures by microbial communities derived from the Caspian Sea. Water samples were collected from the Caspian Sea for study in experimental microcosms. Major taxonomic orders observed in the ambient water samples included Flavobacteriales , Actinomycetales , and Oceanospirillales . Microcosms were inoculated with microbial communities from the deepest waters and amended with oil hydrocarbons for 17 days. Hydrocarbon degradation and shifts in microbial community structure were measured. Surprisingly, oil hydrocarbon biodegradation under anoxic conditions exceeded that under oxic conditions; this was particularly evident in the degradation of aromatic hydrocarbons. Important microbial taxa associated with the anoxic microcosms included known oil degraders such as Oceanospirillaceae . This study provides knowledge about the ambient community structure of the Caspian Sea, which serves as an important reference point for future studies. Furthermore, this may be the first report in which anaerobic biodegradation of oil hydrocarbons exceeds aerobic biodegradation.

Posttraumatic stress disorder (PTSD) occurs following acute threatening events in approximately 12.5% of the primary care population., Objective: The aim of this article is to advance evidence-based clinical practice and collaborative care approaches to PTSD by summarizing targeted-care guidelines., Method: This narrative literature review addresses important aspects of PTSD and management options, in conjunction with expert opinion when indicated. Guidelines were included if they targeted treatment of PTSD in the primary care setting or if the treatments described could be provided in the primary care setting., Results: The implications regarding PTSD, comorbidities, differential diagnosis, screening tools, and treatment are presented., Conclusion: Primary care providers can diagnose and offer initial management of PTSD. Future research should delineate therapies helpful for complex PTSD, including group therapies, those increasing self-compassion, and other optimally effective collaborative care interventions.

Nitrogen fixation, the biological conversion of N 2 to NH 3 , is critical to alleviating nitrogen limitation in many marine ecosystems. To date, few measurements exist of N 2 fixation in deep-sea sediments. Here, we conducted > 400 bottle incubations with sediments from methane seeps, whale falls and background sites off the western coast of the United States from 600 to 2893 m water depth to investigate the potential rates, spatial distribution and biological mediators of benthic N 2 fixation. We found that N 2 fixation was widespread, yet heterogeneously distributed with sediment depth at all sites. In some locations, rates exceeded previous measurements by > 10×, and provided up to 30% of the community anabolic growth requirement for nitrogen. Diazotrophic activity appeared to be inhibited by pore water ammonium: N 2 fixation was only observed if incubation ammonium concentrations were ≤ 25 μM, and experimental additions of ammonium reduced diazotrophy. In seep sediments, N 2 fixation was dependent on CH 4 and coincident with sulphate reduction, consistent with previous work showing diazotrophy by microorganisms mediating sulphate-coupled methane oxidation. However, the pattern of diazotrophy was different in whale-fall and associated reference sediments, where it was largely unaffected by CH 4 , suggesting catabolically different diazotrophs at these sites., (© 2018 Society for Applied Microbiology and John Wiley & Sons Ltd.)

Background: Some veterans face multiple barriers to VA mental healthcare service use. However, there is limited understanding of how veterans' experiences and meaning systems shape their perceptions of barriers to VA mental health service use. In 2015, a participatory, mixed-methods project was initiated to elicit veteran-centered barriers to using mental healthcare services among a diverse sample of US rural and urban veterans. We sought to identify veteran-centric barriers to mental healthcare to increase initial engagement and continuation with VA mental healthcare services., Methods: Cultural Domain Analysis, incorporated in a mixed methods approach, generated a cognitive map of veterans' barriers to care. The method involved: 1) free lists of barriers categorized through participant pile sorting; 2) multi-dimensional scaling and cluster analysis for item clusters in spatial dimensions; and 3) participant review, explanation, and interpretation for dimensions of the cultural domain. Item relations were synthesized within and across domain dimensions to contextualize mental health help-seeking behavior., Results: Participants determined five dimensions of barriers to VA mental healthcare services: concern about what others think; financial, personal, and physical obstacles; confidence in the VA healthcare system; navigating VA benefits and healthcare services; and privacy, security, and abuse of services., Conclusions: These findings demonstrate the value of participatory methods in eliciting meaningful cultural insight into barriers of mental health utilization informed by military veteran culture. They also reinforce the importance of collaborations between the VA and Department of Defense to address the role of military institutional norms and stigmatizing attitudes in veterans' mental health-seeking behaviors.

Introduction: In this era of patient-centered care, telepsychiatry (TP; video or synchronous) provides quality care with outcomes as good as in-person care, facilitates access to care, and leverages a wide range of treatments at a distance., Method: This conceptual review article explores TP as applied to newer models of care (e.g., collaborative, stepped, and integrated care)., Results: The field of psychosomatic medicine (PSM) has developed clinical care models, educates interdisciplinary team members, and provides leadership to clinical teams. PSM is uniquely positioned to steer TP and implement other telebehavioral health care options (e.g., e-mail/telephone, psych/mental health apps) in the future in primary care. Together, PSM and TP provide versatility to health systems by enabling more patient points-of-entry, matching patient needs with provider skills, and helping providers work at the top of their licenses. TP and other technologies make collaborative, stepped, and integrated care less costly and more accessible., Conclusion: Effective health care delivery matches the intensity of the services to the needs of a patient population or clinic, standardizes interventions, and evaluates both process and clinical outcomes. More research is indicated on the application of TP and other technologies to these service delivery models., (Copyright © 2018 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. All rights reserved.)

Rural Veterans Health Administration (VHA) primary care clinics are smaller, have fewer staff, and serve more rural patients compared with urban VHA primary care clinics. This may lead to different challenges to implementation of the Patient-Centered Medical Home (PCMH) model, the Patient Aligned Care Team, in the VHAs' large integrated health system. In this cross-sectional observational study of 905 VHA primary clinics in the United States and Puerto Rico, we found overall PCMH implementation was greater in rural compared to urban primary care clinics. Urban-rural differences in PCMH implementation may largely be related to clinic organizational factors.

Purpose of Review: This article discusses recent applications in telemedicine to promote the goals of population health and population management for people suffering psychiatric disorders., Recent Findings: The use of telemedicine to promote collaborative care, self-monitoring and chronic disease management, and population screening has demonstrated broad applicability and effectiveness. Collaborative care using videoconferencing to facilitate mental health specialty consults has demonstrated effectiveness in the treatment of depression, PTSD, and also ADHD in pediatric populations. Mobile health is currently being harnessed to monitor patient symptom trajectories with the goal of using machine learning algorithms to predict illness relapse. Patient portals serve as a bridge between patients and providers. They provide an electronically secure shared space for providers and patients to collaborate and optimize care. To date, research has supported the effectiveness of telemedicine in promoting population health. Future endeavors should focus on developing the most effective clinical protocols for using these technologies to ensure long-term use and maximum effectiveness in reducing population burden of mental health.

Purpose We describe results from a quality improvement project undertaken to address perinatal mental healthcare for women veterans. Description This quality improvement project was conducted in a single VA healthcare system between 2012 and 2015 and included screening for depressive symptoms with the Edinburgh Postnatal Depression Scale (EPDS) three times during the perinatal period, a dedicated maternity care coordinator (MCC), an on-site clinical social worker, and an on-site obstetrician/gynecologist (Ob/gyn). Information on prior mental health diagnosis was collected by the MCC or Ob/gyn. The prevalence of perinatal depressive symptoms and receipt of mental healthcare among those with such symptoms are reported by presence of a pre-pregnancy mental health diagnosis. Assessment Of the 199 women who used VA maternity benefits between 2012 and 2015, 56% (n = 111) had at least one pre-pregnancy mental health diagnosis. Compared to those without a pre-pregnancy mental health diagnosis, those with such a diagnosis were more likely to be screened for perinatal depressive symptoms at least once (61.5% vs. 46.8%, p = 0.04). Prevalence of depressive symptoms was 46.7% among those with a pre-pregnancy mental health diagnosis and 19.2% among those without. Among those with a pre-pregnancy mental health diagnosis and depressive symptoms (n = 35), 88% received outpatient mental healthcare and 77% met with the clinical social worker. Among those without a pre-pregnancy mental health diagnosis and depressive symptoms (n = 8), none received outpatient mental healthcare, but 77.8% met with the clinical social worker. Conclusion Improving perinatal mental healthcare for women veterans requires a multidisciplinary approach, including on-site integrated mental healthcare.

The objective of this article is to inform psychiatrists and other mental health professionals and primary care providers about the role of telepsychiatry in facilitating integrated care models, particularly in remote primary care practices. A narrative literature review was conducted to highlight the evidence and challenges of using telepsychiatry for integrated care. Telepsychiatry uses communication technologies to facilitate audiovisual interaction between patients and care teams to deliver services and expertise across distances and practice settings. It is particularly suited for integrated care settings, if business model innovations such as collaborative care models are implemented alongside to improve the access and delivery of care to patients. Telepsychiatry has been shown to be equivalent to face-to-face evaluations and, in certain instances, may lead to better outcomes in integrated care settings. Several challenges of adopting telepsychiatry in real practice are highlighted, including reimbursement and licensing across states, which continue to be an important barrier. It is critical to use an established framework to understand the potential users of telepsychiatry and develop and promote competency-based telepsychiatry training for novice, competent, and expert users. Psychiatrists who want to extend their expertise to distant sites, improve access to care, and partake in the new business models of collaborative care will need to consider these benefits and challenges., Competing Interests: The authors report no financial relationships with commercial interests., (Copyright © by the American Psychiatric Association.)

Mesenchymal stem cells (MSCs) are abundant throughout the body and regulate signaling within tumor microenvironments. Wnt signaling is an extrinsically regulated pathway that has been shown to regulate tumorigenesis in many types of cancer. After evaluating a panel of Wnt activating and inhibiting molecules, we show that primary human MSCs increase the expression of Dkk-1, an inhibitor of Wnt signaling, into the extracellular environment following chemotherapy exposure in a p53-dependent manner. Dkk-1 has been shown to promote tumor growth in several models of malignancy, suggesting that MSC-derived Dkk-1 could counteract the intent of cytotoxic chemotherapy, and that pharmacologic inhibition of Dkk-1 in patients receiving chemotherapy treatment for certain malignancies may be warranted.

Mesenchymal stem cells (MSCs) are of interest for use in diverse cellular therapies. Ex vivo expansion of MSCs intended for transplantation must result in generation of cells that maintain fidelity of critical functions. Previous investigations have identified genetic and phenotypic alterations of MSCs with in vitro passage, but little is known regarding how culturing influences the ability of MSCs to repair double strand DNA breaks (DSBs), the most severe of DNA lesions. To investigate the response to DSB stress with passage in vitro, primary human MSCs were exposed to etoposide (VP16) at various passages with subsequent evaluation of cellular damage responses and DNA repair. Passage number did not affect susceptibility to VP16 or the incidence and repair kinetics of DSBs. Nonhomologous end joining (NHEJ) transcripts showed little alteration with VP16 exposure or passage; however, homologous recombination (HR) transcripts were reduced following VP16 exposure with this decrease amplified as MSCs were passaged in vitro. Functional evaluations of NHEJ and HR showed that MSCs were unable to activate NHEJ repair following VP16 stress in cells after successive passage. These results indicate that ex vivo expansion of MSCs alters their ability to perform DSB repair, a necessary function for cells intended for transplantation.

The utrophin-dystrophin deficient (DKO) mouse model has been widely used to understand the progression of Duchenne muscular dystrophy (DMD). However, it is unclear as to what extent muscle pathology affects metabolism. Therefore, the present study was focused on understanding energy expenditure in the whole animal and in isolated extensor digitorum longus (EDL) muscle and to determine changes in metabolic enzymes. Our results show that the 8 week-old DKO mice consume higher oxygen relative to activity levels. Interestingly the EDL muscle from DKO mouse consumes higher oxygen per unit integral force, generates less force and performs better in the presence of pyruvate thus mimicking a slow twitch muscle. We also found that the expression of hexokinase 1 and pyruvate kinase M2 was upregulated several fold suggesting increased glycolytic flux. Additionally, there is a dramatic increase in dynamin-related protein 1 (Drp 1) and mitofusin 2 protein levels suggesting increased mitochondrial fission and fusion, a feature associated with increased energy demand and altered mitochondrial dynamics. Collectively our studies point out that the dystrophic disease has caused significant changes in muscle metabolism. To meet the increased energetic demand, upregulation of metabolic enzymes and regulators of mitochondrial fusion and fission is observed in the dystrophic muscle. A better understanding of the metabolic demands and the accompanied alterations in the dystrophic muscle can help us design improved intervention therapies along with existing drug treatments for the DMD patients.

Veterans have high rates of chronic pain and long-term opioid therapy (LTOT). Understanding predictors of discontinuation from LTOT will clarify the risks for prolonged opioid use and dependence among this population. All veterans with at least 90 days of opioid use within a 180-day period were identified using national Veteran's Health Affairs (VHA) data between 2009 and 2011. Discontinuation was defined as 6 months with no opioid prescriptions. We used Cox proportional hazards analysis to determine clinical and demographic correlates for discontinuation. A total of 550,616 veterans met criteria for LTOT. The sample was primarily male (93%) and white (74%), with a mean age of 57.8 years. The median daily morphine equivalent dose was 26 mg, and 7% received high-dose (>100mg MED) therapy. At 1 year after initiation, 7.5% (n=41,197) of the LTOT sample had discontinued opioids. Among those who discontinued (20%, n=108,601), the median time to discontinuation was 317 days. Factors significantly associated with discontinuation included both younger and older age, lower average dosage, and having received less than 90 days of opioids in the previous year. Although tobacco use disorders decreased the likelihood of discontinuation, co-morbid mental illness and substance use disorders increased the likelihood of discontinuation. LTOT is common in the VHA system and is marked by extended duration of use at relatively low daily doses with few discontinuation events. Opioid discontinuation is more likely in veterans with mental health and substance use disorders. Further research is needed to delineate causes and consequences of opioid discontinuation., (Published by Elsevier B.V.)

Background: The purpose of this document is to provide initial recommendations to telemental health (TMH) professionals for the selection of assessment and outcome measures that best reflect the impacts of mental health treatments delivered via live interactive videoconferencing., Materials and Methods: The guidance provided here was created through an expert consensus process and is in the form of a lexicon focused on identified key TMH outcomes., Results: Each lexical item is elucidated by a definition, recommendations for assessment/measurement, and additional commentary on important considerations. The lexicon is not intended as a current literature review of the field, but rather as a resource to foster increased dialogue, critical analysis, and the development of the science of TMH assessment and evaluation. The intent of this lexicon is to better unify the TMH field by providing a resource to researchers, program managers, funders, regulators and others for assessing outcomes., Conclusions: This document provides overall context for the key aspects of the lexicon.

Biological soil crusts (BSCs) cover extensive portions of the earth's deserts. In order to survive desiccation cycles and utilize short periods of activity during infrequent precipitation, crust microorganisms must rely on the unique capabilities of vegetative cells to enter a dormant state and be poised for rapid resuscitation upon wetting. To elucidate the key events involved in the exit from dormancy, we performed a wetting experiment of a BSC and followed the response of the dominant cyanobacterium, Microcoleus vaginatus, in situ using a whole-genome transcriptional time course that included two diel cycles. Immediate, but transient, induction of DNA repair and regulatory genes signaled the hydration event. Recovery of photosynthesis occurred within 1 h, accompanied by upregulation of anabolic pathways. Onset of desiccation was characterized by the induction of genes for oxidative and photo-oxidative stress responses, osmotic stress response and the synthesis of C and N storage polymers. Early expression of genes for the production of exopolysaccharides, additional storage molecules and genes for membrane unsaturation occurred before drying and hints at preparedness for desiccation. We also observed signatures of preparation for future precipitation, notably the expression of genes for anaplerotic reactions in drying crusts, and the stable maintenance of mRNA through dormancy. These data shed light on possible synchronization between this cyanobacterium and its environment, and provides key mechanistic insights into its metabolism in situ that may be used to predict its response to climate, and or, land-use driven perturbations.

Osteoblasts are a major component of the bone marrow microenvironment, which provide support for hematopoietic cell development. Functional disruption of any element of the bone marrow niche, including osteoblasts, can potentially impair hematopoiesis. We have studied the effect of two widely used drugs with different mechanisms of action, etoposide (VP16) and melphalan, on murine osteoblasts at distinct stages of maturation. VP16 and melphalan delayed maturation of preosteoblasts and altered CXCL12 protein levels, a key regulator of hematopoietic cell homing to the bone marrow. Sublethal concentrations of VP16 and melphalan also decreased the levels of several transcripts which contribute to the composition of the extracellular matrix (ECM) including osteopontin (OPN), osteocalcin (OCN), and collagen 1A1 (Col1a1). The impact of chemotherapy on message and protein levels for some targets was not always aligned, suggesting differential responses at the transcription and translation or protein stability levels. As one of the main functions of a mature osteoblast is to synthesize ECM of a defined composition, disruption of the ratio of its components may be one mechanism by which chemotherapy affects the ability of osteoblasts to support hematopoietic recovery coincident with altered marrow architecture. Collectively, these observations suggest that the osteoblast compartment of the marrow hematopoietic niche is vulnerable to functional dysregulation by damage imposed by agents frequently used in clinical settings. Understanding the mechanistic underpinning of chemotherapy-induced changes on the hematopoietic support capacity of the marrow microenvironment may contribute to improved strategies to optimize patient recovery post-transplantation., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We present the detection of five planets--Kepler-62b, c, d, e, and f--of size 1.31, 0.54, 1.95, 1.61 and 1.41 Earth radii (R⊕), orbiting a K2V star at periods of 5.7, 12.4, 18.2, 122.4, and 267.3 days, respectively. The outermost planets, Kepler-62e and -62f, are super-Earth-size (1.25 R⊕ < planet radius ≤ 2.0 R⊕) planets in the habitable zone of their host star, respectively receiving 1.2 ± 0.2 times and 0.41 ± 0.05 times the solar flux at Earth's orbit. Theoretical models of Kepler-62e and -62f for a stellar age of ~7 billion years suggest that both planets could be solid, either with a rocky composition or composed of mostly solid water in their bulk.

We report the detection of Kepler-47, a system consisting of two planets orbiting around an eclipsing pair of stars. The inner and outer planets have radii 3.0 and 4.6 times that of Earth, respectively. The binary star consists of a Sun-like star and a companion roughly one-third its size, orbiting each other every 7.45 days. With an orbital period of 49.5 days, 18 transits of the inner planet have been observed, allowing a detailed characterization of its orbit and those of the stars. The outer planet's orbital period is 303.2 days, and although the planet is not Earth-like, it resides within the classical "habitable zone," where liquid water could exist on an Earth-like planet. With its two known planets, Kepler-47 establishes that close binary stars can host complete planetary systems.

Background: Mental health and substance abuse are among the most commonly reported reasons for visits to Federally Qualified Health Centers (CHCs), yet only 6.5% of encounters are with on-site behavioral health specialists. Rural CHCs are significantly less likely to have on-site behavioral specialists than urban CHCs. Because of this lack of mental health specialists in rural areas, the most promising approach to improving mental health outcomes is to help rural primary care (PC) providers deliver evidence-based practices (EBPs). Despite the scope of these problems, no research has developed an effective implementation strategy for facilitating the adoption of mental health EBPs for rural CHCs. We sought to describe the conceptual components of an implementation partnership that focuses on the adaption and adoption of mental health EBPs by rural CHCs in Arkansas., Methods: We present a conceptual model that integrates seven separate frameworks: (1) Jones and Wells' Evidence-Based Community Partnership Model, (2) Kitson's Promoting Action on Research Implementation in Health Services (PARiHS) implementation framework, (3) Sackett's definition of evidence-based medicine, (4) Glisson's organizational social context model, (5) Rubenstein's Evidence-Based Quality Improvement (EBQI) facilitation process, (6) Glasgow's RE-AIM evaluation approach, and (7) Naylor's concept of shared decision making., Conclusions: By integrating these frameworks into a meaningful conceptual model, we hope to develop a successful implementation partnership between an academic health center and small rural CHCs to improve mental health outcomes. Findings from this implementation partnership should have relevance to hundreds of clinics and millions of patients, and could help promote the sustained adoption of EBPs across rural America.

Background: Collaborative-care management is an evidence-based practice for improving depression outcomes in primary care. The Department of Veterans Affairs (VA) has mandated the implementation of collaborative-care management in its satellite clinics, known as Community Based Outpatient Clinics (CBOCs). However, the organizational characteristics of CBOCs present added challenges to implementation. The objective of this study was to evaluate the effectiveness of evidence-based quality improvement (EBQI) as a strategy to facilitate the adoption of collaborative-care management in CBOCs., Methods: This nonrandomized, small-scale, multisite evaluation of EBQI was conducted at three VA Medical Centers and 11 of their affiliated CBOCs. The Plan phase of the EBQI process involved the localized tailoring of the collaborative-care management program to each CBOC. Researchers ensured that the adaptations were evidence based. Clinical and administrative staff were responsible for adapting the collaborative-care management program for local needs, priorities, preferences and resources. Plan-Do-Study-Act cycles were used to refine the program over time. The evaluation was based on the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) Framework and used data from multiple sources: administrative records, web-based decision-support systems, surveys, and key-informant interviews., Results: Adoption: 69.0% (58/84) of primary care providers referred patients to the program. Reach: 9.0% (298/3,296) of primary care patients diagnosed with depression who were not already receiving specialty care were enrolled in the program. Fidelity: During baseline care manager encounters, education/activation was provided to 100% (298/298) of patients, barriers were assessed and addressed for 100% (298/298) of patients, and depression severity was monitored for 100% (298/298) of patients. Less than half (42.5%, 681/1603) of follow-up encounters during the acute stage were completed within the timeframe specified. During the acute phase of treatment for all trials, the Patient Health Questionnaire (PHQ9) symptom-monitoring tool was used at 100% (681/681) of completed follow-up encounters, and self-management goals were discussed during 15.3% (104/681) of completed follow-up encounters. During the acute phase of treatment for pharmacotherapy and combination trials, medication adherence was assessed at 99.1% (575/580) of completed follow-up encounters, and side effects were assessed at 92.4% (536/580) of completed follow-up encounters. During the acute phase of treatment for psychotherapy and combination trials, counseling session adherence was assessed at 83.3% (239/287) of completed follow-up encounters. Effectiveness: 18.8% (56/298) of enrolled patients remitted (symptom free) and another 22.1% (66/298) responded to treatment (50% reduction in symptom severity). Maintenance: 91.9% (10/11) of the CBOCs chose to sustain the program after research funds were withdrawn., Conclusions: Provider adoption was good, although reach into the target population was relatively low. Fidelity and maintenance were excellent, and clinical outcomes were comparable to those in randomized controlled trials. Despite the organizational barriers, these findings suggest that EBQI is an effective facilitation strategy for CBOCs., Trial Registration: Clinical trial # NCT00317018.

Context: Mental health (MH) providers in community-based outpatient clinics (CBOCs) are important stakeholders in the development of the Veterans Health Administration (VA) telemental health (TMH) system, but their perceptions of these technologies have not been systematically examined., Purpose: The purpose of this study was to investigate the attitudes of CBOC providers about TMH services, current utilization of these technologies in their clinics, and sources of knowledge regarding TMH., Method: The study employed a mixed-methods design to examine aspects of TMH in CBOCs located in a VA network in the south-central United States. Semistructured, on-site group interviews conducted with 86 CBOC MH providers were followed by in-depth phone surveys with an MH provider identified as a key informant at each of 36 CBOCs in the VA network., Findings: The utilization of TMH services varied widely between CBOCs, and the scope of services provided typically focused on delivery of medication management, with little provision of psychological services. Further, several important barriers to expanded use of TMH were identified, including limited education and training and shortage of dedicated space for TMH encounters., Conclusions: General attitudes toward TMH were positive, and most CBOC providers indicated that they would like to expand use of TMH in their clinics., (© 2011 No claim to original US government works.)

A 54-year-old Caucasian female presented with a 1 year history of intermittent numbness of the left leg progressing to bilateral, lower extremity sensory loss that advanced to include impaired vibration and proprioception. The subsequent thoracic spine magnetic resonance imaging (MRI) scan revealed a heterogeneous, avidly enhancing, centrally situated spinal cord mass involving T7 through T10 in association with thick linear enhancement of the anterior and posterior cord surfaces extending both superiorly and inferiorly. Both the cervical and lumbar spine MRI demonstrated diffuse leptomeningeal disease as well. A brain MRI revealed focal leptomeningeal enhancement in the left and right sylvian fissures, the suprasellar cistern, and the posterior fossa; a pattern consistent with metastatic disease. The patient underwent a T6-T10 laminectomy for tumor biopsy and debulking. Histology revealed a WHO grade III glioneuronal tumor with rosetted neuropil-like islands. Synaptophysin and neurofilament (NF) positive staining was noted within the neural appearing component, whereas, glial fibrillary acidic protein (GFAP) immunopositivity was evident in the fibrillary astrocytoma component of the tumor. The Ki-67 labeling index was 7%. This tumor pattern, now included in the 2007 World Health Organization (WHO) classification of central nervous system tumours as a pattern variation of anaplastic astrocytoma (Kleihues et al. In: Louis et al. (eds) WHO classification of tumours of the central nervous system, 2007), was first described in a four-case series by Teo et al. in 1999. The majority of subsequently reported cases described them as primary tumors of the cerebrum. Herein, we report a unique example of a spinal glioneuronal tumor with neuropil-like islands with associated leptomeningeal dissemination involving the entire craniospinal axis.

Extracorporeal membrane oxygenation (ECMO) is routinely used to support cardiopulmonary failure in infants and children. Suboptimal outcomes for primary cardiac support suggest a need for investigation of the impact of ECMO on the heart. Twenty-four newborn lambs received a brief period of ECMO support to investigate the hypothesis that ECMO produces cardiac dysfunction in newborn lamb. Dorset newborn lambs, 4-7 days of age, were exposed to ECMO for 5 min at a 100 ml/kg flow rate and quickly weaned off. Measurements included echocardiographic mean left ventricular (LV) velocity of circumferential fiber shortening corrected for heart rate (mVCFc), LV shortening fraction, and peak systolic wall stress plus hemodynamic measurement of LV maximum rate of pressure change with time (LV dp/dt max), maximum rate of pressure change divided by developed pressure (LV dp/dtP), right atrial pressure, pulmonary capillary wedge pressure, mean pulmonary artery pressure, LV peak and end-diastolic pressure, and aortic pressure. These measures were also obtained after an exposure to 5 min of ECMO and immediate disconnect for 5 min, followed by ECMO administration for 1 h again, followed by discontinuation of ECMO. LV mVCFc is decreased after exposure to 5 min of ECMO support despite a decrease in LV peak systolic wall stress that provides afterload reduction. LV mVCFc is inversely related to peak systolic wall stress at a significance level of p < 0.0001. The time period after initiation of ECMO is a significant factor in the model (p = 0.0097). Time [baseline] was different from the other time points with p = 0.0010. Average mVCFc at baseline is 1.27 ± 0.35 and decreases to 1.01 ± 0.42 after 5 min of ECMO that is then withdrawn. Peak systolic wall stress decreases from 36.0 ± 13.1 at baseline to 29.8 ± 12.1 after 5 min of ECMO. LV dp/dt max decreases from 1,769 ± 453 mmHg/s at baseline to 1,311 ± 513 mmHg/s after exposure to 5 min of ECMO (p = 0.0005). Baseline LV dp/dt max is different from each point after start of ECMO. Diastolic LVdp/dt min increased from -1,340 ± 477 mmHg/s to -908 ± 393 mmHg/s at 5 min. Echocardiographic mVCFc, when considered in isolation or as a function of LV peak systolic wall stress, shows diminished LV function after ECMO. Hemodynamic measurement of LV dp/dt max and LV dp/dt min confirms the observation. Separation of the humoral from mechanical effect of ECMO with the short exposure to the extracorporeal circuit shows that an immediate decrement of LV function occurs at initiation of ECMO, a finding that has not been stressed with previous studies of extracorporeal support. This implies a potentially outcome-limiting deleterious effect for the patient who requires ECMO support for the heart rather than the lungs. We should continue to strive to understand and ameliorate this deleterious effect of the extracorporeal circulation circuit.

Background: Soldiers often return from war with a variety of combat-related mental health conditions, including posttraumatic stress disorder, depression, and substance-use disorders., Objective: The authors investigated common co-occurring medical and psychiatric conditions and patterns of conditions among returning Iraq/Afghanistan veterans using the Veterans Administration (VA) healthcare systems., Method: Common clusters of ICD-9 diagnostic-related conditions among returning soldiers (N=293,861) were extracted from the VA data center., Results: Diagnoses involving pain are extremely common among returning veterans seeking health care at the VA. In addition to pain-related conditions, psychiatric disorders rank second most prevalent. Psychiatric disorders, and in particular the multimorbid triad of pain, posttraumatic stress disorder, and depression frequently overlap., Conclusion: As more veterans return from war, there will be greater need for effective services. Given the findings of high rates of comorbidity and multimorbidity, VA services should be reorganized so as to co-locate psychiatric staff in pain centers, simultaneously targeting pain and psychiatric disorders.

Objectives: Many veterans return from combat experiencing a variety of mental health concerns. Previous research has documented a stigma associated with seeking treatment that interferes with the decision to seek treatment. This study, conceptualized using the theory of planned behavior, assessed beliefs about mental health treatment in order to understand mental health treatment seeking behavior among a group of returning National Guard soldiers who served in the war in Iraq., Methods: Participants were one hundred and fifty Operation Iraqi Freedom National Guard soldiers who screened positive for depression, posttraumatic stress disorder, generalized anxiety disorder, panic disorder or alcohol abuse disorder on the Mini International Neuropsychiatric Interview (MINI). Participants were asked to complete a questionnaire assessing beliefs about mental health treatment and treatment-seeking behavior., Results: Beliefs related to symptom reduction and work were significantly related to mental health treatment-seeking behavior., Conclusions: Interventions developed to engage veterans into care must be directed toward cognitive factors that motivate treatment seeking in addition to traditionally targeted structural barriers.

The Kepler mission was designed to determine the frequency of Earth-sized planets in and near the habitable zone of Sun-like stars. The habitable zone is the region where planetary temperatures are suitable for water to exist on a planet's surface. During the first 6 weeks of observations, Kepler monitored 156,000 stars, and five new exoplanets with sizes between 0.37 and 1.6 Jupiter radii and orbital periods from 3.2 to 4.9 days were discovered. The density of the Neptune-sized Kepler-4b is similar to that of Neptune and GJ 436b, even though the irradiation level is 800,000 times higher. Kepler-7b is one of the lowest-density planets (approximately 0.17 gram per cubic centimeter) yet detected. Kepler-5b, -6b, and -8b confirm the existence of planets with densities lower than those predicted for gas giant planets.

The Veterans Health Administration (VHA) in the Department of Veteran Affairs (VA) has emerged as a national and international leader in the delivery and research of telehealth-based treatment. Several unique characteristics of care in VA settings intersect to create an ideal environment for telehealth modalities and research. However, the value of telehealth experience and initiatives in VA settings is limited if telehealth strategies cannot be widely exported to other public or private systems. Whereas a hierarchical organization, such as VA, can innovate and fund change relatively quickly based on provider and patient preferences and a growing knowledge base, other health provider organizations and third-party payers may likely require replicable scientific findings over time before incremental investments will be made to create infrastructure, reform regulatory barriers, and amend laws to accommodate expansion of telehealth modalities. Accordingly, large-scale scientifically rigorous telehealth research in VHA settings is essential not only to investigate the efficacy of existing and future telehealth practices in VHA, but also to hasten the development of telehealth infrastructure in private and other public health settings. We propose an expanded partnership between the VA, NIH, and other funding agencies to investigate creative and pragmatic uses of telehealth technology. To this end, we identify six specific areas of research we believe to be particularly relevant to the efficient development of telehealth modalities in civilian and military contexts outside VHA.

The Department of Veterans Affairs (VA) established community-based outpatient clinics to improve veterans' access to primary care. This article compares VA use and expenditures among primary care users at 76 VA-staffed community clinics (n = 17,060) and 32 non-VA contract community clinics receiving capitation (n = 6,842) using VA administrative databases. It estimates utilization using negative binomial models and expenditures using generalized linear one-part or two-part models. Contract community clinic patients are less likely to use all types of outpatient services than VA-staffed community clinic patients but had similar quality of care. For patients seeking care, contract community clinic patients had similar specialty care expenditures but lower primary care, outpatient, and overall expenditures. Results suggest that capitated contract clinics did not shift costs to specialty care and appeared to be an economically efficient mechanism for improving veterans' access to primary care while meeting VA quality of care standards.

Objective: To document time allocated to care management activities and care manager workload capacity using data collected for studies of telephone care management of depression., Study Design: Cross-sectional, descriptive analysis of depression care manager (DCM) activities and workload in 2 collaborative depression care interventions (1 implementation study and 1 effectiveness study) at Department of Veterans Affairs primary care facilities., Methods: Each intervention tracked specific care management activities for 4 weeks, recording the number of events for each activity type and length of time for each activity. Patient workload data were obtained from the patient tracking systems for the 2 projects. We calculated the average time for each activity type, the average total time required to complete an initial assessment call and follow-up call, and the maximum patient panel for both projects., Results: The total time per successful initial assessment was 75 to 95 minutes, and the total time per successful follow-up call was 51 to 60 minutes, with more time spent on ancillary activities (precall preparation, postcall documentation, and provider communication) than on direct patient contact. A significant amount of time was spent in unsuccessful call attempts, requiring 9 to 11 minutes for each attempt. The maximum panel size per care manager per quarter was in the range of 143 to 165 patients., Conclusions: The study found similar DCM time allocations and panel sizes across 2 studies and 3 regions with full-time DCMs. Reductions in DCM time spent on ancillary activities may be achievable through improved informatics and other support for panel management.

Although leukemic stem cells (LSCs) show a symbiotic relationship with bone marrow microenvironmental niches, the mechanism by which the marrow microenvironment contributes to self-renewal and proliferation of LSCs remains elusive. In the present study, we identified a unique subpopulation of Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL) cells coexpressing markers of endothelial cells (including VE-cadherin, PECAM-1, and Flk-1) and committed B-lineage progenitors. After long-term coculture with bone marrow stromal cells, tumor cells formed hematopoietic colonies and cords, expressed early stem- cell markers, and showed endothelial sprouting. Gene expression profiles of LSCs were altered in the presence of stromal cell contact. Stromal cell contact promoted leukemic cell VE-cadherin expression, stabilized beta-catenin, and up-regulated Bcr-abl fusion gene expression. Our study indicates that these specific tumor cells are uniquely positioned to respond to microenvironment-derived self-renewing and proliferative cues. Ph(+)/VE-cadherin(+) tumor subpopulation circumvents the requirement of exogenous Wnt signaling for self-renewal through stromal cell support of leukemic cell VE-cadherin expression and up-regulated Bcr-abl tyrosine kinase activity. These data suggest that strategies targeting signals in the marrow microenvironment that amplify the Bcr-abl/VE-cadherin/beta-catenin axis may have utility in sensitizing drug-resistant leukemic stem cells.

This study measured geographic variation in depression hospitalizations and identified community-level risk factors. Depression hospitalizations were identified from the Statewide Inpatient Database. The dependent variable was specified as the indirectly standardized hospitalization rate. County-level data for 14 states were collected from federal agencies. The Bayesian spatial regression model included socio-demographic, economic, and health system characteristics as independent variables. There were 8.5 depression hospitalizations per 1,000 residents. 8.8% of counties had hospitalization rates 33% greater than the standardized rate. Significant risk factors included unemployment, poverty, physician supply, and hospital bed supply. Significant protective factors included rurality, economic dependence, and housing stress.

Context: Federally qualified health centers across the country are adopting depression disease management programs following federally mandated training; however, little is known about the relative effectiveness of depression disease management in rural versus urban patient populations., Purpose: To explore whether a depression disease management program has a comparable impact on clinical outcomes over 2 years in patients treated in rural and urban primary care practices and whether the impact is mediated by receiving evidence-based care (antidepressant medication and specialty care counseling)., Methods: A preplanned secondary analysis was conducted in a consecutively sampled cohort of 479 depressed primary care patients recruited from 12 practices in 10 states across the country participating in the Quality Enhancement for Strategic Teaming study., Findings: Depression disease management improved the mental health status of urban patients over 18 months but not rural patients. Effects were not mediated by antidepressant medication or specialty care counseling in urban or rural patients., Conclusions: Depression disease management appears to improve clinical outcomes in urban but not rural patients. Because these programs compete for scarce resources, health care organizations interested in delivering depression disease management to rural populations need to advocate for programs whose clinical effectiveness has been demonstrated for rural residents.

Objective: We have previously demonstrated that bone marrow stromal cells (BMSCs) exposed to etoposide (VP-16) have reduced support of CXCR4(+) cell chemotaxis and diminished stromal cell derived factor-1 (CXCL12) in the supernatants. Based on the identification of CXCL12 as a matrix metalloproteinase-2 (MMP-2) substrate, we investigated potential dysregulation of MMP-2 expression or activity in chemotherapy-treated BMSCs., Methods: BMSCs exposed to VP-16 were evaluated for MMP-2 expression by gelatin zymography, ELISA, and western blot. Chemotaxis assays were completed to evaluate pro-B cell chemotaxis toward either MMP-2(-/-) BMSCs or BMSCs exposed to MMP-2 inhibitors., Results: BMSC exposure to VP-16 resulted in an immediate, transient, increase in MMP-2, followed by reduced MMP-2 protein expression. MMP-2 reduction correlated with diminished CXCL12 protein and reduced support of pro-B cell chemotaxis. BMSCs derived from MMP-2 knockout mice had less chemotactic support of CXCR4(+) cells than wild-type controls. Inhibition of BMSC MMP-2 activity by OA-Hy also reduced chemotactic support and CXCL12 protein detected in BMSC supernatants. VP-16-induced reduction of BMSC support of hematopoietic cell migration was restored by supplementing cultures with recombinant MMP-2 protein., Conclusions: These data suggest that MMP-2 is sensitive to chemotherapy-induced stress, and may regulate BMSC support of pro-B cell chemotaxis. Increased MMP-2 expression during the acute phase of chemotherapy exposure potentially inactivates CXCL12. Subsequently, chronic exposure to chemotherapy, with the associated downregulation of MMP-2, interrupts CXCL12 release from the extracellular matrix, also blunting BMSC support of pro-B cell migration.

Although employers commonly review administrative database indicators to assess depression treatment quality, they do not know whether these indicators predict relevant outcomes like absenteeism. In 230 employed patients in five health plans, we tested how administrative database-derived indicators for antidepressant medication and psychotherapy provided during the first 6 months of a new depression treatment episode predicted patient-reported absenteeism change over 12 months. The medication indicator was not significantly associated with absenteeism change over 12 months (p = .64); however, the psychotherapy indicator was significantly associated with an average 26.1% improvement in absenteeism over 12 months (p < .05). If subsequent studies confirm the results we report, quality monitoring initiatives interested in employer-relevant indicators of depression treatment quality should examine administrative database indicators of psychotherapy.

Dose-escalated chemotherapy has proven utility in a variety of treatment settings, including preparative regimens before bone marrow or hematopoietic stem cell transplantation. However, the potential damage imposed by aggressive regimens on the marrow microenvironment warrants further investigation. In the present study, we tested the hypothesis that dose-escalated chemotherapy, with etoposide as a model chemotherapeutic agent, activates the transforming growth factor beta-1 (TGF-beta1) signaling pathway in bone marrow stromal cells. After high-dose etoposide exposure in vitro, Smad3 protein was phosphorylated in a time-and dose-dependent manner in marrow-derived stromal cells, coincident with the release of active and latent TGF-beta1 from the extracellular matrix. Phosphorylation was modulated by p38 kinase, with translocation of Smad3 from the cytoplasm to the nucleus subsequent to its phosphorylation. Etoposide induced activation of TGF-beta1 followed the generation of reactive oxygen species and required matrix metalloproteinase-2 (MMP-2) protein availability. Chemotherapy effects were diminished in MMP-2(-/-) knockout stromal cells and TGF-beta1 knockdown small interfering RNA-transfected stromal cells, in which phosphorylation of Smad3 was negligible after etoposide exposure. Stable transfection of a human MMP-2 cDNA into bone marrow stromal cells resulted in elevated phosphorylation of Smad3 during chemotherapy. These data suggest TGF-beta1/p38/Smad3 signaling cascades are activated in bone marrow stromal cells after dose-escalated chemotherapy and may contribute to chemotherapy-induced alterations of the marrow microenvironment.

Three categories of precursor cells have been identified in postnatal mammals: tissue-committed progenitor cells, germ layer lineage-committed stem cells and lineage-uncommitted pluripotent stem cells. Progenitor cells are the immediate precursors of differentiated tissues. Germ layer lineage stem cells can be induced to form multiple cell types belonging to their respective ectodermal, mesodermal, and endodermal embryological lineages. Pluripotent stem cells will form somatic cell types from all three primary germ layer lineages. Progenitor cells demonstrate a finite life span before replicative senescence and cell death occur. Both germ layer lineage stem cells and pluripotent stem cells are telomerase positive and display extensive capabilities for self-renewal. Stem cells which undergo such extensive replication have the potential for undergoing mutations that may subsequently alter cellular functions. Gross mutations in the genome may be visualized as chromosomal aneuploidy and/or chromosomes that appear aberrant. This study was designed to determine whether any gross genomic mutations occurred within the adult pluripotent stem cells. Karyotypic analysis was performed using pluripotent stem cells purified from adult male rats using established procedures. Giemsa Banding was used in conjunction with light microscopy to visualize metaphase chromosome spreads. To date over 800 metaphase spreads have been analyzed. We found that the metaphase spreads averaged 42 chromosomes and concluded that these pluripotent stem cells isolated from adult rats have a normal karyotype.

Background: Employers recently requested a valid metric of depression treatment quality. Such an indicator needs to measure the proportion of the population in need who receive high-quality care, and to predict clinical improvement., Methods: We constructed an administrative database indicator derived from HEDIS criteria for antidepressant medication management, and tested it in 230 employed patients in five health plans., Results: Indicator rates were 7.0% in the population in need. Conformance to indicator criteria in this population was associated with 23.0% improvement in depression severity over 1 year (p = .02)., Conclusions: Administrative database indicators that predict clinical improvement are a very rare accomplishment. Existing depression indicators may need to be calculated for the population in need to provide a valid metric for employer purchasers.

Most low-resource settings depend on hormonal contraceptives for their family planning programmes and cervical cancer occurs in higher frequency in these populations. To determine whether hormonal contraception use increases cervical carcinoma in-situ (CIS) risk, a case-control study was conducted in the Kingston and St Andrew Corporate area of Jamaica, using 119 cases from the Jamaica Tumour Registry and 304 population controls matched on year of Papanicolaou (Pap) smear and clinic where Pap smear was obtained. While CIS cases were more likely to have 'ever used' combined oral contraceptives (COC) (OR = 1.4, 95% CI: 0.8, 2.5), depo-medroxyprogesterone acetate (DMPA) use was similar. Compared to women who never used hormonal contraceptives, the risk of CIS was elevated in: women who had used COCs five years or more (OR = 2.1, 95% CI: 1.0, 4.6), women who first used COC for less than 10 years prior to the interview (OR = 1.8, 95% CI: 0.9, 3.7) and women who were 18 to 24 years old when they first used COCs (OR = 1.8, 95% CI: 0.9, 3.4). Similarly, compared to women who never used DMPA, the risk of CIS was elevated in: women using DMPA five years or more (OR = 1.9, 95% CI: 0.7, 4.8), women reporting use within a year prior to interview (OR = 2.8, 95% CI: 0.7, 10.7) and women who initiated use of DMPA when they were 20 and 24 years old (OR = 1.4, 95% CI: 0.7, 3.1). These results suggest that if hormonal contraceptive use confers any risk of CIS, it is confined to long-term users. Increased risk in some groups, however, warrant further study.