Search

The goal of emergency medical services (EMS) is to provide urgent medical care and stabilization prior to patient transport to a healthcare facility for definitive treatment. The number and variety of interventions performed in the field by EMS providers continues to grow as early management of severe injuries and critical illness in the pre-hospital setting has been shown to improve patient outcomes. The sequela of many field interventions, including those associated with airway management, emergent vascular access, cardiopulmonary resuscitation (CPR), patient immobilization, and hemorrhage control may be appreciated on emergency department admission imaging. Attention to these imaging findings is important for the emergency radiologist, who may be the first to identify a malpositioned device or an iatrogenic complication arising from pre-hospital treatment. Recognition of these findings may allow for earlier corrective action to be taken in the acute care setting. This review describes common EMS interventions and their imaging findings. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate quantitative and qualitative spermatic cord CT abnormalities and presence of unilateral or bilateral symptomatic scrotal pathology (SSP) at ultrasound. Methods: This retrospective study included 122 male patients (mean age 47.8 years) undergoing scrotal ultrasound within 24 h of contrast-enhanced CT (n = 85), non-contrast CT (NECT, n = 32) or CT-Urogram (n = 5). CECT quantitative analysis assessed differential cord enhancement using maximum Hounsfield unit measurements. Three fellowship trained body radiologists independently assessed qualitative cord abnormalities for both CECT and NECT. Qualitative and quantitative findings were compared with the presence of SSP. Reader performance, interobserver agreement and reader confidence were assessed for NECT and CECT. Quantitative cutoff points were identified which maximized accuracy, specificity, negative predictive value, and other measures. Results: SSP was present in 36/122 patients (29.5%). Positive cases were unilateral in 30 (83.3%) and bilateral in 6 (16.6%). At quantitative assessment, 25% differential cord enhancement had the highest diagnostic accuracy (88.9%), with 90.5% positive predictive value, 88.4% negative predictive value, 96.8% specificity, and 70.4% sensitivity. At qualitative evaluation, CECT reader performance was excellent (aggregate AUC = 0.86; P <.001); NECT was poorly discriminatory, although remained significant (aggregate AUC = 0.67; P =.002). Readers had significantly higher confidence levels with CECT (P <.001). Qualitative inter-observer agreement was high for both CECT and NECT (ICC = 0.981 and 0.963, respectively). Conclusion: Simple quantitative assessment of differential cord enhancement is highly accurate and specific for SSP at CECT. Qualitative abnormalities at CECT and NECT are also both predictors of SSP, however, CECT significantly out-performs non-contrast exams. [ABSTRACT FROM AUTHOR]

Evidence of early initiation of substance use among American Indian youth and links between early initiation and substance use disorder make prevention imperative. The Thiwáhe Gluwáš'akapi Program (TG, Sacred home in which family is made strong) is a group-based and family-centered intervention that was culturally adapted from the Strengthening Families Program for Parents and Youth 10–14 to address this need. Groups of families participated in TG together for seven weeks; this study explored whether the social networks of parents participating in this program were enhanced through this group experience, particularly with regard to connections that support parenting. Parents completed social network surveys at baseline and post-intervention (n = 106) that included questions about who they would go to when they experienced challenges in parenting their children. Average network centrality and desire to seek parenting advice from TG program peers both increased at post-test. The findings from this preliminary study suggest that group-based interventions have the potential to impact social networks and point to the need for rigorous study of how networks are influenced by such interventions and, in turn, may affect their impact. Highlights: Social networks as a lever for substance use prevention for American Indian youth. Interdependent systems often typify American Indian tribal-based communities. Social network analysis as a tool for examining group-based prevention programs. [ABSTRACT FROM AUTHOR]

Metabolic flexibility enables fungi to invade challenging host environments. In Candida albicans, a common cause of life-threatening infections in humans, an important contributor to flexibility is alternative oxidase (Aox) activity. Dramatic induction of this activity occurs under respiratory-stress conditions, which impair the classical electron transport chain (ETC). Here, we show that deletion of the inducible AOX2 gene cripples C. albicans virulence in mice by increasing immune recognition. To investigate further, we examined transcriptional regulation of AOX2 in molecular detail under host-relevant, ETC-inhibitory conditions. We found that multiple transcription factors, including Rtg1/Rtg3, Cwt1/Zcf11, and Zcf2, bind and regulate the AOX2 promoter, conferring thousand-fold levels of inducibility to AOX2 in response to distinct environmental stressors. Further dissection of this complex promoter revealed how integration of stimuli ranging from reactive species of oxygen, nitrogen, and sulfur to reduced copper availability is achieved at the transcriptional level to regulate AOX2 induction and enable pathogenesis. Metabolic flexibility allows fungi to invade hostile niches. Here, Liu et al. dissect the molecular mechanisms by which Candida albicans upregulates virulence-enabling alternative oxidase expression in response to host-relevant respiratory stresses. [ABSTRACT FROM AUTHOR]

Adolescence is a critical period for reducing skin cancer risks, yet the development of effective interventions for middle and high school youth has lagged behind those for younger children. We developed and implemented the "Youth Engaged Strategies for Changing Adolescent Norms!" (YESCAN!) program, a school-based peer leader program that uses a youth-researcher partnership approach and a project-based curriculum to support high school students in developing and delivering short narrative videos and related material about skin cancer prevention to middle school students. Participating middle and high school students completed pre- and post-program surveys assessing skin cancer attitudes, perceived norms, and behavioral intentions. Middle school students (N = 97) reported positive pre- to post-program changes in future intentions to engage in sun protection and reduce UV exposure behaviors and on numerous measures of normative beliefs and attitudes. High school students (N = 13) reported positive changes on a smaller set of behavioral intentions, normative beliefs, and attitudes. These findings add to a growing body of support for youth-participatory, peer-led approaches to adolescent risk reduction in general and to skin cancer risks specifically. The YESCAN! program fills a need for effective skin cancer prevention among adolescents, while at the same time addressing educational objectives to develop 21st Century Skills. [ABSTRACT FROM AUTHOR]

This addendum to an article published in Nature Communications discusses a correction to the original findings. The original article reported that a molecule produced by Lactobacillus species inhibits the ability of the fungal pathogen Candida albicans to transition into a more virulent form. However, it was later discovered that the presence of the molecule in the Lactobacillus-conditioned medium was not due to bacterial biosynthesis, but rather a result of chemical reactions during the sterilization process. The correction clarifies that while the molecule does have the ability to block Candida albicans morphogenesis, it is not synthesized by the bacteria. The other findings related to the molecule's mode of action and therapeutic potential remain valid. [Extracted from the article]

In vitro evolution and whole genome analysis were used to comprehensively identify the genetic determinants of chemical resistance in Saccharomyces cerevisiae. Sequence analysis identified many genes contributing to the resistance phenotype as well as numerous amino acids in potential targets that may play a role in compound binding. Our work shows that compound-target pairs can be conserved across multiple species. The set of 25 most frequently mutated genes was enriched for transcription factors, and for almost 25 percent of the compounds, resistance was mediated by one of 100 independently derived, gain-of-function SNVs found in a 170 amino acid domain in the two Zn2C6 transcription factors YRR1 and YRM1 (p < 1 × 10−100). This remarkable enrichment for transcription factors as drug resistance genes highlights their important role in the evolution of antifungal xenobiotic resistance and underscores the challenge to develop antifungal treatments that maintain potency. Ottilie et al. employ an experimental evolution approach to investigate the role of transcription factors in yeast chemical resistance. Most emergent mutations in resistant strains were enriched in transcription factor coding genes, highlighting their importance in drug resistance. [ABSTRACT FROM AUTHOR]

The fungus Candida albicans is an opportunistic pathogen that can exploit imbalances in microbiome composition to invade its human host, causing pathologies ranging from vaginal candidiasis to fungal sepsis. Bacteria of the genus Lactobacillus are colonizers of human mucosa and can produce compounds with bioactivity against C. albicans. Here, we show that some Lactobacillus species produce a small molecule under laboratory conditions that blocks the C. albicans yeast-to-filament transition, an important virulence trait. It remains unexplored whether the compound is produced in the context of the human host. Bioassay-guided fractionation of Lactobacillus-conditioned medium linked this activity to 1-acetyl-β-carboline (1-ABC). We use genetic approaches to show that filamentation inhibition by 1-ABC requires Yak1, a DYRK1-family kinase. Additional biochemical characterization of structurally related 1-ethoxycarbonyl-β-carboline confirms that it inhibits Yak1 and blocks C. albicans biofilm formation. Thus, our findings reveal Lactobacillus-produced 1-ABC can prevent the yeast-to-filament transition in C. albicans through inhibition of Yak1. Alterations of the mucosal microbiota, including Lactobacillus bacteria, are associated with infections caused by the fungus Candida albicans. Here, MacAlpine et al. show that some Lactobacillus strains produce a small molecule that blocks C. albicans filamentation and biofilm formation, and thus virulence, through inhibition of a fungal kinase. [ABSTRACT FROM AUTHOR]

The purpose of this study was to examine whether psychological needs satisfaction mediated the association between helicopter parenting and emerging adults' prosocial tendencies. There were 288 participants with an average age of 19.72 (SD = 1.77) who completed an online survey including measures of maternal and paternal helicopter parenting; satisfaction of the psychological needs for autonomy, competence, and relatedness; as well as the prosocial outcomes of empathic concern, perspective-taking, and helping others. There was an indirect effect of maternal helicopter parenting on empathetic concern, perspective-taking, and prosocial behaviors through autonomy. There was also an indirect effect of both maternal and paternal helicopter parenting on empathetic concern through relatedness. Helicopter parenting was associated with less autonomy and sense of relatedness, which were both associated with fewer prosocial tendencies among emerging adults. There were no other direct or indirect effects of maternal or paternal helicopter parenting on emerging adults' prosocial tendencies. Given that satisfaction of psychological needs has been found to promote intrinsically motivated behavior and facilitate the internal regulation of behavior that is extrinsically motivated in prior research, the relationship between helicopter parenting and decreased psychological needs satisfaction found in this study is concerning. If helicopter parenting shifts emerging adults' motivation for prosocial behavior from more intrinsic to extrinsic sources, then they may engage in fewer prosocial behaviors and may not experience the sense of well-being typically associated with doing them. Highlights: No direct relationship was found between helicopter parenting and various prosocial tendencies, but an indirect effect was found through psychological needs satisfaction. Maternal helicopter parenting was associated with decreased empathetic concern, perspective-taking, and prosocial behaviors in emerging adults through its negative impact on their sense of autonomy. Both maternal and paternal helicopter parenting were associated with decreased empathetic concern among emerging adults due to its negative association with their sense of relatedness. [ABSTRACT FROM AUTHOR]

Candida auris is an emerging fungal pathogen that exhibits resistance to multiple drugs, including the most commonly prescribed antifungal, fluconazole. Here, we use a combinatorial screening approach to identify a bis-benzodioxolylindolinone (azoffluxin) that synergizes with fluconazole against C. auris. Azoffluxin enhances fluconazole activity through the inhibition of efflux pump Cdr1, thus increasing intracellular fluconazole levels. This activity is conserved across most C. auris clades, with the exception of clade III. Azoffluxin also inhibits efflux in highly azole-resistant strains of Candida albicans, another human fungal pathogen, increasing their susceptibility to fluconazole. Furthermore, azoffluxin enhances fluconazole activity in mice infected with C. auris, reducing fungal burden. Our findings suggest that pharmacologically targeting Cdr1 in combination with azoles may be an effective strategy to control infection caused by azole-resistant isolates of C. auris. The fungal pathogen Candida auris is resistant to multiple drugs including the common antifungal fluconazole. Here, Iyer et al. identify a compound that potentiates fluconazole activity against C. auris in vitro and in vivo by inhibiting a major efflux pump and thus increasing intracellular fluconazole accumulation. [ABSTRACT FROM AUTHOR]

Research in indigenous communities is at the forefront of innovation currently influencing several new perspectives in engaged intervention science. This is innovation born of necessity, involving efforts to create health equity complicated by a history of distrust of research. Immense diversity across indigenous cultures, accompanied by variation in associated explanatory models, health beliefs, and health behaviors, along with divergent structural inequities add further complexity to this challenge. The aim of this Supplemental Issue on Promoting Health Equity through Rigorous, Culturally Informed Intervention Science: Innovations with Indigenous Populations in the United States is to highlight the promising new approaches and perspectives implemented by a group of engaged researchers and their community partners, as they seek to move intervention research forward within indigenous communities. Case studies presented are from projects led by members of the National Institutes of Health Intervention Research to Improve Native American Health (IRINAH) consortioum, investigators who conduct health promotion and disease prevention research among American Indians, Alaska Natives, and Native Hawaiians. The promising practices profiled include new strategies in (a) community partnerships, engagement, and capacity building; (b) integration of indigenous and academic perspectives; (c) alignment of interventions with indigenous cultural values and practices; and (d) implementation and evaluation of multilevel interventions responsive to complex cultural contexts. The IRINAH projects illustrate the evolution of an intervention science responsive to the needs, realities, and promise of indigenous communities, with application to health research among other culturally distinct health inequity groups. [ABSTRACT FROM AUTHOR]

This concluding article to the Supplemental Issue on Promoting Health Equity through Rigorous, Culturally Informed Intervention Science: Innovations with Indigenous Populations in the United States draws themes and conclusions from the innovative practices implemented by the National Institutes of Health Intervention Research to Improve Native American Health (IRINAH) consortium. The IRINAH work highlights promising practices for advancing the diverse and underrepresented perspectives essential to develop and test culturally appropriate, effective health interventions in American Indian, Alaska Native, and Native Hawaiian settings. Four emergent themes appear through the IRINAH work. First, community-based participatory research (CBPR) has provided projects an intersectional worldview for bridging cultures and informing an ethics of local control. Second, culture is fundamental as a central organizing principle in IRINAH research and intervention implementation. Third, crucial demands for sustainability of interventions in Indigenous intervention science require a rethinking of the intervention development process. Finally, tensions persist in Indigenous health research, even as significant strides are made in the field. These themes collectively inform an ethical and rigorous Indigenous intervention science. Collectively, they suggest a roadmap for advancing Indigenous perspectives and self-determination in health intervention research. IRINAH studies are leading innovation in intervention science by advancing applications of CBPR in intervention science, promoting new directions in small populations health research, and demonstrating value of participatory team science. [ABSTRACT FROM AUTHOR]

Indigenous communities often face disproportionate challenges across a variety of health domains, and effective prevention strategies are sorely needed. Unfortunately, evidence is scant regarding what approaches are effective for these communities. A common approach is to take an evidence-based practice or program with documented effectiveness in other populations and implement it with Indigenous populations. While a science of intervention adaptation is emerging, there remains little guidance on processes for adaptation that strategically leverage both existing scientific evidence and Indigenous prevention strategies. In this paper, two case studies illustrate promising practices for adaptation, documenting the approaches of two research teams funded under the National Institutes of Health's initiative to support Intervention Research to Improve Native American Health (IRINAH). These teams worked with distinct Indigenous populations in the USA and Canada to culturally adapt the same prevention program, the Iowa Strengthening Families Program for Parents and Youth 10-14. The approaches of these two teams and the programs that resulted are compared and contrasted, and critical elements of adaptation in partnership with Indigenous communities are discussed. [ABSTRACT FROM AUTHOR]

The mammalian cortex is a laminar structure containing many areas and cell types that are densely interconnected in complex ways, and for which generalizable principles of organization remain mostly unknown. Here we describe a major expansion of the Allen Mouse Brain Connectivity Atlas resource1, involving around a thousand new tracer experiments in the cortex and its main satellite structure, the thalamus. We used Cre driver lines (mice expressing Cre recombinase) to comprehensively and selectively label brain-wide connections by layer and class of projection neuron. Through observations of axon termination patterns, we have derived a set of generalized anatomical rules to describe corticocortical, thalamocortical and corticothalamic projections. We have built a model to assign connection patterns between areas as either feedforward or feedback, and generated testable predictions of hierarchical positions for individual cortical and thalamic areas and for cortical network modules. Our results show that cell-class-specific connections are organized in a shallow hierarchy within the mouse corticothalamic network. Using mouse lines in which subsets of neurons are genetically labelled, the authors provide generalized anatomical rules for connections within and between the cortex and thalamus. [ABSTRACT FROM AUTHOR]

Initiation of substance use often occurs earlier among American Indian (AI) youth than among other youth in the USA, bringing increased risk for a variety of poor health and developmental outcomes. Effective prevention strategies are needed, but the evidence base remains thin for this population. Research makes clear that prevention strategies need to be culturally coherent; programs with an evidence base in one population cannot be assumed to be effective in another. However, guidance on effective adaptation is lacking. This paper reports on cultural adaptation of an evidence-based program utilizing the multiphase optimization strategy (MOST) framework embedded within a community-engaged process to evaluate intervention components. The Strengthening Families Program for Parents and Youth 10-14 was adapted to become the Thiwáhe Gluwáš'akapi Program for American Indian youth and families. Three program components were evaluated for their effectiveness with regard to outcomes (youth substance use, theoretical mediators of program effects on substance use, and program attendance) in a sample of 98 families (122 youth and 137 adults). Consistent with the MOST framework, the value of components was also evaluated with regard to efficiency, economy, and scalability. Expanding on the MOST framework for cultural adaptation, we also considered the results of the MOST findings regarding the acceptability of each component from the perspectives of community members and participants. The promise of a strategic component-based approach to adapting evidence-based interventions is discussed, including the benefits of engaging community to ensure relevance and considering both cultural and scientific rationale for each component to enhance impact. [ABSTRACT FROM AUTHOR]

This study drew on the Theory of Gender and Power (TGP) as a framework to assess power inequalities within heterosexual dyads and their effects on women. Structural equation modeling was used to better understand the relationship between structural and interpersonal power and HIV sexual risk within African American and Latina women’s heterosexual dyads. The main outcome variable was women’s sexual HIV risk in the dyad and was created using women’s reports of condomless sex with their main male partners and partners’ reports of their HIV risk behaviors. Theoretical associations developed a priori yielded a well-fitting model that explained almost a quarter of the variance in women’s sexual HIV risk in main partner dyads. Women’s and partner structural power were indirectly associated with women’s sexual HIV risk through substance use and interpersonal power. Interpersonal power was directly associated with risk. In addition, this study found that not identifying as heterosexual was directly and indirectly associated with women’s heterosexual sex risk. This study provides further support for the utility of the TGP and the relevance of gender-related power dynamics for HIV prevention among heterosexually-active women. [ABSTRACT FROM AUTHOR]

Sickle cell disease is one of the most common hereditary hemoglobinopathies worldwide, and its vaso-occlusive and hemolytic crises cause considerable patient morbidity. A growing body of evidence has shown that sleep-disordered breathing, and in particular, obstructive sleep apnea, occurs at high frequency in the sickle cell population, and that there is significant overlap in the underlying pathophysiology of these two conditions. Through a variety of mechanisms including nocturnal hypoxemia and increased oxidative stress, production of pro-inflammatory cytokines, and endothelial dysfunction, sickle cell anemia and sleep-disordered breathing potentiate each other's clinical effects and end-organ complications. Here, we will review the shared pathophysiologic mechanisms of these conditions and discuss their clinical sequelae. We will also examine the results of studies that have been carried out with clinical intervention of nocturnal hypoxemia in patients with sickle cell disease in the attempts to overcome the complications of the disease. Finally, we will propose the areas of investigation that merit further investigations in future in patients with sickle cell disease and sleep-disordered breathing. [ABSTRACT FROM AUTHOR]

Objective: To develop a model for binding and catalysis associated with the stimulation of 4-fluorophenol (4-FP) oxidation in the presence of long chain aldehydes by the enzymatic catalyst, cytochrome P450-F87G. Results: A variation of the Michaeli-Menten kinetic model was employed to describe interactions at the active site of the enzyme, along with computer aided modeling approaches. In addition to the hydroquinone product arising from de-fluorination of 4-FP, a second product ( p-fluorocatechol) was also observed and, like the hydroquinone, its rate of formation increased in the presence of the aldehyde. When only aldehyde was present with the enzyme, BM3-F87G catalyzed its oxidation to the corresponding carboxylic acid; however, this activity was inhibited when 4-FP was added to the reaction. A 3D computer model of the active site containing both aldehyde and 4-FP was generated, guided by these kinetic observations. Finally, partitioning between the two phenolic products was examined with an emphasis on the conditions directing the initial epoxidation at either the 2,3- or 3,4-positions on the substrate. Temperature, reaction time, substrate concentration, and the structure of the aldehyde had no substantial effect on the overall product ratios, however the NADPH coupling efficiency decreased when unsaturated aldehydes were included, or when the temperature of the reaction was reduced. Conclusions: The unsaturated aldehyde, trans-2-decenal, stimulates BM3-F87G catalyzed oxidation of 4-fluorophenol through a cooperative active site binding mode that doesn't influence product distributions or coupling efficiencies, while 4-fluorophenol acts as a competitive inhibitor of aldehyde oxidation. [ABSTRACT FROM AUTHOR]

Drugs that act more promiscuously provide fewer routes for the emergence of resistant mutants. This benefit, however, often comes at the cost of serious off-target and dose-limiting toxicities. The classic example is the antifungal amphotericin B (AmB), which has evaded resistance for more than half a century. We report markedly less toxic amphotericins that nevertheless evade resistance. They are scalably accessed in just three steps from the natural product, and they bind their target (the fungal sterol ergosterol) with far greater selectivity than AmB. Hence, they are less toxic and far more effective in a mouse model of systemic candidiasis. To our surprise, exhaustive efforts to select for mutants resistant to these more selective compounds revealed that they are just as impervious to resistance as AmB. Thus, highly selective cytocidal action and the evasion of resistance are not mutually exclusive, suggesting practical routes to the discovery of less toxic, resistance-evasive therapies. [ABSTRACT FROM AUTHOR]

This study aims to investigate the effect of iterative reconstruction (IR) on MDCT image quality and radiologists' ability to diagnose and grade blunt solid organ injuries. One hundred (100) patients without and 52 patients with solid organ injuries were scanned on a 64-slice MDCT scanner using reference 300 mAs, 120 kVp, and fixed 75 s delay. Raw data was reconstructed using filtered back projection (FBP) and three levels of iterative reconstruction (Philips iDose levels 2, 4, and 6). Four emergency radiologists, blinded to the reconstruction parameters and original interpretation, independently reviewed each case, assessed image quality, and assigned injury grades. Each reader was then asked to determine if they thought that IR was used and, if so, what level. There was no significant difference in diagnostic accuracy between FBP and the various IR levels or effect on the detection and grading of solid organ injuries ( p > 0.8). Images reconstructed using iDose level 2 were judged to have the best overall image quality ( p < 0.01). The radiologists had high sensitivity in detecting if IR was used (80 %, 95 % CI 76-84 %). IR performed comparably to FBP with no effect on radiologist ability to accurately detect and grade blunt solid organ injuries. [ABSTRACT FROM AUTHOR]

Intravascular thrombosis and thromboembolism are critical diagnoses which are frequently made on contrast-enhanced computed tomography (CECT) or Doppler ultrasound. For a variety of reasons, some patients with acute intravascular pathology are imaged using CT without intravenous contrast. In the acute setting, the increased Hounsfield unit (HU) density of the thrombus compared to the blood pool allows the diagnosis to be made, or at least suggested, on non-enhanced computed tomography (NECT). The increased density of the clot is commonly referred to as the 'hyperdense vessel sign.' This is a well-known finding in the setting of stroke, but hyperdense vessels can also signal arterial or venous thrombosis in the chest, abdomen, pelvis, and extremities. Once a hyperdense vessel sign is noted on NECT, further exploration with CECT, angiography, or ultrasound may then be performed. Here, we present a pictorial review of the appearance of acute intravascular thrombosis as seen on non-enhanced computed tomography. [ABSTRACT FROM AUTHOR]

Substance use often begins earlier among American Indians compared to the rest of the United States, a troubling reality that puts Native youth at risk for escalating and problematic use. We need to understand more fully patterns of emergent substance use among young American Indian adolescents, risk factors associated with escalating use trajectories, and protective factors that can be parlayed into robust prevention strategies. We used growth mixture modeling with longitudinal data from middle-school students on a Northern Plains reservation (Wave 1 N = 381, M age at baseline = 12.77, 45.6 % female) to identify subgroups exhibiting different trajectories of cigarette, alcohol, and marijuana use. We explored how both risk (e.g., exposure to stressful events, deviant peers) and protective (e.g., positive parent-child relationships, cultural identity) factors were related to these trajectories. For all substances, most youth showed trajectories characterized by low rates of substance use (nonuser classes), but many also showed patterns characterized by high and/or escalating use. Across substances, exposure to stress, early puberty, and deviant peer relationships were associated with the more problematic patterns, while strong relationships with parents and prosocial peers were associated with nonuser classes. Our measures of emergent cultural identity were generally unrelated to substance use trajectory classes among these young adolescents. The findings point to the importance of early substance use prevention programs for American Indian youth that attenuate the impact of exposure to stressful events, redirect peer relationships, and foster positive parent influences. They also point to the need to explore more fully how cultural influences can be captured. [ABSTRACT FROM AUTHOR]

The interaction between the HSP90 chaperone and its client kinases is sensitive to the conformational status of the kinase, and stabilization of the kinase fold by small molecules strongly decreases chaperone interaction. Here we exploit this observation and assay small-molecule binding to kinases in living cells, using chaperones as 'thermodynamic sensors'. The method allows determination of target specificities of both ATP-competitive and allosteric inhibitors in the kinases' native cellular context in high throughput. We profile target specificities of 30 diverse kinase inhibitors against >300 kinases. Demonstrating the value of the assay, we identify ETV6-NTRK3 as a target of the FDA-approved drug crizotinib (Xalkori). Crizotinib inhibits proliferation of ETV6-NTRK3-dependent tumor cells with nanomolar potency and induces the regression of established tumor xenografts in mice. Finally, we show that our approach is applicable to other chaperone and target classes by assaying HSP70/steroid hormone receptor and CDC37/kinase interactions, suggesting that chaperone interactions will have broad application in detecting drug-target interactions in vivo. [ABSTRACT FROM AUTHOR]

Purpose: To determine conditional risk of posttraumatic stress disorder (PTSD) in two culturally distinct American Indian reservation communities. Method: Data derived from the American Indian Service Utilization, Psychiatric Epidemiology, Risk and Protective Factors Project, a cross-sectional population-based survey that was completed between 1997 and 2000. This study focused on 1,967 participants meeting the DSM-IV criteria for trauma exposure. Traumas were grouped into interpersonal, non-interpersonal, witnessed, and 'trauma to close others' categories. Analyses examined distribution of worst traumas, conditional rates of PTSD following exposure, and distributions of PTSD cases deriving from these events. Bivariate and multivariate logistic regressions estimated associations of lifetime PTSD with trauma type. Results: Overall, 15.9 % of those exposed to DSM-IV trauma qualified for lifetime PTSD, a rate comparable to similar US studies. Women were more likely to develop PTSD than were men. The majority (60 %) of cases of PTSD among women derived from interpersonal trauma exposure (in particular, sexual and physical abuse); among men, cases were more evenly distributed across trauma categories. Conclusions: Previous research has demonstrated higher rates of both trauma exposure and PTSD in American Indian samples compared to other Americans. This study shows that conditional rates of PTSD are similar to those reported elsewhere, suggesting that the elevated prevalence of this disorder in American Indian populations is largely due to higher rates of trauma exposure. [ABSTRACT FROM AUTHOR]

Introduction: Intracranial hemorrhage (ICH) has been rarely described in the setting of posterior reversible encephalopathy syndrome (PRES). However, existing studies have even more rarely addressed the imaging pattern of PRES-related intracranial hemorrhage. The primary purpose of this study was to define the imaging characteristics of subarachnoid and intraparenchymal hemorrhage in the setting of PRES, including the location of hemorrhage with respect to the regions of parenchymal edema. We also reviewed PRES-related clinical features. Methods: We conducted a retrospective review of 263 patients with PRES seen at our institution between 2001 and 2008, and identified patients with PRES-related hemorrhage. We reviewed clinical charts and imaging studies of these patients in detail. The clinical data studied included factors predisposing to PRES (such as hypertension, eclampsia, immunosuppressant toxicity, etc.), mean arterial pressure, and coagulation parameters. Imaging characteristics we analyzed included the amount of hemorrhage, its location, multiplicity, and spatial relationship with parenchymal edema. Results: We identified a total of 51 patients with PRES-related hemorrhage. The blood pressure was elevated in 80% of these patients, while 47% patients showed coagulopathy. Intraparenchymal hemorrhage (IPH) was present in 46 patients and subarachnoid hemorrhage (SAH) in 14. SAH spared basal cisterns in all patients, and was usually small in amount. IPH was often multifocal, and associated mass effect was rare. In most of the 51 patients, hemorrhage occurred near the parenchymal edema. Conclusions: The prevalence of ICH in PRES was 19.4% in our series. Both SAH and IPH can occur in association with PRES, typically in a location approximating that of parenchymal edema. [ABSTRACT FROM AUTHOR]

In spite of significant disparities in sexual health outcomes for American Indian youth, no studies exist examining the effectiveness of HIV-prevention interventions. Circle of Life is an HIV-prevention intervention specifically developed for American Indian middle-school youth. We describe the rationale, methodology, and baseline results of a longitudinal randomized trial of Circle of Life conducted among American Indian youth aged 11–15 in a reservation community. The innovative design includes two pre-intervention waves to determine patterns of behavior prior to the intervention that might be associated with a differential impact of the intervention on sexual risk. We used one-way analysis of variance and chi-square tests to test for significant differences between randomized group assignment at each baseline wave and generalized estimating equations (GEE) to test significant differences in the rate of change in outcomes by group longitudinally. We present the collaborative and adaptive strategies for consenting, assenting, and data collection methodology in this community. Achieved response rates are comparable to other similar studies. Results from the two baseline waves indicate that few outcomes significantly varied by randomized intervention assignment. Ten percent of youth reported having had sex at Wave 1, rising to 15% at Wave 2. Among those who had had sex, the majority (>70%) reported using a condom at last sex. The project is well positioned to carry out the longitudinal assessments of the intervention to determine the overall impact of the Circle of Life and the differential impact by pre-intervention patterns of behavior across youth. [ABSTRACT FROM AUTHOR]

To evaluate the Health-Related Quality of Life (HRQoL) of American Indians with diabetes, hypertension, or both conditions using the SF36; and to explore how the HRQoL is associated with help seeking among American Indians with and without these chronic conditions. We analyzed data obtained from respondents with diabetes and/or hypertension who participated in a large epidemiological study of two culturally distinct American Indian tribes. Comparison data were provided by an age, gender, and tribe matched sample from the same study who did not report either condition. The respondents with both diabetes and hypertension had the lowest HRQoL on all eight subscales of SF36. Confirmatory factor analysis (CFA) showed that the assumption of equivalent factor loadings for participants with and without diabetes and/or hypertension was not satisfied. Biomedical service use was significantly associated with the SF36 physical health factor in those with hypertension only. Help seeking from traditional healers was significantly negatively related to physical factor scores for all the respondents except those with diabetes only. Participants with comorbid diabetes and hypertension had worse HRQoL. The relationships between HRQoL and different types of help seeking varied depending on the comorbidity status of the respondents. [ABSTRACT FROM AUTHOR]

Youth use the Internet and computers in unprecedented numbers. We have yet to identify interventions that can reach and retain large numbers of diverse youth online and demonstrate HIV prevention efficacy. We tested a single session condom promotion Internet intervention for 18–24 year olds in two RCTs: one sample recruited online and one recruited in clinics. All study elements were carried out on the Internet. Using repeated measures structural equation models we analyzed change in proportion of sex acts protected by condoms (PPA) over time. Among sexually active youth in the Internet sample, persons exposed to the intervention had very slight increases in condom norms, and this was the only factor impacting PPA. We saw no intervention effects in the clinic sample. Internet-based interventions need to be more intensive to see greater effects. We need to do more to reach high risk youth online and keep their attention for multiple sessions. [ABSTRACT FROM AUTHOR]

The actin cytoskeleton supports diverse cellular processes such as endocytosis, oriented growth, adhesion and migration. The dynamic nature of the cytoskeleton, however, has made it difficult to define the roles of the many accessory molecules that modulate actin organization, especially the multifunctional adapter protein annexin II (refs. 2,3). We now report that the compound withaferin A (1) can alter cytoskeletal architecture in a previously unknown manner by covalently binding annexin II and stimulating its basal F-actin cross-linking activity. Drug-mediated disruption of F-actin organization is dependent on annexin II expression by cells and markedly limits their migratory and invasive capabilities at subcytotoxic concentrations. Given the extensive ethnobotanical history of withaferin-containing plant preparations in the treatment of cancer and inflammatory and neurological disorders, we suggest that annexin II represents a feasible, previously unexploited target for therapeutic intervention by small-molecule drugs. [ABSTRACT FROM AUTHOR]

Standing watch over the proteome, molecular chaperones are an ancient and evolutionarily conserved class of proteins that guide the normal folding, intracellular disposition and proteolytic turnover of many of the key regulators of cell growth, differentiation and survival. This essential guardian function is subverted during oncogenesis to allow malignant transformation and to facilitate rapid somatic evolution. Pharmacologically 'bribing' the essential guard duty of the chaperone HSP90 (heat-shock protein of 90 kDa) seems to offer a unique anticancer strategy of considerable promise. [ABSTRACT FROM AUTHOR]

Supercritical CO[sub 2] (scCO[sub 2]) has been used as a reaction medium for the photocatalytic oxidative degradation of n-octanol on a partially desilanized hydrophobic suspension of TiO[sub 2] as photocatalyst. Hydrophobic sites on the catalyst surface are necessary to maintain a sustained suspension, and hence surface-mediated interfacial electron exchange, in this non-polar medium. The reaction rates for photooxidative degradation, ultimately to complete mineralization, depend only weakly on temperature and pressure of the supercritical fluid near the critical point. Product distributions were monitored in situ by on-line gas chromatographic analysis, which provides a convenient and rapid method for comparisons and optimization of the reaction conditions. [ABSTRACT FROM AUTHOR]

Chronic myelogenous leukemia (CML) is a clonal disorder characterized by proliferation of cells that possess the bcr-abl fusion gene resulting in the production of one of two possible chimeric 210-kDa tyrosine kinase proteins. Since these chimeric proteins are expressed only in leukemic cells they have the potential to serve as tumor-specific antigens for cytotoxic T lymphocytes (CTL). Using the 12B1 murine leukemia cell line, derived by retroviral transformation of BALB/c bone marrow cells with the bcr-abl (b3a2) fusion gene, we have demonstrated that intravenous inoculation of 12B1 cells into BALB/c mice results in a disseminated acute leukemia analogous to human CML in blast crisis. Histological sections of liver and spleen and polymerase chain reaction analysis of peripheral blood, bone marrow, liver, spleen and lymph nodes confirmed the presence of bcr-abl+ leukemia cells in these murine tissues, while Western blot data demonstrated the expression of the fusion protein in 12B1 cells. Immunization of mice with dendritic cells (DC) loaded with the synthetic bcr-abl chimeric nonapeptide, GFKQSSKAL, led to a 150 times higher frequency of bcr-abl-specific CTL precursors in the spleen than in mice immunized with peptide alone. In vitro re-stimulation of DC-peptide-primed splenocytes resulted in substantial secretion of interferon γ and augmented cytolytic activity against 12B1 targets. Finally, vaccination with peptide-loaded DC significantly prolonged survival of BALB/c mice that were challenged with 12B1 leukemia. The capacity to generate bcr-abl-specific CTL in vivo by DC-based immunization may have clinical implications in the treatment of CML. [ABSTRACT FROM AUTHOR]

Continuous venovenous hemofiltration/hemodiafiltration (CVVH/D) is commonly used to provide renal replacement therapy for critically ill patients who are hemodynamically unstable. Occasionally, the addition of plasmapheresis therapy is necessary for some conditions, including immune-mediated acute renal failure, sepsis, fulminant hepatic failure, and thrombotic thrombocytopenic purpura/hemolytic uremic syndrome. Most tertiary care facilities provide centrifugation plasmapheresis instead of membrane plasmapheresis, because of the requirement for both therapeutic plasma exchange and pheresis of cellular blood products. We report a new technique where centrifugation plasmapheresis and CVVHD (P-CVVHD) are combined and used concurrently. Blood from the patient was concurrently filtered utilizing a Hospal BSM 22 machine with a Multiflow 60 hemofilter and a Cobe Spectra continuous cell separator in a parallel configuration. P-CVVHD is technically possible and can be used for long periods of time with limited risks. There may be advantages to P-CVVHD compared with discontinuous combined CVVH/D and plasmapheresis therapy. [ABSTRACT FROM AUTHOR]

Mutation of the tumor suppressor gene p53 is the most common genetic abnormality detected in human cancers. Wild type p53 is a short-lived protein with very low basal intracellular levels. Most mutated forms of the protein, however, display markedly increased intracellular levels as an essential feature of their positive transforming activity. In this report, we have used selective inhibitors of the 20S proteasome to demonstrate that processing of p53 by ubiquitination and proteasome-mediated degradation is impaired by commonly occuring mutations of the protein. We found that this impairment of p53 turnover can be reversed by treatment of tumor cells with the benzoquinone ansamycin, geldanamycin, leading to a marked reduction in intracellular p53 levels. Finally, using cells which over-express a mutant p53 protein, we were able to demonstrate that restoration of proteasome-mediated degradation by geldanamycin is accompanied by p53 polyubiquitination. Although much remains to be learned about the mechanisms involved, our data demonstrate that selective de-stabilization of mutant transforming proteins such as p53 can be achieved pharmacologically with agents such as geldanamycin which modify the function of molecular chaperone proteins within tumor cells. [ABSTRACT FROM AUTHOR]

Coronary artery disease causes an increase in glutamate uptake and alanine output by the heart. We assessed the effects of acute myocardial ischemia on alanine and glutamate exchange and ammonia production in 10 anesthetized open-chest domestic swine (46.9±0.7 kg). Coronary blood flow was controlled through an extracorporal perfusion circuit. After a nonischemic control period (aerobic) the blood flow in the left anterior descending coronary artery was reduced by 60%. Arterial and anterior interventricular venous samples where drawn before and during 35 min of ischemia. Subendocardial blood flow, measured using radiolabeled microspheres, decreased from 1.27±0.16 to 0.25±0.09 (ml/g)/min, and left-ventricular wall-thickening fell to 47% of aerobic values. Ischemia resulted in a significant increase in the rate of glucose uptake (p<0.05) and a switch to net lactate production (p<0.01). Ischemia did not affect the rates of alanine output (−0.9±1.0 vs. −0.3±0.3 μmol/min) or glutamate uptake (−0.4±1.1 vs. 0.3±0.6 μmol/min), but did increase the venous-arterial difference for ammonia (−4.1±4.1 to 52.7±5.5 μM, p<0.0001) and the ammonia output (−0.33±0.24 to 1.34±0.14 μmol/min, p<0.0001). In conclusion, acute ischemia did not stimulate greater alanine output or glutamate uptake. However, acute ischemia did cause an increase in anaerobic glycolysis rate and ammonia output, which reflects a profound disruption in myocardial energy metabolism. [ABSTRACT FROM AUTHOR]

Fatty acid metabolites (long-chain esters of CoA and carnitine) which collect in ischemic myocardium can form amphiphiles capable of disrupting subcellular performance. It is important to document the role of these amphiphiles in intact tissue. D-Octanoylcarnitine was chosen because of its previously described effects on inhibiting palmitoylcarnitine transferasc (PCT-II) in in vitro and in vivo liver preparations. This inhibition will shift tissue levels of CoA and carnitine intermediates and thus alter amphiphile levels. The compound's actions in cardiac muscle are unknown. Dose response curves were developed in intact hearts to test the influence of D-octanoylcarnitine at pharmacological concentrations. Measurements were obtained in working, extracorporeally perfused, swine hearts. Drug was administered either systemically (IV) or via dircct intracoronary (IC) infusions into the left anterior descending coronary circulation. Excess fatty acids were provided to ensure adequate fatty acid substrate for oxidation. Coronary flow was controlled at aerobic levels. Systemic administration of D-octanoylcarnitine (0.8-6.8 mM) resulted in transient peripheral hypotension which caused correlative decreascs inCO production from labeled palmitate. Infusion of D-octanoylcarnitine (0.5-3.9 mM) IC did not cause appreciable hypotension and was not associated with suppression of fatty acid oxidation. No build-up of carnitine esters was noted in treated hearts but acyl CoA levels were reduced (p<-0.002). This latter finding was modestly related to increasing dose schedule of the compound in the IC group. The lack of suppression in fatty acid oxidation argues against significant inhibition of PCT II and lessens the attractiveness of using D-octanoylcarnitine in intact myocardium to selectively bloock fatty acid utilization at this locus. [ABSTRACT FROM AUTHOR]

A method for estimating regional contractility is described using the end-systolic relationships between left ventricular pressure and myocardial segment-lengths in rapidly volume-loaded beats. The approach was based on the success of previously developed end-systolic relationships between left ventricular used to describe glopal contractility in beating hearts. The regional end-systolic relationship was more complicated than its global counterpart, which was load independent, and appeared curvilinear to rapid volume loading. As an approximation of this relationship, a linear slope was constructed between maximum and minimum (pre-ejection) loaded beats of equal cycle length. Because of its load dependency and in order to compare slope relationships between interventions, slope functions were derived only from similarly loaded beats either within or between interventions. Slopes generated by this technique had a reasonable constancy at control conditions and coronary flows with an average SEM of 9.1% of the slope means. End-systolic slopes also appeared sensitive to changes in contractile state, increasing appropriately following treatments with dobutamine and decreasing after propranolol. Following shifts in the end-systolic slopes were unreliable, however, in describing the regional changes in contractility with ischemia. At milder levels of flow restriction, the slopes declined as expected. At moderate levels of flow restriction, the pressure-segment loops shifted markedly rightward and the slope increased. At advanced levels of ischemia, the loops were so distorted, that end-systole could not be identified accurately and the loops essentially described the diastolic compliance characteristics of the left ventricle. Thus the slope estimates of regional contractility as described in this report provided a reliable assessment of inotropic background during modifications with positive and negative inotropic drugs but became invalid as systolic shortening was replaced by aneurysmal bulging high-grade ischemia. [ABSTRACT FROM AUTHOR]

In recordings from anterior piriform cortex in awake behaving mice, we found that neuronal firing early in the olfactory pathway simultaneously conveyed fundamentally different information: odor value (is the odor rewarded?) and identity (what is the smell?). Thus, this sensory system performs early multiplexing of information reflecting stimulus-specific characteristics with that used for decision-making. [ABSTRACT FROM AUTHOR]

New strategies are needed to counter the escalating threat posed by drug-resistant fungi. The molecular chaperone Hsp90 affords a promising target because it supports survival, virulence and drug-resistance across diverse pathogens. Inhibitors of human Hsp90 under development as anticancer therapeutics, however, exert host toxicities that preclude their use as antifungals. Seeking a route to species-selectivity, we investigate the nucleotide-binding domain (NBD) of Hsp90 from the most common human fungal pathogen, Candida albicans. Here we report structures for this NBD alone, in complex with ADP or in complex with known Hsp90 inhibitors. Encouraged by the conformational flexibility revealed by these structures, we synthesize an inhibitor with >25-fold binding-selectivity for fungal Hsp90 NBD. Comparing co-crystals occupied by this probe vs. anticancer Hsp90 inhibitors revealed major, previously unreported conformational rearrangements. These insights and our probe's species-selectivity in culture support the feasibility of targeting Hsp90 as a promising antifungal strategy. The chaperone Hsp90 is a potential target for the development of drugs against fungal pathogens. Here the authors determine the structure of the Hsp90 nucleotide-binding domain from Candida albicans, which they use to design an inhibitor and demonstrate its selectivity for the fungal enzyme, both biochemically and in cells. [ABSTRACT FROM AUTHOR]

IPEX is a fatal disorder characterized by immune dysregulation, polyendocrinopathy, enteropathy and X-linked inheritance (MIM 304930). We present genetic evidence that different mutations of the human gene FOXP3, the ortholog of the gene mutated in scurfy mice (Foxp3), causes IPEX syndrome. Recent linkage analysis studies mapped the gene mutated in IPEX to an interval of 17?20-cM at Xp11.23?Xq13.3 (refs. 1,2). [ABSTRACT FROM AUTHOR]

It is estimated that approximately 1.1 billion people globally drink unsafe water. We previously reported both a novel copper-alginate bead, which quickly reduces pathogen loading in waste streams and the incorporation of these beads into a novel swirl flow bioreactor (SFB), of low capital and running costs and of simple construction from commercially available plumbing pipes and fittings. The purpose of the present study was to trial this system for pathogen reduction in waste streams from an operating Dewats system in Hinjewadi, Pune, India and in both simulated and real waste streams in Seattle, Washington, USA. The trials in India, showed a complete inactivation of coliforms in the discharged effluent (Mean Log removal Value (MLRV) = 3.51), accompanied by a total inactivation of E. coli with a MLRV of 1.95. The secondary clarifier effluent also showed a 4.38 MLRV in viable coliforms during treatment. However, the system was slightly less effective in reducing E. coli viability, with a MLRV of 1.80. The trials in Seattle also demonstrated the efficacy of the system in the reduction of viable bacteria, with a LRV of 5.67 observed of viable Raoultella terrigena cells (100%). [ABSTRACT FROM AUTHOR]

Examines the Savings and Loans Association's problems by considering traditional managerial rules, legal regulations and the nature of examinations by regulations in United States. Characteristics of the association's problems; Three primary concerns on deregulation.