Cellular impermeability and uptake of biocides and antibiotics in Gram-positive bacteria and mycobacteria

Gram-positive bacteria possess a permeable cell wall that usually does not restrict the penetration of antimicrobials. However, resistance due to restricted penetration can occur, as illustrated by vancomycin-intermediate resistant Staphylococcus aureus strains (VISA) which produce a markedly thickened cell wall. Alterations in these strains include increased amounts of nonamidated glutamine residues in the peptidoglycan and it is suggested that the resistance mechanism involves 'affinity trapping' of vancomycin in the thickened cell wall. VISA strains have reduced doubling times, lower sensitivity to lysostaphin and reduced autolytic activity, which may reflect changes in the D-alanyl ester content of the wall and membrane teichoic acids. Mycobacterial cell walls have a high lipid content, which is assumed to act as a major barrier to the penetration of antimicrobial agents. Relatively hydrophobic antibiotics such as rifampicin and fluoroquinolones may be able to cross the cell wall by diffusion through the hydrophobic bilayer composed of long chain length mycolic acids and glycolipids. Hydrophilic antibiotics and nutrients cannot diffuse across this layer and are thought to use porin channels which have been reported in many species of mycobacteria. The occurrence of porins in a lipid bilayer supports the view that the mycobacterial wall has an outer membrane analogous to that of gram-negative bacteria. However, mycobacterial porins are much less abundant than in the gram-negative outer membrane and allow only low rates of uptake for small hydrophilic nutrients and antibiotics.

Representation of people of South Asian origin in cardiovascular outcome trials of glucose-lowering therapies in Type 2 diabetes

Aims : Our aim was to investigate the proportional representation of people of South Asian origin in cardiovascular outcome trials of glucose-lowering drugs or strategies in Type 2 diabetes, noting that these are among the most significant pieces of evidence used to formulate the guidelines on which clinical practice is largely based. Methods : We searched for cardiovascular outcome trials in Type 2 diabetes published before January 2015, and extracted data on the ethnicity of participants. These were compared against expected values for proportional representation of South Asian individuals, based on population data from the USA, from the UK, and globally. Results : Twelve studies met our inclusion criteria and, of these, eight presented a sufficiently detailed breakdown of participant ethnicity to permit numerical analysis. In general, people of South Asian origin were found to be under-represented in trials compared with UK and global expectations and over-represented compared with US expectations. Among the eight trials for which South Asian representation could be reliably estimated, seven under-represented this group relative to the 11.2% of the UK diabetes population estimated to be South Asian, with the representation in these trials ranging from 0.0% to 10.0%. Conclusions : Clinicians should exercise caution when generalizing the results of trials to their own practice, with regard to the ethnicity of individuals. Efforts should be made to improve reporting of ethnicity and improve diversity in trial recruitment, although we acknowledge that there are challenges that must be overcome to make this a reality.

Eigen-Adaptation and Distributed Representation of 2-D Phase, Energy, Scale and Orientation in Spatial Vision

Distributed representations (DR) of cortical channels are pervasive in models of spatio-temporal vision. A central idea that underpins current innovations of DR stems from the extension of 1-D phase into 2-D images. Neurophysiological evidence, however, provides tenuous support for a quadrature representation in the visual cortex, since even phase visual units are associated with broader orientation tuning than odd phase visual units (J.Neurophys.,88,455–463, 2002). We demonstrate that the application of the steering theorems to a 2-D definition of phase afforded by the Riesz Transform (IEEE Trans. Sig. Proc., 49, 3136–3144), to include a Scale Transform, allows one to smoothly interpolate across 2-D phase and pass from circularly symmetric to orientation tuned visual units, and from more narrowly tuned odd symmetric units to even ones. Steering across 2-D phase and scale can be orthogonalized via a linearizing transformation. Using the tiltafter effect as an example, we argue that effects of visual adaptation can be better explained by via an orthogonal rather than channel specific representation of visual units. This is because of the ability to explicitly account for isotropic and cross-orientation adaptation effect from the orthogonal representation from which both direct and indirect tilt after-effects can be explained.

A developmental intervention science outreach research approach to promoting positive youth development

Recent intervention efforts in promoting positive identity in troubled adolescents have begun to draw on the potential for an integration of the self-construction and self-discovery perspectives in conceptualizing identity processes, as well as the integration of quantitative and qualitative data analytic strategies. This study reports an investigation of the Changing Lives Program (CLP), using an Outcome Mediation (OM) evaluation model, an integrated model for evaluating targets of intervention, while theoretically including a Self-Transformative Model of Identity Development (STM), a proposed integration of self-discovery and self-construction identity processes. This study also used a Relational Data Analysis (RDA) integration of quantitative and qualitative analysis strategies and a structural equation modeling approach (SEM), to construct and evaluate the hypothesized OM/STM model. The CLP is a community supported positive youth development intervention, targeting multi-problem youth in alternative high schools in the Miami Dade County Public Schools (M-DCPS). The 259 participants for this study were drawn from the CLP’s archival data file. The model evaluated in this study utilized three indices of core identity processes (1) personal expressiveness, (2) identity conflict resolution, and (3) informational identity style that were conceptualized as mediators of the effects of participation in the CLP on change in two qualitative outcome indices of participants’ sense of self and identity. Findings indicated the model fit the data (χ2 (10) = 3.638, p = .96; RMSEA = .00; CFI = 1.00; WRMR = .299). The pattern of findings supported the utilization of the STM in conceptualizing identity processes and provided support for the OM design. The findings also suggested the need for methods capable of detecting and rendering unique sample specific free response data to increase the likelihood of identifying emergent core developmental research concepts and constructs in studies of intervention/developmental change over time in ways not possible using fixed response methods alone.

The Influence of Psychological Predictors and Cognitive Behavioral Stress Management Intervention on Antiretroviral Therapy (ART) Adherence Among HIV-Positive Female Haitian Alcohol Users

Purpose: Over half the HIV-infected persons in the Caribbean, the second most HIV-impacted region in the world, live in Haiti. Using secondary data from a parent study, this research assessed the effects of psychological and social factors on antiretroviral therapy (ART) adherence among Haitian, HIV-positive, female alcohol users. Theoretical Foundation and Research Questions: Using the Theory of Planned Behavior/Reasoned Action and the Information, Motivation, Behavior skills model as guiding theoretical frameworks, the study examined the effectiveness of an adapted cognitive behavioral stress management (CBSM-A) intervention in improving ART adherence. The effect of psychological factors (depression, anxiety, beliefs about medicine, and social support), social factors (stigma, relationship status, and educational attainment), and alcohol on adherence to ART was assessed. Methods: The sample consisted of 116 female ART patients who were randomly assigned to the CBSM-A intervention or the wait-list control group. Participants completed intervention sessions as well as pre- and post-test assessments. Analyses of variance, t-tests, and point biserial correlations were used to test hypotheses. Results: Surprisingly, ART adherence rates significantly decreased for both groups combined [F (1, 108) = 8.79, p = .004]; there was no significant difference between the intervention and control groups with regard to the magnitude of change between baseline and post assessment. On average, depression decreased significantly among participants in the CBSM-A group only [(t (62) = 5.54, p < .001)]. For both groups combined, alcohol use significantly decreased between baseline and post-assessment [(F (1, 78) = 34.70, p < .001)]; there was no significant difference between the intervention and control groups with regard to the magnitude of change between baseline and post-assessment. None of the variables were significantly correlated with ART adherence. Discussion: Adherence to ART did not improve in this sample, nor were any of the variables significantly associated with adherence. The findings suggest that additional supportive and psychological services may be needed in order to promote higher adherence to ART among HIV-positive females. More research may be needed on this sample; a focus on mental health issues, partner conflict, family and sexual history may allow for better targeting and more successful interventions.

Screening for AmpR-Specific Inhibitors to Combat P. aeruginosa Infections

Pseudomonas aeruginosa, a Gram-negative bacterium, an opportunistic pathogen that infects individuals suffering from reduced immunity or damaged tissue. The treatment of these infections has become a major problem due to its increasing antibiotic resistance. Many multi-drug resistant isolates of P. aeruginosa can thwart most antibiotic classes including ?- lactams, fluoroquinolones, and aminoglycosides. Its ability to combat ?-lactams is in part due to expression of AmpC, a major chromosomally encoded ?-lactamase. The expression of ampC is positively regulated by AmpR. Besides antibiotic resistance, AmpR is an important regulator of various factors that are required for establishing acute and chronic infections. Loss of ampR makes P. aeruginosa susceptible to ?-lactams and less virulent than the wild type. We hypothesize that AmpR is a potential therapeutic target. In the absence of new drugs in the pipeline, the aim of this study is to find an AmpR-specific inhibitor to assist and improve the use of currently available ?- lactam treatment. A small-molecule library from Torrey Pines Institute will be used in this study. Two reporter systems, lux and lacZ, fused to a PampC promotor will be used to assess AmpR activity. Positive hits will be those that inhibit 50% PampC activity in the presence of sub inhibitory concentration of imipenem, a ?- lactam. The top positive hits will be screened for their ability to cause human cell-cytotoxicity. The non-cytotoxic hits will be assessed for their ability to affect P. aeruginosa virulence and antibiotic resistance using various in vitro assays. Determination of potential AmpR inhibitors will prove to be useful in fighting off infections and may save countless patients suffering from these infections.

Noradrenergic modulatoins of odor learning and odor representation in the rat

How experience alters neuronal ensemble dynamics and how locus coeruleus-mediated norepinephrine release facilitates memory formation in the brain are the topics of this thesis. Here we employed a visualization technique, cellular compartment analysis of temporal activity by fluorescence in situ hybridization (catFISH), to assess activation patterns of neuronal ensembles in the olfactory bulb (OB) and anterior piriform cortex (aPC) to repeated odor inputs. Two associative learning models were used, early odor preference learning in rat pups and adult rat go-no-go odor discrimination learning. With catFISH of an immediate early gene, Arc, we showed that odor representation in the OB and aPC was sparse (~5-10%) and widely distributed. Odor associative learning enhanced the stability of the rewarded odor representation in the OB and aPC. The stable component, indexed by the overlap between the two ensembles activated by the rewarded odor at two time points, increased from ~25% to ~50% (p = 0.004-1.43E⁻4; Chapter 3 and 4). Adult odor discrimination learning promoted pattern separation between rewarded and unrewarded odor representations in the aPC. The overlap between rewarded and unrewarded odor representations reduced from ~25% to ~14% (p = 2.28E⁻⁵). However, learning an odor mixture as a rewarded odor increased the overlap of the component odor representations in the aPC from ~23% to ~44% (p = 0.010; Chapter 4). Blocking both α- and β-adrenoreceptors in the aPC prevented highly similar odor discrimination learning in adult rats, and reduced OB mitral and granule ensemble stability to the rewarded odor. Similar treatment in the OB only slowed odor discrimination learning. However, OB adrenoceptor blockade disrupted pattern separation and ensemble stability in the aPC when the rats demonstrated deficiency in discrimination (Chapter 5). In another project, the role of α₂-adrenoreceptors in the OB during early odor preference learning was studied. OB α2-adrenoceptor activation was necessary for odor learning in rat pups. α₂-adrenoceptor activation was additive with β-adrenoceptor mediated signalling to promote learning (Chapter 2). Together, these experiments suggest that odor representations are highly adaptive at the early stages of odor processing. The OB and aPC work in concert to support odor learning and top-down adrenergic input exerts a powerful modulation on both learning and odor representation.

Impacto na epidemiologia da sepse tardia após a mudança do protocolo de antimicrobianos em uma UTIN de um serviço universitário

Advances in neonatology resulted in reducing the mortality rate and the consequent increase in survival of newborn pre terms (PTN). On the other hand, there was also a considerable increase in the risk of developing health care-related infection (HAI) in its most invasive, especially for bloodstream. This situation is worrying, and prevent the occurrence of it is a challenge and becomes one of the priorities in the Neonatal Intensive Care Unit (NICU). Sepsis is the main cause of death in critical neonates and affects more than one million newborns each year, representing 40% of all deaths in neonates. The incidence of late sepsis can reach 50% in NICUs. Currently the major responsible for the occurrence of sepsis in developed countries is the coagulase negative Staphylococcus (CoNS), followed by S. aureus. The cases of HAIs caused by resistant isolates for major classes of antimicrobial agents have been increasingly frequent in the NICU. Therefore, vancomycin has to be prescribed more frequently, and, today, the first option in the treatment of bloodstream infections by resistant Staphylococcus. The objectives of this study were to assess the impact on late sepsis in epidemiology III NICU after the change of the use of antimicrobials protocol; check the frequency of multiresistant microorganisms; assess the number of neonates who came to death. This study was conducted in NICU Level III HC-UFU. three study groups were formed based on the use of the proposed late sepsis treatment protocol, with 216 belonging to the period A, 207 B and 209 to the C. The work was divided into three stages: Period A: data collected from neonates admitted to the unit between September 2010 to August 2011. was using treatment of late sepsis: with oxacillin and gentamicin, oxacillin and amikacin, oxacillin and cefotaxime. Period B: data were collected from March 2012 to February 2013. Data collection was started six months after protocol change. Due to the higher prevalence of CoNS, the initial protocol was changed to vancomycin and cefotaxime. Period C: data were collected from newborns inteerne in the unit from September 2013 to August 2014. Data collection was started six months after the protocol change, which occurred in March 2013. From the 632 neonates included in this study, 511 (80,8%) came from the gynecology and obstetrics department of the HC-UFU. The mean gestational age was 33 weeks and the prevailing sex was male (55,7%). Seventy-nine percent of the studied neonates were hospitalized at the NICU HC-UFU III because of complications related to the respiratory system. Suspicion of sepsis took to hospitalization in the unit of 1,9% of newborns. In general, the infection rate was 34,5%, and the most frequent infectious sepsis syndrome 81,2%. There was a tendency to reduce the number of neonates who died between periods A 11 and C (p = 0,053). From the 176 cases of late sepsis, 73 were clinical sepsis and 103 had laboratory confirmation, with greater representation of Gram positive bacteria, which corresponded to 67.2% of the isolates and CoNS the most frequent micro-organism (91,5%). There was a statistically significant difference in the reduction of isolation of Gram positive microorganisms between periods A and C (p = 0,0365) as well as in reducing multidrug-resistant CoNS (A and B period p = 0,0462 and A and C period, p = 0,158). This study concluded that: the CoNS was the main microorganism responsible for the occurrence of late sepsis in neonates in the NICU of HC-UFU; the main risk factors for the occurrence of late sepsis were: birth weight <1500 g, use of PICC and CUV, need for mechanical ventilation and parenteral nutrition, SNAPPE> 24 and length of stay more than seven days; the new empirical treatment protocol late sepsis, based on the use of vancomycin associated cefepime, it was effective, since promoted a reduction in insulation CoNS blood cultures between the pre and post implementation of the Protocol (A and C, respectively); just as there was a reduction in the number of newborns who evolved to death between periods A and C.

Representation of Maximally Regular Textures in Human Visual Cortex

Copyright © 2016 the authors 0270-6474/16/360714-16$15.00/0. This research was supported by National Science Foundation INSPIRE Grant 1248076, which was awarded to Y.L. and A.M.N.

Parvalbumin-positive interneurons of the prefrontal cortex support working memory and cognitive flexibility

We were supported by the Biotechnology and Biological Sciences Research Council grant BB/H001123/1 (P.W.), the Medical Research Council grants G0601498 and G1100546/2 (P.W.), Tenovus Scotland Grant G09/17 (A.J.M.) and the University of Aberdeen (P.W.). We thank O. Tüscher for discussion, P. Teismann and the microscopy core facility at the University of Aberdeen for the use of microscopy equipment, L. Strachan, A. Plano, S. Deiana for help with behavioral testing.

Evaluating the Impact of the Positive Choices Intervention on Substance Use, Psychological, and Care Engagement Outcomes Relevant to Current National HIV Prevention Goals

<p>The HIV epidemic in the United States continues to be a significant public health problem, with approximately 50,000 new infections occurring each year. National public health priorities have shifted in recent years towards targeted HIV prevention efforts among people living with HIV/AIDS (PLWHA) that include: increasing engagement in and retention in care, improving HIV treatment adherence, and increasing screening for and treatment of substance use and psychological difficulties. This study evaluated the efficacy of Positive Choices (PC), a brief, care-based, theory-driven, 3-session counseling intervention for newly HIV-diagnosed men who have sex with men (MSM), in the context of current national HIV prevention priorities. The study involved secondary analysis of data from a preliminary efficacy trial of the PC intervention (n=102). Descriptive statistics examined baseline substance use, psychological characteristics and strategies, and care engagement and HIV-related biological outcomes. Generalized Estimating Equations (GEE) examined longitudinal changes in these variables by study condition. Results indicated that PC improved adherence to HIV treatment, but increased use of illicit drugs, specifically amyl nitrates and other stimulant drugs; additionally, moderation analyses indicated differences in patterns of change over time in viral load by baseline depression status. Implications of the findings and suggestions for future research are discussed.p>

Role of Hydrological Process Representation on Erosion, Deposition, and Sediment Yield Estimate

<p>Soil erosion by water is a major driven force causing land degradation. Laboratory experiments, on-site field study, and suspended sediments measurements were major fundamental approaches to study the mechanisms of soil water erosion and to quantify the erosive losses during rain events. The experimental research faces the challenge to extent the result to a wider spatial scale. Soil water erosion modeling provides possible solutions for scaling problems in erosion research, and is of principal importance to better understanding the governing processes of water erosion. However, soil water erosion models were considered to have limited value in practice. Uncertainties in hydrological simulations are among the reasons that hindering the development of water erosion model. Hydrological models gained substantial improvement recently and several water erosion models took advantages of the improvement of hydrological models. It is crucial to know the impact of changes in hydrological processes modeling on soil erosion simulation. p><p>This dissertation work first created an erosion modeling tool (GEOtopSed) that takes advantage of the comprehensive hydrological model (GEOtop). The newly created tool was then tested and evaluated at an experimental watershed. The GEOtopSed model showed its ability to estimate multi-year soil erosion rate with varied hydrological conditions. To investigate the impact of different hydrological representations on soil erosion simulation, a 11-year simulation experiment was conducted for six models with varied configurations. The results were compared at varied temporal and spatial scales to highlight the roles of hydrological feedbacks on erosion. Models with simplified hydrological representations showed agreement with GEOtopSed model on long temporal scale (longer than annual). This result led to an investigation for erosion simulation at different rainfall regimes to check whether models with different hydrological representations have agreement on the soil water erosion responses to the changing climate. Multi-year ensemble simulations with different extreme precipitation scenarios were conducted at seven climate regions. The differences in erosion simulation results showed the influences of hydrological feedbacks which cannot be seen by purely rainfall erosivity method.p>

Screening for Sexual Trauma, Intimate Partner Violence and Mental Health Symptoms among HIV Positive South African Women

<p>Background: The psychological sequelae of sexual trauma and physical intimate partner violence (IPV) exposure can lead to poor HIV care outcomes, including poor treatment adherence. This study aimed to estimate the prevalence of and factors associated with mental health symptoms and trauma among HIV positive women. Additionally, the study aimed to assess the feasibility and acceptability of screening for trauma and mental health symptoms among HIV positive South African women. Finally, the study aimed to elicit healthcare workers’ perceptions related to sexual trauma and the provision of care and services for HIV positive women with trauma histories.p><p>Methods: The study utilized a mixed-methods approach that included a cross-sectional survey of 70 HIV positive women recruited through referral sampling and key informant interviews with seven healthcare workers (HCWs). A study-screening instrument consisting of 24 items from standard measures was used to screen women for sexual trauma, physical intimate partner violence (IPV), depression and PTSD. Sexual trauma and IPV were assessed across the lifetime, while depression and PTSD were current assessments. Logistic regression models were used to explore the relationship between trauma exposure and mental health symptoms, while controlling for age and education. Interview transcripts were coded and analyzed for emergent themes on HCWs perceptions on sexual trauma and HIV care.p><p>Results: Among participants, 51% had sexual trauma experience and 75% had intimate partner violence (IPV) experience. Among participants, 36% met screening criteria for major depression; among those with traumatic experiences (n=57), 70% met screening criteria for post-traumatic stress disorder (PTSD). Compared to having no sexual trauma or IPV exposure, having both sexual trauma and IPV was significantly associated with higher odds of depression (OR = 8.11; 95% CI 1.48-44.34), while having either IPV or sexual trauma individually was not significantly associated with increased odds of depression. Compared to having either IPV or sexual trauma, having both sexual trauma and IPV was not significantly associated with PTSD. Responses from participants’ feedback on screening process suggest that screening was feasible and acceptable to participants. Some of the health care workers (HCWs) did not perceive dealing with trauma to be part of their duties, but instead viewed social workers or psychologists as the appropriate health cadre to provide care related to trauma and mental health.p><p>Conclusions: High levels of sexual trauma, IPV and mental health distress were reported among HIV positive women in this setting. Screening for trauma and mental health symptoms was acceptable to the participants, but several challenges were encountered in implementing screening. Given the potential impact of trauma and mental health on HIV care engagement, interventions to address trauma and its psychological sequelae are needed.p>

Cervical cancer precursors and hormonal contraceptive use in HIV-positive women: application of a causal model and semi-parametric estimation methods.

OBJECTIVE: To demonstrate the application of causal inference methods to observational data in the obstetrics and gynecology field, particularly causal modeling and semi-parametric estimation. BACKGROUND: Human immunodeficiency virus (HIV)-positive women are at increased risk for cervical cancer and its treatable precursors. Determining whether potential risk factors such as hormonal contraception are true causes is critical for informing public health strategies as longevity increases among HIV-positive women in developing countries. METHODS: We developed a causal model of the factors related to combined oral contraceptive (COC) use and cervical intraepithelial neoplasia 2 or greater (CIN2+) and modified the model to fit the observed data, drawn from women in a cervical cancer screening program at HIV clinics in Kenya. Assumptions required for substantiation of a causal relationship were assessed. We estimated the population-level association using semi-parametric methods: g-computation, inverse probability of treatment weighting, and targeted maximum likelihood estimation. RESULTS: We identified 2 plausible causal paths from COC use to CIN2+: via HPV infection and via increased disease progression. Study data enabled estimation of the latter only with strong assumptions of no unmeasured confounding. Of 2,519 women under 50 screened per protocol, 219 (8.7%) were diagnosed with CIN2+. Marginal modeling suggested a 2.9% (95% confidence interval 0.1%, 6.9%) increase in prevalence of CIN2+ if all women under 50 were exposed to COC; the significance of this association was sensitive to method of estimation and exposure misclassification. CONCLUSION: Use of causal modeling enabled clear representation of the causal relationship of interest and the assumptions required to estimate that relationship from the observed data. Semi-parametric estimation methods provided flexibility and reduced reliance on correct model form. Although selected results suggest an increased prevalence of CIN2+ associated with COC, evidence is insufficient to conclude causality. Priority areas for future studies to better satisfy causal criteria are identified.