High Treatment Success Rates When Switching to Once Daily Nevirapine Containing Antiretroviral Therapy

INTRODUCTION: Two recent studies have highlighted low rates of virological response to once daily nevirapine containing combination antiretroviral therapy (CART) in treatment naïve HIV-1 infected subjects. AIM: We assessed factors associated with treatment responses in a cohort of HIV-1 infected, therapy naïve individuals, commencing nevirapine CART with two nucleoside reverse transcriptase inhibitors (NRTI) containing either lamivudine or emtricitabine. RESULTS: Between January 2002 and 2006, 173 subjects (80 female) met the study inclusion criteria. All subjects initially commenced on twice daily nevirapine with six different NRTI backbones. Mean follow up was 802 days. 49 (28%) subjects switched to once daily nevirapine, 23 (13%) within the first year. After 48 weeks of therapy, HIV RNA was < 50 copies/mL in 154/173 subjects (89%). A trend was observed towards improved virological outcome (HIV RNA < 50 copies/mL) and switching to once daily nevirapine during the first year of therapy (p=0.051). CONCLUSION: Whilst awaiting the results of prospective studies assessing once daily nevirapine, our data describe high treatment success rates and good safety responses when switching to once daily nevirapine

Maternal concentration of polychlorinated biphenyls and dichlorodiphenyl dichlorethylene and birth weight in Michigan fish eaters: a cohort study

BACKGROUND: Studies on maternal exposure to polychlorinated biphenyls (PCBs) reported inconsistent findings regarding birth weight: some studies showed no effect, some reported decreased birth weight, and one study found an increase in weights. These studies used different markers of exposure, such as measurement of PCBs in maternal serum or questionnaire data on fish consumption. Additionally maternal exposures, such as dichlorodiphenyl-dichloroethylene (DDE), which are related to PCB exposure and may interfere with the PCB effect, were rarely taken into account. METHODS: Between 1973 and 1991, the Michigan Department of Community Health conducted three surveys to assess PCB and DDE serum concentrations in Michigan anglers. Through telephone interviews with parents, we gathered information on the birth characteristics of their offspring, focusing on deliveries that occurred after 1968. We used the maternal organochlorine (OC) measurement closest to the date of delivery as the exposure. Although one mother may have contributed more than one child, serum concentrations derived from measurements in different surveys could vary for different children from the same mother. The maternal DDE and PCB serum concentrations were categorized as follows: 0 -< 5 microg / L, 5 -< 15 microg / L, 15 -< 25 microg / L, ≥25 microg / L. Using repeated measurement models (Generalized Estimation Equation), we estimated the adjusted mean birth weight controlling for gender, birth order, gestational age, date of delivery as well as maternal age, height, education, and smoking status. RESULTS: We identified 168 offspring who were born after 1968 and had maternal exposure information. We found a reduced birth weight for the offspring of mothers who had a PCB concentration ≥25 microg / L (adjusted birth weight = 2,958 g, p = 0.022). This group, however, was comprised of only seven observations. The association was not reduced when we excluded preterm deliveries. The birth weight of offspring was increased in women with higher DDE concentrations when controlling for PCBs; however, this association was not statistically significant. CONCLUSION: Our results contribute to the body of evidence that high maternal serum PCB concentration may reduce the birth weight in offspring. However, only a small proportion of mothers may actually be exposed to PCB concentrations ≥25 microg / L

Macrocyclic colibactin induces DNA double-strand breaks via copper-mediated oxidative cleavage.

Colibactin is an assumed human gut bacterial genotoxin, whose biosynthesis is linked to the clb genomic island that has a widespread distribution in pathogenic and commensal human enterobacteria. Colibactin-producing gut microbes promote colon tumour formation and enhance the progression of colorectal cancer via cellular senescence and death induced by DNA double-strand breaks (DSBs); however, the chemical basis that contributes to the pathogenesis at the molecular level has not been fully characterized. Here, we report the discovery of colibactin-645, a macrocyclic colibactin metabolite that recapitulates the previously assumed genotoxicity and cytotoxicity. Colibactin-645 shows strong DNA DSB activity in vitro and in human cell cultures via a unique copper-mediated oxidative mechanism. We also delineate a complete biosynthetic model for colibactin-645, which highlights a unique fate of the aminomalonate-building monomer in forming the C-terminal 5-hydroxy-4-oxazolecarboxylic acid moiety through the activities of both the polyketide synthase ClbO and the amidase ClbL. This work thus provides a molecular basis for colibactin's DNA DSB activity and facilitates further mechanistic study of colibactin-related colorectal cancer incidence and prevention

Parents’ perspectives on their children’s music therapy: A synthesis of qualitative literature

There is no existing qualitative synthesis of the music therapy literature on parents’ perspectives on their children’s music therapy. This study seeks to fill this gap, motivated by the first author’s experiences as a clinician/researcher. A systematic search of health databases, hand searches of key journals and searches of doctoral theses were undertaken to identify relevant studies. Thirteen studies which met inclusion criteria, including a total of 102 participants, were identified. Relevant data were extracted from these studies for comparison and analysis, with quality of studies assessed using the CASP appraisal tool. Findings were analysed following procedures of thematic synthesis. Six descriptive themes were grouped into three analytic themes: Parents perceived positive impacts of music therapy on their children; parents experienced music therapy as a nurturing environment for themselves and their children; and some parents experienced challenges to their engagement with music therapy. Most studies (12/13) explored parents’ perceptions of music therapy where they were included in sessions. The findings identify positive perceptions of family-centred models of music therapy for children and parents. Parents’ perceptions of children were altered positively through experiencing them in new ways in music therapy. Parents also perceived positive outcomes for their children. These findings identify an emphasis in the qualitative literature on parents’ perceptions on research into music therapy which includes parents in sessions. Only one study explored perceptions of a model where parents were not present during their child’s sessions. More research is needed into parents’ perceptions of music therapy where parents are not present during sessions. Further intervention studies into family-centred models of music therapy with children are also recommended

Tear fluid biomarkers in ocular and systemic disease: potential use for predictive, preventive and personalised medicine

In the field of predictive, preventive and personalised medicine, researchers are keen to identify novel and reliable ways to predict and diagnose disease, as well as to monitor patient response to therapeutic agents. In the last decade alone, the sensitivity of profiling technologies has undergone huge improvements in detection sensitivity, thus allowing quantification of minute samples, for example body fluids that were previously difficult to assay. As a consequence, there has been a huge increase in tear fluid investigation, predominantly in the field of ocular surface disease. As tears are a more accessible and less complex body fluid (than serum or plasma) and sampling is much less invasive, research is starting to focus on how disease processes affect the proteomic, lipidomic and metabolomic composition of the tear film. By determining compositional changes to tear profiles, crucial pathways in disease progression may be identified, allowing for more predictive and personalised therapy of the individual. This article will provide an overview of the various putative tear fluid biomarkers that have been identified to date, ranging from ocular surface disease and retinopathies to cancer and multiple sclerosis. Putative tear fluid biomarkers of ocular disorders, as well as the more recent field of systemic disease biomarkers, will be shown

Cyclic Nucleotide-Gated Channels Contribute to Thromboxane A2-Induced Contraction of Rat Small Mesenteric Arteries

Background: Thromboxane A 2 (TxA 2)-induced smooth muscle contraction has been implicated in cardiovascular, renal and respiratory diseases. This contraction can be partly attributed to TxA2-induced Ca 2+ influx, which resulted in vascular contraction via Ca 2+-calmodulin-MLCK pathway. This study aims to identify the channels that mediate TxA2-induced Ca 2+ influx in vascular smooth muscle cells. Methodology/Principal Findings: Application of U-46619, a thromboxane A2 mimic, resulted in a constriction in endothelium-denuded small mesenteric artery segments. The constriction relies on the presence of extracellular Ca 2+, because removal of extracellular Ca 2+ abolished the constriction. This constriction was partially inhibited by an L-type Ca 2+ channel inhibitor nifedipine (0.5–1 mM). The remaining component was inhibited by L-cis-diltiazem, a selective inhibitor for CNG channels, in a dose-dependent manner. Another CNG channel blocker LY83583 [6-(phenylamino)-5,8-quinolinedione] had similar effect. In the primary cultured smooth muscle cells derived from rat aorta, application of U46619 (100 nM) induced a rise in cytosolic Ca 2+ ([Ca 2+]i), which was inhibited by L-cis-diltiazem. Immunoblot experiments confirmed the presence of CNGA2 protein in vascular smooth muscle cells. Conclusions/Significance: These data suggest a functional role of CNG channels in U-46619-induced Ca 2+ influx and contraction of smooth muscle cells

Quantitative estimation of tissue blood flow rate

The rate of blood flow through a tissue (F) is a critical parameter for assessing the functional efficiency of a blood vessel network following angiogenesis. This chapter aims to provide the principles behind the estimation of F, how F relates to other commonly used measures of tissue perfusion, and a practical approach for estimating F in laboratory animals, using small readily diffusible and metabolically inert radio-tracers. The methods described require relatively nonspecialized equipment. However, the analytical descriptions apply equally to complementary techniques involving more sophisticated noninvasive imaging. Two techniques are described for the quantitative estimation of F based on measuring the rate of tissue uptake following intravenous administration of radioactive iodo-antipyrine (or other suitable tracer). The Tissue Equilibration Technique is the classical approach and the Indicator Fractionation Technique, which is simpler to perform, is a practical alternative in many cases. The experimental procedures and analytical methods for both techniques are given, as well as guidelines for choosing the most appropriate method

Examining the Relationship Between Genetic Counselors’ Attitudes Toward Deaf People and the Genetic Counseling Session

Given the medical and cultural perspectives on deafness it is important to determine if genetic counselors’ attitudes toward deaf people can affect counseling sessions for deafness genes. One hundred fifty-eight genetic counselors recruited through the National Society of Genetic Counselors Listserv completed an online survey assessing attitudes toward deaf people and scenario-specific comfort levels discussing and offering genetic testing for deafness. Respondents with deaf/Deaf friends or who work in prenatal or pediatric settings had more positive attitudes toward deaf people than those without deaf/Deaf friends or those working in ‘other’ settings. More positive attitudes toward deaf people correlated with higher comfort level talking about genetic testing for the two scenarios involving culturally Deaf clients; and correlated with higher comfort level offering genetic testing to culturally Deaf clients wishing to have a deaf child. Attitudes and comfort level were not correlated in the scenarios involving hearing or non-culturally deaf clients. These results suggest that genetic counselors’ attitudes could affect information provision and the decision making process of culturally Deaf clients. Cultural sensitivity workshops in genetic counseling training programs that incorporate personal interactions with culturally Deaf individuals are recommended. Additional suggestions for fostering personal interactions are provided

Education for Environmental Citizenship and Responsible Environmental Behaviour

The notion of Environmental Citizenship embodies behaviour – an actively involved citizen who exercises his/her environmental rights and obligations in the private and public spheres. Education for Environmental Citizenship implies behavioural change; its goal is to facilitate an individual’s intellectual growth (cognitive domain) and emotional capacity (affective domain) that may lead to a critical and actively engaged individual. Human behaviour is overwhelmingly sophisticated, and what shapes pro-environmental behaviour is complex and context specific. Furthermore, empirical research indicates a discrepancy between possessing environmental knowledge and environmentally supportive attitudes and behaving pro-environmentally. The point of departure of this chapter is that the social and psychological study of behaviour has much to inform the study of environmental behaviour and, deriving from this, to inform regarding the type of education towards behaviour/action in the goal of sustainable socioecological transformation. The chapter focuses on internal (psychosocial) factors. It presents selected models regarding factors influencing behavioural decisions that are acknowledged as influential theoretical frameworks for investigating pro-environmental behaviour, as well as various theories that inform these models. These are categorised into knowledge-based models; attitude-, value- and norm-oriented models; skills, self-efficacy and situational factors; and new approaches to environmental behaviour models. The chapter concludes with suggestions for Education for Environmental Citizenship deriving from the various models