Plasmodium chabaudi chabaudi malaria parasites can develop stable resistance to atovaquone with a mutation in the cytochrome b gene

<p>Abstract</p> <p>Background</p> <p><it>Plasmodium falciparum</it>, has developed resistance to many of the drugs in use. The recommended treatment policy is now to use drug combinations. The atovaquone-proguanil (AP) drug combination, is one of the treatment and prophylaxis options. Atovaquone (ATQ) exerts its action by inhibiting plasmodial mitochondria electron transport at the level of the cytochrome bc1 complex. <it>Plasmodium falciparum in vitro </it>resistance to ATQ has been associated with specific point mutations in the region spanning codons 271-284 of the <it>cytochrome b </it>gene. ATQ -resistant <it>Plasmodium yoelii </it>and <it>Plasmodium berghei </it>lines have been obtained and resistant lines have amino acid mutations in their CYT <it>b </it>protein sequences. <it>Plasmodium chabaudi </it>model for studying drug-responses and drug-resistance selection is a very useful rodent malaria model but no ATQ resistant parasites have been reported so far. The aim of this study was to determine the ATQ sensitivity of the <it>P. chabaudi </it>clones, to select a resistant parasite line and to perform genotypic characterization of the <it>cytb </it>gene of these clones.</p> <p>Methods</p> <p>To select for ATQ resistance, <it>Plasmodium. chabaudi chabaudi </it>clones were exposed to gradually increasing concentrations of ATQ during several consecutive passages in mice. <it>Plasmodium chabaudi cytb </it>gene was amplified and sequenced.</p> <p>Results</p> <p>ATQ resistance was selected from the clone AS-3CQ. In order to confirm whether an heritable genetic mutation underlies the response of AS-ATQ to ATQ, the stability of the drug resistance phenotype in this clone was evaluated by measuring drug responses after (i) multiple blood passages in the absence of the drug, (ii) freeze/thawing of parasites in liquid nitrogen and (iii) transmission through a mosquito host, <it>Anopheles stephensi</it>. ATQ resistance phenotype of the drug-selected parasite clone kept unaltered. Therefore, ATQ resistance in clone AS-ATQ is genetically encoded. The Minimum Curative Dose of AS-ATQ showed a six-fold increase in MCD to ATQ relative to AS-3CQ.</p> <p>Conclusions</p> <p>A mutation was found on the <it>P. chabaudi cytb </it>gene from the AS-ATQ sample a substitution at the residue Tyr268 for an Asn, this mutation is homologous to the one found in <it>P. falciparum </it>isolates resistant to ATQ.</p

Understanding animal fears: a comparison of the cognitive vulnerability and harm-looming models

Background: The Cognitive Vulnerability Model holds that both clinical and sub-clinical manifestations of animal fears are a result of how an animal is perceived, and can be used to explain both individual differences in fear acquisition and the uneven distribution of fears in the population. This study looked at the association between fear of a number of animals and perceptions of the animals as uncontrollable, unpredictable, dangerous and disgusting. Also assessed were the perceived loomingness, prior familiarity, and negative evaluation of the animals as well as possible conditioning experiences. Methods: 162 first-year University students rated their fear and perceptions of four high-fear and four low-fear animals. Results: Perceptions of the animals as dangerous, disgusting and uncontrollable were significantly associated with fear of both high- and low-fear animals while perceptions of unpredictability were significantly associated with fear of high-fear animals. Conditioning experiences were unrelated to fear of any animals. In multiple regression analyses, loomingness did not account for a significant amount of the variance in fear beyond that accounted for by the cognitive vulnerability variables. However, the vulnerability variables accounted for between 20% and 51% of the variance in all animals fears beyond that accounted for by perceptions of the animals as looming. Perceptions of dangerousness, uncontrollability and unpredictability were highly predictive of the uneven distribution of animal fears. Conclusion: This study provides support for the Cognitive Vulnerability Model of the etiology of specific fears and phobias and brings into question the utility of the harm-looming model in explaining animal fearJason M Armfiel

Multilocus genotyping reveals high heterogeneity and strong local population structure of the Plasmodium vivax population in the Peruvian Amazon

<p>Abstract</p> <p>Background</p> <p>Peru is one of the Latin American countries with the highest malaria burden, mainly due to <it>Plasmodium vivax </it>infections. However, little is known about <it>P. vivax </it>transmission dynamics in the Peruvian Amazon, where most malaria cases occur. The genetic diversity and population structure of <it>P. vivax </it>isolates collected in different communities around Iquitos city, the capital of the Peruvian Amazon, was determined.</p> <p>Methods</p> <p><it>Plasmodium vivax </it>population structure was determined by multilocus genotyping with 16 microsatellites on 159 <it>P. vivax </it>infected blood samples (mono-infections) collected in four sites around Iquitos city. The population characteristics were assessed only in samples with monoclonal infections (n = 94), and the genetic diversity was determined by calculating the expected heterozygosity and allelic richness. Both linkage disequilibrium and the genetic differentiation (<it>θ</it>) were estimated.</p> <p>Results</p> <p>The proportion of polyclonal infections varied substantially by site (11% - 70%), with the expected heterozygosity ranging between 0.44 and 0.69; no haplotypes were shared between the different populations. Linkage disequilibrium was present in all populations (<it>I</it>_A^S0.14 - 0.61) but was higher in those with fewer polyclonal infections, suggesting inbreeding and a clonal population structure. Strong population differentiation (<it>θ </it>= 0.45) was found and the Bayesian inference cluster analysis identified six clusters based on distinctive allele frequencies.</p> <p>Conclusion</p> <p>The <it>P. vivax </it>populations circulating in the Peruvian Amazon basin are genetically diverse, strongly differentiated and they have a low effective recombination rate. These results are in line with the low and clustered pattern of malaria transmission observed in the region around Iquitos city.</p

Scopolamine Administration Modulates Muscarinic, Nicotinic and NMDA Receptor Systems

Studies on the effect of scopolamine on memory are abundant but so far only regulation of the muscarinic receptor (M1) has been reported. We hypothesized that levels of other cholinergic brain receptors as the nicotinic receptors and the N-methyl-D-aspartate (NMDA) receptor, known to be involved in memory formation, would be modified by scopolamine administration

Identification of Intracellular and Plasma Membrane Calcium Channel Homologues in Pathogenic Parasites

Ca2+ channels regulate many crucial processes within cells and their abnormal activity can be damaging to cell survival, suggesting that they might represent attractive therapeutic targets in pathogenic organisms. Parasitic diseases such as malaria, leishmaniasis, trypanosomiasis and schistosomiasis are responsible for millions of deaths each year worldwide. The genomes of many pathogenic parasites have recently been sequenced, opening the way for rational design of targeted therapies. We analyzed genomes of pathogenic protozoan parasites as well as the genome of Schistosoma mansoni, and show the existence within them of genes encoding homologues of mammalian intracellular Ca2+ release channels: inositol 1,4,5-trisphosphate receptors (IP3Rs), ryanodine receptors (RyRs), two-pore Ca2+ channels (TPCs) and intracellular transient receptor potential (Trp) channels. The genomes of Trypanosoma, Leishmania and S. mansoni parasites encode IP3R/RyR and Trp channel homologues, and that of S. mansoni additionally encodes a TPC homologue. In contrast, apicomplexan parasites lack genes encoding IP3R/RyR homologues and possess only genes encoding TPC and Trp channel homologues (Toxoplasma gondii) or Trp channel homologues alone. The genomes of parasites also encode homologues of mammalian Ca2+ influx channels, including voltage-gated Ca2+ channels and plasma membrane Trp channels. The genome of S. mansoni also encodes Orai Ca2+ channel and STIM Ca2+ sensor homologues, suggesting that store-operated Ca2+ entry may occur in this parasite. Many anti-parasitic agents alter parasite Ca2+ homeostasis and some are known modulators of mammalian Ca2+ channels, suggesting that parasite Ca2+ channel homologues might be the targets of some current anti-parasitic drugs. Differences between human and parasite Ca2+ channels suggest that pathogen-specific targeting of these channels may be an attractive therapeutic prospect

Effect of a web-based chronic disease management system on asthma control and health-related quality of life: study protocol for a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Asthma is a prevalent and costly disease resulting in reduced quality of life for a large proportion of individuals. Effective patient self-management is critical for improving health outcomes. However, key aspects of self-management such as self-monitoring of behaviours and symptoms, coupled with regular feedback from the health care team, are rarely addressed or integrated into ongoing care. Health information technology (HIT) provides unique opportunities to facilitate this by providing a means for two way communication and exchange of information between the patient and care team, and access to their health information, presented in personalized ways that can alert them when there is a need for action. The objective of this study is to evaluate the acceptability and efficacy of using a web-based self-management system, My Asthma Portal (MAP), linked to a case-management system on asthma control, and asthma health-related quality of life.</p> <p>Methods</p> <p>The trial is a parallel multi-centered 2-arm pilot randomized controlled trial. Participants are randomly assigned to one of two conditions: a) MAP and usual care; or b) usual care alone. Individuals will be included if they are between 18 and 70, have a confirmed asthma diagnosis, and their asthma is classified as not well controlled by their physician. Asthma control will be evaluated by calculating the amount of fast acting beta agonists recorded as dispensed in the provincial drug database, and asthma quality of life using the Mini Asthma Related Quality of Life Questionnaire. Power calculations indicated a needed total sample size of 80 subjects. Data are collected at baseline, 3, 6, and 9 months post randomization. Recruitment started in March 2010 and the inclusion of patients in the trial in June 2010.</p> <p>Discussion</p> <p>Self-management support from the care team is critical for improving chronic disease outcomes. Given the high volume of patients and time constraints during clinical visits, primary care physicians have limited time to teach and reinforce use of proven self-management strategies. HIT has the potential to provide clinicians and a large number of patients with tools to support health behaviour change.</p> <p>Trial Registration</p> <p>Current Controlled Trials <a href="http://www.controlled-trials.com/ISRCTN34326236">ISRCTN34326236</a>.</p

Impulsivity and response inhibition in alcohol dependence and problem gambling

INTRODUCTION: Impulsivity is a central feature of drug addiction and may arise as a result of impaired inhibitory control. The extent to which inhibitory deficits arise as a consequence of drug exposure or relate to pre-existing addiction vulnerability is unknown. MATERIALS AND METHODS: This study compared measures of impulsivity in outpatients with alcohol dependence (n = 23) and problem gambling (n = 21), a putative behavioural addiction where direct effects of drug exposure may be minimal. Healthy controls (n = 27) were also tested, in a cross-sectional design. Subjects completed the stop-signal test as a neurocognitive probe of response inhibition, alongside self-report ratings of impulsivity, adult ADHD and OCD. RESULTS: On the stop-signal test, Go reaction time and stop-signal reaction time were significantly slower in the alcohol-dependent group, compared with healthy controls. Healthy controls slowed their responding after successful and failed stop trials. Slowing after failed stop trials was significantly attenuated in the alcohol-dependent subjects. Go reaction time and post-error slowing were correlated with chronicity and severity, respectively, in the alcohol-dependent subjects. Problem gamblers did not differ significantly from controls on the stop-signal test, despite trait elevations in impulsivity ratings. CONCLUSION: Inhibitory control is impaired in alcohol dependence but occurs in the context of psychomotor slowing. In addition, alcohol-dependent individuals failed to show behavioral adjustment following failed stops. These deficits may represent direct effects of chronic alcohol administration on fronto-striatal circuitry