Effects of DSP4 and methylphenidate on spatial memory performance in rats

In this experiment, we have investigated the spatial memory performance of rats following a central noradrenaline depletion induced by three different doses of the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) and following administration of three different doses of methylphenidate (MPH). The rats were required to find food pellets hidden on a holeboard. The sole administration of DSP4 induced only minor cognitive deficits. However, the treatment with MPH increased the reference memory error, the impulsivity and the motor activity of the DSP4-treated rats. Since the noradrenergic terminals in a DSP4-treated rat are significantly reduced, the administration of MPH has little effect on the noradrenergic system and increases dopaminergic rather than noradrenergic activity, resulting in an imbalance with relatively high dopaminergic and low noradrenergic activities. It is suggested that a reduction of noradrenaline and an increase of dopamine induce ADHD-related deficits and that the depletion of noradrenaline is not sufficient for an appropriate rat model of ADHD

Physicians and nurses use and recommend dietary supplements: report of a survey

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Use of dietary supplements by cardiologists, dermatologists and orthopedists: report of a survey

<p>Abstract</p> <p>Background</p> <p>Dietary supplements are regularly used by a majority of the American population, and usage by health professionals is also common. There is considerable interest in usage patterns within the population and in the reasons for using dietary supplements. The "Life...supplemented" Healthcare Professionals 2008 Impact Study (HCP Impact Study) surveyed usage of dietary supplements by physicians in three specialties: cardiology, dermatology, and orthopedics.</p> <p>Methods</p> <p>The HCP Impact Study was conducted online by Ipsos Public Affairs for the Council for Responsible Nutrition (CRN), a trade association of the dietary supplement industry. Respondents were 900 physicians, including 300 each from three specialties - cardiology, dermatology, and orthopedics.</p> <p>Results</p> <p>Fifty-seven percent of cardiologists said they use dietary supplements at least occasionally, as did 75% of dermatologists and 73% of orthopedists. The product most commonly reported to be used was a multivitamin, but over 25% in each specialty said they used omega-3 fatty acids and over 20% said they used some botanical supplements. Regular dietary supplement use was reported by 37% of cardiologists, 59% of dermatologists, and 50% of orthopedists. Seventy-two percent of cardiologists, 66% of dermatologists, and 91% of orthopedists reported recommending dietary supplements to their patients. The primary reason given for recommending dietary supplements to patients was for heart health or lowering cholesterol for the cardiologists; benefits for skin, hair and nails for the dermatologists; and bone and joint health for the orthopedists.</p> <p>Conclusions</p> <p>Reported dietary supplement use was relatively common in this sample of physicians, and when they recommended dietary supplements to patients, they tended to do so for reasons related to their specialty.</p

Fitness Trade-Offs in the Evolution of Dihydrofolate Reductase and Drug Resistance in Plasmodium falciparum

Background: Patterns of emerging drug resistance reflect the underlying adaptive landscapes for specific drugs. In Plasmodium falciparum, the parasite that causes the most serious form of malaria, antifolate drugs inhibit the function of essential enzymes in the folate pathway. However, a handful of mutations in the gene coding for one such enzyme, dihydrofolate reductase, confer drug resistance. Understanding how evolution proceeds from drug susceptibility to drug resistance is critical if new antifolate treatments are to have sustained usefulness. Methodology/Principal Findings: We use a transgenic yeast expression system to build on previous studies that described the adaptive landscape for the antifolate drug pyrimethamine, and we describe the most likely evolutionary trajectories for the evolution of drug resistance to the antifolate chlorcycloguanil. We find that the adaptive landscape for chlorcycloguanil is multi-peaked, not all highly resistant alleles are equally accessible by evolution, and there are both commonalities and differences in adaptive landscapes for chlorcycloguanil and pyrimethamine. Conclusions/Significance: Our findings suggest that cross-resistance between drugs targeting the same enzyme reflect the fitness landscapes associated with each particular drug and the position of the genotype on both landscapes. The possibl

Identification of pyrimethamine- and chloroquine-resistant Plasmodium falciparum in Africa between 1984 and 1998: genotyping of archive blood samples

<p>Abstract</p> <p>Background</p> <p>Understanding the geographical distribution of drug resistance of <it>Plasmodium falciparum </it>is important for the effective treatment of malaria. Drug resistance has previously been inferred mainly from records of clinical resistance. However, clinical resistance is not always consistent with the parasite's genetic resistance. Thus, molecular identification of the parasite's drug resistance is required. In Africa, clinical resistance to pyrimethamine (Pyr) and chloroquine (CQ) was evident before 1980 but few studies investigating the genetic resistance to these drugs were conducted before the late 1990s. In this study, genotyping of genes involved in resistance to Pyr and CQ was performed using archive blood samples from Africa between 1984 and 1998.</p> <p>Methods</p> <p>Parasite DNA was extracted from <it>P. falciparum</it>-infected blood smears collected from travellers returning to Japan from Africa between 1984 and 1998. Genotypes of the dihydrofolate reductase gene (<it>dhfr</it>) and CQ-resistance transporter gene (<it>pfcrt) </it>were determined by polymerase chain reaction amplification and sequencing.</p> <p>Results</p> <p>Genotyping of <it>dhfr </it>and <it>pfcrt </it>was successful in 59 and 80 samples, respectively. One wild-type and seven mutant <it>dhfr </it>genotypes were identified. Three <it>dhfr </it>genotypes lacking the S108N mutation (NRSI, ICSI, IRSI; amino acids at positions 51, 59, 108, and 164 with mutations underlined) were highly prevalent before 1994 but reduced after 1995, accompanied by an increase in genotypes with the S108N mutation. The <it>dhfr </it>IRNI genotype was first identified in Nigeria in 1991 in the present samples, and its frequency gradually increased. However, two double mutants (ICNI and NRNI), the latter of which was exclusively found in West Africa, were more frequent than the IRNI genotype. Only two <it>pfcrt </it>genotypes were found, the wild-type and a Southeast Asian type (CVIET; amino acids at positions 72-76 with mutations underlined). The CVIET genotype was already present as early as 1984 in Tanzania and Nigeria, and appeared throughout Africa between 1984 and 1998.</p> <p>Conclusions</p> <p>This study is the first to report the molecular identification of Pyr- and CQ-resistant genotypes of <it>P. falciparum </it>in Africa before 1990. Genotyping of <it>dhfr </it>and <it>pfcrt </it>using archive samples has revealed new aspects of the evolutionary history of Pyr- and CQ-resistant parasites in Africa.</p

Characterization and structural determination of a new anti-MET function-blocking antibody with binding epitope distinct from the ligand binding domain

The growth and motility factor Hepatocyte Growth Factor/Scatter Factor (HGF/SF) and its receptor, the product of the MET proto-oncogene, promote invasion and metastasis of tumor cells and have been considered potential targets for cancer therapy. We generated a new Met-blocking antibody which binds outside the ligand-binding site, and determined the crystal structure of the Fab in complex with its target, which identifies the binding site as the Met Ig1 domain. The antibody, 107_A07, inhibited HGF/SF-induced cell migration and proliferation in vitro and inhibited growth of tumor xenografts in vivo. In biochemical assays, 107_A07 competes with both HGF/SF and its truncated splice variant NK1 for MET binding, despite the location of the antibody epitope on a domain (Ig1) not reported to bind NK1 or HGF/SF. Overlay of the Fab-MET crystal structure with the InternalinB-MET crystal structure shows that the 107_A07 Fab comes into close proximity with the HGF/SF-binding SEMA domain when MET is in the “compact”, InternalinB-bound conformation, but not when MET is in the “open” conformation. These findings provide further support for the importance of the “compact” conformation of the MET extracellular domain, and the relevance of this conformation to HGF/SF binding and signaling

Patterns of smoking behavior among physicians in Yerevan, Armenia

BACKGROUND: Physicians can play an important role in smoking prevention and control. This study will identify smoking prevalence among physicians in Yerevan, Armenia. It will also explore how the smoking behaviors of physicians, their perceived ability to influence patient smoking behavior, and their knowledge about health outcomes related to smoking influence their interaction with patients. METHODS: A cross-sectional, self-administered, anonymous survey was conducted in July, 2004, among 12 healthcare facilities in Yerevan. Analyses are based on responses from 240 physicians, representing a 70% response rate. RESULTS: The percentage of current smokers was significantly higher in men than women (48.5% vs. 12.8% regular and 6.8% vs. 4.5% occasional). Among current smokers, 52.7% of men compared with 13.0% of women had previously smoked in the presence of patients. Only 35.3% felt well prepared to assist patients to quit smoking. Physicians who smoke are less likely to ask their patients about their smoking behavior or believe their example is likely to influence their patients. Level of perceived preparedness to assist patients to quit smoking was positively associated with knowledge about known health risks associated with smoking. CONCLUSION: Smoking prevalence is high among physicians in the 12 healthcare facilities in Yerevan, and a large percentage of physician smoke in the presence of their patients. Physician smoking behavior and knowledge of smoking related health outcomes in Yerevan influences whether they counsel patients regarding smoking

Discovery of 4,6-disubstituted pyrimidines as potent inhibitors of the heat shock factor 1 (HSF1) stress pathway and CDK9.

Heat shock factor 1 (HSF1) is a transcription factor that plays key roles in cancer, including providing a mechanism for cell survival under proteotoxic stress. Therefore, inhibition of the HSF1-stress pathway represents an exciting new opportunity in cancer treatment. We employed an unbiased phenotypic screen to discover inhibitors of the HSF1-stress pathway. Using this approach we identified an initial hit (1) based on a 4,6-pyrimidine scaffold (2.00 μM). Optimisation of cellular SAR led to an inhibitor with improved potency (25, 15 nM) in the HSF1 phenotypic assay. The 4,6-pyrimidine 25 was also shown to have high potency against the CDK9 enzyme (3 nM)

Semen molecular and cellular features: these parameters can reliably predict subsequent ART outcome in a goat model

Currently, the assessment of sperm function in a raw or processed semen sample is not able to reliably predict sperm ability to withstand freezing and thawing procedures and in vivo fertility and/or assisted reproductive biotechnologies (ART) outcome. The aim of the present study was to investigate which parameters among a battery of analyses could predict subsequent spermatozoa in vitro fertilization ability and hence blastocyst output in a goat model. Ejaculates were obtained by artificial vagina from 3 adult goats (Capra hircus) aged 2 years (A, B and C). In order to assess the predictive value of viability, computer assisted sperm analyzer (CASA) motility parameters and ATP intracellular concentration before and after thawing and of DNA integrity after thawing on subsequent embryo output after an in vitro fertility test, a logistic regression analysis was used. Individual differences in semen parameters were evident for semen viability after thawing and DNA integrity. Results of IVF test showed that spermatozoa collected from A and B lead to higher cleavage rates (0 < 0.01) and blastocysts output (p < 0.05) compared with C. Logistic regression analysis model explained a deviance of 72% (p < 0.0001), directly related with the mean percentage of rapid spermatozoa in fresh semen (p < 0.01), semen viability after thawing (p < 0.01), and with two of the three comet parameters considered, i.e tail DNA percentage and comet length (p < 0.0001). DNA integrity alone had a high predictive value on IVF outcome with frozen/thawed semen (deviance explained: 57%). The model proposed here represents one of the many possible ways to explain differences found in embryo output following IVF with different semen donors and may represent a useful tool to select the most suitable donors for semen cryopreservation