1,541 research outputs found
The incidence of liver injury in Uyghur patients treated for TB in Xinjiang Uyghur autonomous region, China, and its association with hepatic enzyme polymorphisms nat2, cyp2e1, gstm1 and gstt1.
No full textBACKGROUND AND OBJECTIVE: Of three first-line anti-tuberculosis (anti-TB) drugs, isoniazid is most commonly associated with hepatotoxicity. Differences in INH-induced toxicity have been attributed to genetic variability at several loci, NAT2, CYP2E1, GSTM1and GSTT1, that code for drug-metabolizing enzymes. This study evaluated whether the polymorphisms in these enzymes were associated with an increased risk of anti-TB drug-induced hepatitis in patients and could potentially be used to identify patients at risk of liver injury. METHODS AND DESIGN: In a cross-sectional study, 2244 tuberculosis patients were assessed two months after the start of treatment. Anti-TB drug-induced liver injury (ATLI) was defined as an ALT, AST or bilirubin value more than twice the upper limit of normal. NAT2, CYP2E1, GSTM1 and GSTT1 genotypes were determined using the PCR/ligase detection reaction assays. RESULTS: 2244 patients were evaluated, there were 89 cases of ATLI, a prevalence of 4% 9 patients (0.4%) had ALT levels more than 5 times the upper limit of normal. The prevalence of ATLI was greater among men than women, and there was a weak association with NAT2*5 genotypes, with ATLI more common among patients with the NAT2*5*CT genotype. The sensitivity of the CT genotype for identifying patients with ATLI was 42% and the positive predictive value 5.9%. CT ATLI was more common among slow acetylators (prevalence ratio 2.0 (95% CI 0.95,4.20) )compared to rapid acetylators. There was no evidence that ATLI was associated with CYP2E1 RsaIc1/c1genotype, CYP2E1 RsaIc1/c2 or c2/c2 genotypes, or GSTM1/GSTT1 null genotypes. CONCLUSIONS: In Xinjiang Uyghur TB patients, liver injury was associated with the genetic variant NAT2*5, however the genetic markers studied are unlikely to be useful for screening patients due to the low sensitivity and low positive predictive values for identifying persons at risk of liver injury
BCG vaccination and leprosy protection: review of current evidence and status of BCG in leprosy control.
No full textThe bacillus Calmette-Guérin (BCG) vaccine, initially developed to provide protection against TB, also protects against leprosy; and the magnitude of this effect varies. Previous meta-analyses did not provide a summary estimate of the efficacy due to the heterogeneity of the results. We conducted a meta-analysis of published data including recently published studies (up to June 2009) to determine the efficacy of BCG protection on leprosy and to investigate whether age at vaccination, clinical form, number of doses, type of study, the latitude of study area and year of publication influence the degree of efficacy and explain the variation. In the light of the results, we argue for more emphasis on the role of BCG vaccination in leprosy control and research
A four-month gatifloxacin-containing regimen for treating tuberculosis.
No full textBACKGROUND: Shortening the course of treatment for tuberculosis would be a major improvement for case management and disease control. This phase 3 trial assessed the efficacy and safety of a 4-month gatifloxacin-containing regimen for treating rifampin-sensitive pulmonary tuberculosis. METHODS: We conducted a noninferiority, randomized, open-label, controlled trial involving patients 18 to 65 years of age with smear-positive, rifampin-sensitive, newly diagnosed pulmonary tuberculosis in five sub-Saharan African countries. A standard 6-month regimen that included ethambutol during the 2-month intensive phase was compared with a 4-month regimen in which gatifloxacin (400 mg per day) was substituted for ethambutol during the intensive phase and was continued, along with rifampin and isoniazid, during the continuation phase. The primary efficacy end point was an unfavorable outcome (treatment failure, recurrence, or death or study dropout during treatment) measured 24 months after the end of treatment, with a noninferiority margin of 6 percentage points, adjusted for country. RESULTS: A total of 1836 patients were assigned to the 4-month regimen (experimental group) or the standard regimen (control group). Baseline characteristics were well balanced between the groups. At 24 months after the end of treatment, the adjusted difference in the risk of an unfavorable outcome (experimental group [21.0%] minus control group [17.2%]) in the modified intention-to-treat population (1356 patients) was 3.5 percentage points (95% confidence interval, -0.7 to 7.7). There was heterogeneity across countries (P=0.02 for interaction, with differences in the rate of an unfavorable outcome ranging from -5.4 percentage points in Guinea to 12.3 percentage points in Senegal) and in baseline cavitary status (P=0.04 for interaction) and body-mass index (P=0.10 for interaction). The standard regimen, as compared with the 4-month regimen, was associated with a higher dropout rate during treatment (5.0% vs. 2.7%) and more treatment failures (2.4% vs. 1.7%) but fewer recurrences (7.1% vs. 14.6%). There was no evidence of increased risks of prolongation of the QT interval or dysglycemia with the 4-month regimen. CONCLUSIONS: Noninferiority of the 4-month regimen to the standard regimen with respect to the primary efficacy end point was not shown. (Funded by the Special Program for Research and Training in Tropical Diseases and others; ClinicalTrials.gov number, NCT00216385.)
Modulation of ion channels by natural products - identification of hERG channel inhibitors and GABAA receptor ligands from plant extracts
No full textIon channels are expressed in virtually all cell types in the human body and are involved in various physiological processes. Hence, it is not surprising that ion channels play an important role in modern drug discovery. Lead compounds are nowadays routinely tested against a panel of ion channels to evaluate selectivity and potential off-target activities.
The human ether-à-go-go-related gene (hERG) channel, a voltage-gated potassium channel, is the currently most critical antitarget with respect to cardiac safety. Inhibition of the hERG channel can prolong the QT interval on the electrocardiogram (ECG) and, as a consequence, lead to life-threatening arrhythmia. Considering the daily intake of plant-derived foods and herbal products, surprisingly few natural products have been tested for hERG blocking properties. In the course of an interdisciplinary hERG project, a selection of widely used herbal drugs and dietary plants was screened by means of a two-microelectrode voltage-clamp assay with Xenopus oocytes. Moderate hERG block was observed for the traditional Chinese herbal drug Coptidis rhizoma and black pepper fruits, and successfully tracked by HPLC-based activity profiling to dihydroberberine and piperine, respectively. The hERG blocking activity of cinnamon, guarana, and nutmeg, in contrast, was attributed to tannins. Our screening data suggest that major European medicinal plants and frequently consumed food plants are associated with a low risk for hERG inhibition. However, the case of Coptidis rhizoma pointed towards a need for a more thorough assessment of herbal drugs of the traditional Chinese medicine (TCM). Subsequent screening of a plant-derived alkaloid library led to the identification of several potent hERG blockers. Further investigations are certainly warranted to assess the cardiac safety profile of these alkaloids.
Dehydroevodiamine (DHE), a major bioactive constituent of the traditional Chinese herbal drug Evodiae fructus, has been previously shown to inhibit several cardiac ion currents in vitro. For further evaluation of its in vivo pharmacological and toxicological properties, gram amounts of DHE were needed. Since DHE is not commercially available, we developed an efficient method for its gram-scale isolation from a crude Evodia extract. Our approach is based on a combination of cation-exchange chromatography and preparative RP-HPLC. Moreover, the DHE content in commercially available Evodia products was assessed by HPLC-PDA analysis. A daily intake of up to mg amounts of DHE was calculated from recommended doses of these products. We also devised a procedure for the production of DHE-depleted Evodia products, should DHE indeed turn out to be toxicologically relevant.
The gamma-aminobutyric acid type A (GABAA) receptor, a ligand-gated chloride channel, mediates fast inhibitory neurotransmission in the central nervous system (CNS), and is thus a clinically important drug target. In the search for positive α1β2γ2S GABAA receptor modulators of plant origin, we investigated an extract of Curcuma kwangsiensis rhizomes. HPLC-based activity profiling was used in combination with a two-microelectrode voltage-clamp assay on Xenopus oocytes to identify the active constituents. Targeted isolation afforded a series of 11 structurally related labdane diterpenoids, including four new natural products. Structure elucidation was achieved by comprehensive analysis of HR-ESI-TOF-MS and NMR data. The absolute configuration of the compounds was assigned by electronic circular dichroism (ECD). The highest GABAA receptor modulating activity was observed for zerumin A.
From a more general perspective, this study demonstrates that HPLC-based activity profiling is an effective strategy to characterize bioactive compounds in crude natural extracts
Genome-Wide Identification, Functional Analysis and Expression Profiling of the Aux/IAA Gene Family in Tomato
No full textAuxin is a central hormone that exerts pleiotropic effects on plant growth including the development of roots, shoots,
flowers and fruit. The perception and signaling of the plant
hormone auxin rely on the cooperative action of several components,among which auxin/indole-3-acetic acid (Aux/IAA)
proteins play a pivotal role. In this study, we identified and comprehensively analyzed the entire Aux/IAA gene family in tomato (Solanum lycopersicum), a reference species for Solanaceae plants, and the model plant for fleshy fruit development. Functional characterization using a dedicated single cell system revealed that tomato Aux/IAA proteins function as active repressors of auxin-dependent gene transcription, with, however, different Aux/IAA members displaying varying levels of repression. Phylogenetic analysis indicated that the Aux/IAA gene family is slightly contracted in tomato compared with Arabidopsis, with a lower representation of non-canonical proteins. Sl-IAA genes display distinctive expression pattern in different tomato organs and tissues, and some of them display differential responses to auxin and ethylene, suggesting that Aux/IAAs may play a role in linking both hormone signaling pathways. The data presented here shed more light on Sl-IAA genes and provides new leads towards the elucidation of their function during plant development and in mediating hormone cross-talk
Evaluation of Microcracking and Chemical Deterioration in Concrete Pavements Final Report, October 31, 1995
No full textThe major objective of this research project was to investigate the chemistry and morphology of portland cement concrete pavements in Iowa. The integrity of the various pavements was evaluated qualitatively, based on the presence or absence of microcracks, the presence or absence of sulfate minerals, and the presence or absence of alkali-silica
gel(s). Major equipment delays and subsequent equipment replacements resulted in significant delays over the course of this research project. However, all these details were resolved and the equipment is currently in place and fully operational. The equipment that was purchased for this project included: ( I ) a LECO VP 50, 12-inch diameter, variable speed grinder/polisher: (2) a Hitachi S-2460N variable pressure scanning electron microscope; and (3) a OXFORD Instruments Link ISIS microanalysis system
with a GEM (high-purity germanium) X-ray detector. This study has indicated that many of the concrete pavements contained evidence of multiple deterioration mechanisms: and hence,
the identification of a single reason for the distress that was observed in any given pavement typically had to be based on opinion rather than empirical evidence
Evaluation of Microcracking and Chemical Deterioration in Concrete Pavements, October 31, 1995
No full textThe major objective of this research project was to investigate the chemistry and morphology of portland cement concrete pavements in Iowa. The integrity of the various pavements was evaluated qualitatively, based on the presence or absence of microcracks, the presence or absence of sulfate minerals, and the presence or absence of alkali-silica
gel(s). Major equipment delays and subsequent equipment replacements resulted in significant delays over the course of this research project. However, all these details were resolved and the equipment is currently in place and fully operational. The equipment that was purchased for this project included: (I) a LECO VP 50, 12-inch diameter, variable speed grinder/polisher: (2) a Hitachi S-2460N variable pressure scanning electron microscope; and (3) a OXFORD Instruments Link ISIS microanalysis system
with a GEM (high-purity germanium) X-ray detector. This study has indicated that many of the concrete pavements contained evidence of multiple deterioration mechanisms: and hence,
the identification of a single reason for the distress that was observed in any given pavement typically had to be based on opinion rather than empirical evidence
The wMel Wolbachia strain blocks dengue and invades caged Aedes aegypti populations
No full textDengue fever is the most important mosquito-borne viral disease of humans with more than 50 million cases estimated annually in more than 100 countries. Disturbingly, the geographic range of dengue is currently expanding and the severity of outbreaks is increasing. Control options for dengue are very limited and currently focus on reducing population abundance of the major mosquito vector, Aedes aegypti. These strategies are failing to reduce dengue incidence in tropical communities and there is an urgent need for effective alternatives. It has been proposed that endosymbiotic bacterial Wolbachia infections of insects might be used in novel strategies for dengue control. For example, the wMelPop-CLA Wolbachia strain reduces the lifespan of adult A. aegypti mosquitoes in stably transinfected lines. This life-shortening phenotype was predicted to reduce the potential for dengue transmission. The recent discovery that several Wolbachia infections, including wMelPop-CLA, can also directly influence the susceptibility of insects to infection with a range of insect and human pathogens has markedly changed the potential for Wolbachia infections to control human diseases. Here we describe the successful transinfection of A. aegypti with the avirulent wMel strain of Wolbachia, which induces the reproductive phenotype cytoplasmic incompatibility with minimal apparent fitness costs and high maternal transmission, providing optimal phenotypic effects for invasion. Under semi-field conditions, the wMel strain increased from an initial starting frequency of 0.65 to near fixation within a few generations, invading A. aegypti populations at an accelerated rate relative to trials with the wMelPop-CLA strain. We also show that wMel and wMelPop-CLA strains block transmission of dengue serotype 2 (DENV-2) in A. aegypti, forming the basis of a practical approach to dengue suppression
Four-year stability of anthropometric and cardio-metabolic parameters in a prospective cohort of older adults
No full textAim: To examine the medium-term stability of anthropometric and cardio-metabolic parameters in the general population. Materials & methods: Participants were 5160 men and women from the English Longitudinal Study of Ageing (age ≥50 years) assessed in 2004 and 2008. Anthropometric data included height, weight, BMI and waist circumference. Cardio-metabolic parameters included blood pressure, serum lipids (total cholesterol, HDL, LDL, triglycerides), hemoglobin, fasting glucose, fibrinogen and C-reactive protein. Results: Stability of anthropometric variables was high (all intraclass correlations >0.92), although mean values changed slightly (-0.01 kg weight, +1.33 cm waist). Cardio-metabolic parameters showed more variation: correlations ranged from 0.43 (glucose) to 0.81 (HDL). The majority of participants (71–97%) remained in the same grouping relative to established clinical cut-offs. Conclusion: Over a 4-year period, anthropometric and cardio-metabolic parameters showed good stability. These findings suggest that when no means to obtain more recent data exist, a one-time sample will give a reasonable approximation to average levels over the medium-term, although reliability is reduced
Wolbachia variability and host effects on crossing type in Culex mosquitoes
No full textWolbachia is a common maternally inherited bacterial symbiont able to induce crossing sterilities known as cytoplasmic incompatibility (CI) in insects1, 2. Wolbachia-modified sperm are unable to complete fertilization of uninfected ova, but a rescue function allows infected eggs to develop normally. By providing a reproductive advantage to infected females, Wolbachia can rapidly invade uninfected populations3, and this could provide a mechanism for driving transgenes through pest populations4, 5. CI can also occur between Wolbachia-infected populations and is usually associated with the presence of different Wolbachia strains1. In the Culex pipiens mosquito group (including the filariasis vector C. quinquefasciatus) a very unusual degree of complexity of Wolbachia-induced crossing-types has been reported, with partial or complete CI that can be unidirectional or bidirectional6, 7, 8, 9, 10, 11, yet no Wolbachia strain variation was found11. Here we show variation between incompatible Culex strains in two Wolbachia ankyrin repeat-encoding genes associated with a prophage region, one of which is sex-specifically expressed in some strains, and also a direct effect of the host nuclear genome on CI rescue
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