Rapid Diagnostic Algorithms as a Screening Tool for Tuberculosis: An Assessor Blinded Cross-Sectional Study

Background: A major obstacle to effectively treat and control tuberculosis is the absence of an accurate, rapid, and low-cost diagnostic tool. A new approach for the screening of patients for tuberculosis is the use of rapid diagnostic classification algorithms. Methods: We tested a previously published diagnostic algorithm based on four biomarkers as a screening tool for tuberculosis in a Central European patient population using an assessor-blinded cross-sectional study design. In addition, we developed an improved diagnostic classification algorithm based on a study population at a tertiary hospital in Vienna, Austria, by supervised computational statistics. Results: The diagnostic accuracy of the previously published diagnostic algorithm for our patient population consisting of 206 patients was 54% (CI: 47%–61%). An improved model was constructed using inflammation parameters and clinical information. A diagnostic accuracy of 86% (CI: 80%–90%) was demonstrated by 10-fold cross validation. An alternative model relying solely on clinical parameters exhibited a diagnostic accuracy of 85% (CI: 79%–89%). Conclusion: Here we show that a rapid diagnostic algorithm based on clinical parameters is only slightly improved by inclusion of inflammation markers in our cohort. Our results also emphasize the need for validation of new diagnostic algorithms in different settings and patient populations

Comparison of herbarium label data and published medicinal use: herbaria as an underutilized source of ethnobotanical information

The use of herbarium specimens as vouchers to support ethnobotanical surveys is well established. However, herbaria may be underutilized resources for ethnobotanical research that depends on the analysis of large datasets compiled across multiple sites. Here, we compare two medicinal use datasets, one sourced from published papers and the other from online herbaria to determine whether herbarium and published data are comparable and to what extent herbarium specimens add new data and fill gaps in our knowledge of geographical extent of plant use. Using Brazilian legumes as a case study, we compiled 1400 use reports from 105 publications and 15 Brazilian herbaria. Of the 319 species in 107 genera with cited medicinal uses, 165 (51%) were recorded only in the literature and 55 (17%) only on herbarium labels. Mode of application, plant part used, or therapeutic use was less often documented by herbarium specimen labels (17% with information) than publications (70%). However, medicinal use of 21 of the 128 species known from only one report in the literature was substantiated from independently collected herbarium specimens, and 58 new therapeutic applications, 25 new plant parts, and 16 new modes of application were added for species known from the literature. Thus, when literature reports are few or information-poor, herbarium data can both validate and augment these reports. Herbarium data can also provide insights into the history and geographical extent of use that are not captured in publications

Artemisinin derivatives versus quinine in treating severe malaria in children: a systematic review

<p>Abstract</p> <p>Background</p> <p>The efficacy of intravenous quinine, which is the mainstay for treating severe malaria in children, is decreasing in South East Asia and Africa. Artemisinin derivatives are a potential alternative to quinine. However, their efficacy compared to quinine in treating severe malaria in children is not clearly understood. The objective of this review was to assess the efficacy of parenteral artemisinin derivatives versus parenteral quinine in treating severe malaria in children.</p> <p>Methods</p> <p>All randomized controlled studies comparing parenteral artemisinin derivatives with parenteral quinine in treating severe malaria in children were included in the review. Data bases searched were: The Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 4, 2007), MEDLINE (1966 to February 2008), EMBASE (1980 to February 2008), and LILACS (1982 to February 2008). Dichotomous variables were compared using risk ratios (RR) and the continuous data using weighted mean difference (WMD).</p> <p>Results</p> <p>Twelve trials were included (1,524 subjects). There was no difference in mortality between artemisinin derivatives and quinine (RR = 0.90, 95% CI 0.73 to 1.12). The artemisinin derivatives resolved coma faster than quinine (WMD = -4.61, 95% CI: -7.21 to -2.00, fixed effect model), but when trials with adequate concealment only were considered this differences disappeared. There was no statistically significant difference between the two groups in parasite clearance time, fever clearance time, incidence of neurological sequelae and 28^thday cure rate. One trial reported significantly more local reactions at the injection site with intramuscular quinine compared to artemether. None of the trials was adequately powered to demonstrate equivalence.</p> <p>Conclusion</p> <p>There was no evidence that treatment of children with severe malaria with parenteral artemisinin derivatives was associated with lower mortality or long-term morbidity compared to parenteral quinine. Future studies require adequately powered equivalence trial design to decide whether both drugs are equally effective.</p

Cure of Chronic Viral Infection and Virus-Induced Type 1 Diabetes by Neutralizing Antibodies

The use of neutralizing antibodies is one of the most successful methods to interfere with receptor–ligand interactions in vivo. In particular blockade of soluble inflammatory mediators or their corresponding cellular receptors was proven an effective way to regulate inflammation and/or prevent its negative consequences. However, one problem that comes along with an effective neutralization of inflammatory mediators is the general systemic immunomodulatory effect. It is, therefore, important to design a treatment regimen in a way to strike at the right place and at the right time in order to achieve maximal effects with minimal duration of immunosuppression or hyperactivation. In this review, we reflect on two examples of how short time administration of such neutralizing antibodies can block two distinct inflammatory consequences of viral infection. First, we review recent findings that blockade of IL-10/IL-10R interaction can resolve chronic viral infection and second, we reflect on how neutralization of the chemokine CXCL10 can abrogate virus-induced type 1 diabetes

Molecular markers of anti-malarial drug resistance in Central, West and East African children with severe malaria.

BACKGROUND: The Plasmodium falciparum multidrug resistance 1 (PfMDR1), P. falciparum Ca(2+)-ATPase (PfATP6) and Kelch-13 propeller domain (PfK13) loci are molecular markers of parasite susceptibility to anti-malarial drugs. Their frequency distributions were determined in the isolates collected from children with severe malaria originating from three African countries. METHODS: Samples from 287 children with severe malaria [(Gabon: n = 114); (Ghana: n = 89); (Kenya: n = 84)] were genotyped for pfmdr1, pfatp6 and pfk13 loci by DNA sequencing and assessing pfmdr1 copy number variation (CNV) by real-time PCR. RESULTS: Pfmdr1-N86Y mutation was detected in 48, 10 and 10% in Lambaréné, Kumasi and Kisumu, respectively. At codon 184, the prevalence of the mutation was 73% in Lambaréné, 63% in Kumasi and 49% Kisumu. The S1034C and N1042D variants were absent at all three sites, while the frequency of the D1246Y mutation was 1, 3 and 13% in Lambaréné, Kumasi and Kisumu, respectively. Isolates with two pfmdr1 gene copy number predominantly harboured the N86Y wild-type allele and were mostly found in Kumasi (10%) (P < 0.0001). Among the main pfmdr1 haplotypes (NFD, NYD and YFD), NYD was associated with highest parasitaemia (P = 0.04). At the pfatp6 locus, H243Y and A623E mutations were observed at very low frequency at all three sites. The prevalence of the pfatp6 E431K variant was 6, 18 and 17% in Lambaréné, Kumasi and Kisumu, respectively. The L263E and S769N mutations were absent in all isolates. The pfk13 variants associated with artemisinin resistance in Southeast Asia were not observed. Eleven novel substitutions in the pfk13 locus occurring at low frequency were observed. CONCLUSIONS: Artemisinins are still highly efficacious in large malaria-endemic regions though declining efficacy has occurred in Southeast Asia. The return of chloroquine-sensitive strains following the removal of drug pressure is observed. However, selection of wild-type alleles in the multidrug-resistance gene and the increased gene copy number is associated with reduced lumefantrine sensitivity. This study indicates a need to constantly monitor drug resistance to artemisinin in field isolates from malaria-endemic countries

Automatic structure classification of small proteins using random forest

<p>Abstract</p> <p><b>Background</b></p> <p>Random forest, an ensemble based supervised machine learning algorithm, is used to predict the SCOP structural classification for a target structure, based on the similarity of its structural descriptors to those of a template structure with an equal number of secondary structure elements (SSEs). An initial assessment of random forest is carried out for domains consisting of three SSEs. The usability of random forest in classifying larger domains is demonstrated by applying it to domains consisting of four, five and six SSEs.</p> <p><b>Result</b>s</p> <p>Random forest, trained on SCOP version 1.69, achieves a predictive accuracy of up to 94% on an independent and non-overlapping test set derived from SCOP version 1.73. For classification to the SCOP <it>Class, Fold, Super-family </it>or <it>Family </it>levels, the predictive quality of the model in terms of Matthew's correlation coefficient (MCC) ranged from 0.61 to 0.83. As the number of constituent SSEs increases the MCC for classification to different structural levels decreases.</p> <p>Conclusions</p> <p>The utility of random forest in classifying domains from the place-holder classes of SCOP to the true <it>Class, Fold, Super-family </it>or <it>Family </it>levels is demonstrated. Issues such as introduction of a new structural level in SCOP and the merger of singleton levels can also be addressed using random forest. A real-world scenario is mimicked by predicting the classification for those protein structures from the PDB, which are yet to be assigned to the SCOP classification hierarchy.</p

αA-Crystallin Peptide 66SDRDKFVIFLDVKHF80 Accumulating in Aging Lens Impairs the Function of α-Crystallin and Induces Lens Protein Aggregation

The eye lens is composed of fiber cells that are filled with α-, β- and γ-crystallins. The primary function of crystallins is to maintain the clarity of the lens through ordered interactions as well as through the chaperone-like function of α-crystallin. With aging, the chaperone function of α-crystallin decreases, with the concomitant accumulation of water-insoluble, light-scattering oligomers and crystallin-derived peptides. The role of crystallin-derived peptides in age-related lens protein aggregation and insolubilization is not understood.We found that αA-crystallin-derived peptide, (66)SDRDKFVIFLDVKHF(80), which accumulates in the aging lens, can inhibit the chaperone activity of α-crystallin and cause aggregation and precipitation of lens crystallins. Age-related change in the concentration of αA-(66-80) peptide was estimated by mass spectrometry. The interaction of the peptide with native crystallin was studied by multi-angle light scattering and fluorescence methods. High molar ratios of peptide-to-crystallin were favourable for aggregation and precipitation. Time-lapse recordings showed that, in the presence of αA-(66-80) peptide, α-crystallin aggregates and functions as a nucleus for protein aggregation, attracting aggregation of additional α-, β- and γ-crystallins. Additionally, the αA-(66-80) peptide shares the principal properties of amyloid peptides, such as β-sheet structure and fibril formation.These results suggest that crystallin-derived peptides such as αA-(66-80), generated in vivo, can induce age-related lens changes by disrupting the structure and organization of crystallins, leading to their insolubilization. The accumulation of such peptides in aging lenses may explain a novel mechanism for age-related crystallin aggregation and cataractogenesis

Effect of folate derivatives on the activity of antifolate drugs used against malaria and cancer

The folate derivatives folic acid (FA) and folinic acid (FNA) decrease the in vivo and in vitro activities of antifolate drugs in Plasmodium falciparum. However, the effects of 5-methyl-tetrahydrofolate (5-Me-THF) and tetrahydrofolate (THF), the two dominant circulating folate forms in humans, have not been explored yet. We have investigated the effects of FA, FNA, 5-Me-THF, and THF on the in vitro activity of the antimalarial antifolates pyrimethamine and chlorcycloguanil and the anticancer antifolates methotrexate (MTX), aminopterin, and trimetrexate (TMX), against P. falciparum. The results indicate that these anticancers are potent against P. falciparum, with IC50 < 50 nM. 5-Me-THF does not significantly decrease the activity of all tested drugs, and none of the tested folate derivatives significantly decrease the activity of these anticancers. Thus, malaria folate metabolism has features different from those in human, and the exploitation of this difference could lead to the discovery of new drugs to treat malaria. For instance, the combination of 5-Me-THF with a low dose of TMX could be used to treat malaria. In addition, the safety of a low dose of MTX in the treatment of arthritis indicates that this drug could be used alone to treat malaria

Association between tobacco use and body mass index in urban Indian population: implications for public health in India

BACKGROUND: Body mass index [BMI, weight (kg)/height (m(2))], a measure of relative weight, is a good overall indicator of nutritional status and predictor of overall health. As in many developing countries, the high prevalence of very low BMIs in India represents an important public health risk. Tobacco, smoked in the form of cigarettes or bidis (handmade by rolling a dried rectangular piece of temburni leaf with 0.15–0.25 g of tobacco) or chewed, is another important determinant of health. Tobacco use also may exert a strong influence on BMI. METHODS: The relationship between very low BMI (< 18.5 kg/m(2)) and tobacco use was examined using data from a representative cross-sectional survey of 99,598 adults (40,071 men and 59,527 women) carried out in the city of Mumbai (formerly known as Bombay) in western India. Participants were men and women aged ≥ 35 years who were residents of the main city of Mumbai. RESULTS: All forms of tobacco use were associated with low BMI. The prevalence of low BMI was highest in bidi-smokers (32% compared to 13% in non-users). For smokers, the adjusted odds ratio (OR) and 95% confidence interval (CI) were OR = 1.80(1.65 to 1.96) for men and OR = 1.59(1.09 to 2.32) for women, respectively, relative to non-users. For smokeless tobacco and mixed habits (smoking and smokeless tobacco), OR = 1.28(1.19 to 1.38) and OR = 1.83(1.67 to 2.00) for men and OR = 1.50(1.43 to 1.59) and OR = 2.19(1.90 to 3.41) for women, respectively. CONCLUSION: Tobacco use appears to be an independent risk factor for low BMI in this population. We conclude that in such populations tobacco control research and interventions will need to be conducted in concert with nutrition research and interventions in order to improve the overall health status of the population