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Search Results: 1 - 10 of 148106 matches for " Farhad F. Vasanwala equal contributor "
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Predictive Value of Proteinuria in Adult Dengue Severity
Farhad F. Vasanwala equal contributor,Tun-Linn Thein equal contributor,Yee-Sin Leo ,Victor C. Gan,Ying Hao,Linda K. Lee,David C. Lye
PLOS Neglected Tropical Diseases , 2014, DOI: 10.1371/journal.pntd.0002712
Abstract: Background Dengue is an important viral infection with different presentations. Predicting disease severity is important in triaging patients requiring hospital care. We aim to study the value of proteinuria in predicting the development of dengue hemorrhagic fever (DHF), utility of urine dipstick test as a rapid prognostic tool. Methodology and principal findings Adult patients with undifferentiated fever (n = 293) were prospectively enrolled at the Infectious Disease Research Clinic at Tan Tock Seng Hospital, Singapore from January to August 2012. Dengue infection was confirmed in 168 (57%) by dengue RT-PCR or NS1 antigen detection. Dengue cases had median fever duration of 6 days at enrolment. DHF was diagnosed in 34 cases according to the WHO 1997 guideline. Dengue fever (DF) patients were predominantly younger and were mostly seen in the outpatient setting with higher platelet level. Compared to DF, DHF cases had significantly higher peak urine protein creatinine ratio (UPCR) during clinical course (26 vs. 40 mg/mmol; p<0.001). We obtained a UPCR cut-off value of 29 mg/mmol based on maximum AUC in ROC curves of peak UPCR for DF versus DHF, corresponding to 76% sensitivity and 60% specificity. Multivariate analysis with other readily available clinical and laboratory variables increased the AUC to 0.91 with 92% sensitivity and 80% specificity. Neither urine dipstick at initial presentation nor peak urine dipstick value during the entire illness was able to discriminate between DF and DHF. Conclusions Proteinuria measured by a laboratory-based UPCR test may be sensitive and specific in prognosticating adult dengue patients.
Could peak proteinuria determine whether patient with dengue fever develop dengue hemorrhagic/dengue shock syndrome? - A prospective cohort study
Farhad F Vasanwala, Rukshini Puvanendran, Stephanie Fook-Chong, Joo-Ming Ng, Sufi M Suhail, Kheng-Hock Lee
BMC Infectious Diseases , 2011, DOI: 10.1186/1471-2334-11-212
Abstract: We included patients admitted to hospital with suspected dengue fever. Starting at enrollment until discharge, each patient's daily spot urine protein creatinine ratio (UPCR) was measured. We classified those with confirmed dengue infection as DF or DHF (including DSS) based on WHO criteria. Peak and day of onset of proteinuria was compared between both groups.Compared to those with DF, patients with DHF had significantly higher median peak proteinuria levels (0.56 versus 0.08 g/day; p < 0.001). For patients with DHF, the median day of onset of proteinuria was at 6 days of defervescence, with a range of -2 to +3 days after defervescence. There were three patients with DF who did not have proteinuria during their illness; the five remaining patients with DF had a median day of onset of proteinuria of was at 6 days of defervescence with a range of 0 to +28 days.Peak UPCR could potentially predict DHF in patients with dengue requiring close monitoring and treatment.Dengue is the most prevalent mosquito- borne viral disease in South East Asia [1]. It is caused by four dengue virus strains from the genus Flavivirus and transmitted by the Aedes aegypti mosquito. The risk of severe disease and death underscores the importance of early detection of dengue fever (DF) and monitoring for signs of progression to severe disease. Currently, there are no simple clinical and laboratory markers that can predict whether a patient with DF will develop life threatening dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS) [2]. There is a need to develop a simple effective predictor that can identify patients at risk of severe disease. Ideally, the test should be cheap, fast, highly sensitive and specific.Previous studies have documented proteinuria during the course dengue fever. In 1995, Garcia et al observed proteinuria in 22% of dengue fever patients, 38% of whom had it within the first 4 days of the onset of constitutional symptoms [3]. But the authors did not compare the o
U87MG Decoded: The Genomic Sequence of a Cytogenetically Aberrant Human Cancer Cell Line
Michael James Clark equal contributor,Nils Homer equal contributor,Brian D. O'Connor equal contributor,Zugen Chen equal contributor,Ascia Eskin,Hane Lee,Barry Merriman,Stanley F. Nelson
PLOS Genetics , 2010, DOI: 10.1371/journal.pgen.1000832
Abstract: U87MG is a commonly studied grade IV glioma cell line that has been analyzed in at least 1,700 publications over four decades. In order to comprehensively characterize the genome of this cell line and to serve as a model of broad cancer genome sequencing, we have generated greater than 30× genomic sequence coverage using a novel 50-base mate paired strategy with a 1.4kb mean insert library. A total of 1,014,984,286 mate-end and 120,691,623 single-end two-base encoded reads were generated from five slides. All data were aligned using a custom designed tool called BFAST, allowing optimal color space read alignment and accurate identification of DNA variants. The aligned sequence reads and mate-pair information identified 35 interchromosomal translocation events, 1,315 structural variations (>100 bp), 191,743 small (<21 bp) insertions and deletions (indels), and 2,384,470 single nucleotide variations (SNVs). Among these observations, the known homozygous mutation in PTEN was robustly identified, and genes involved in cell adhesion were overrepresented in the mutated gene list. Data were compared to 219,187 heterozygous single nucleotide polymorphisms assayed by Illumina 1M Duo genotyping array to assess accuracy: 93.83% of all SNPs were reliably detected at filtering thresholds that yield greater than 99.99% sequence accuracy. Protein coding sequences were disrupted predominantly in this cancer cell line due to small indels, large deletions, and translocations. In total, 512 genes were homozygously mutated, including 154 by SNVs, 178 by small indels, 145 by large microdeletions, and 35 by interchromosomal translocations to reveal a highly mutated cell line genome. Of the small homozygously mutated variants, 8 SNVs and 99 indels were novel events not present in dbSNP. These data demonstrate that routine generation of broad cancer genome sequence is possible outside of genome centers. The sequence analysis of U87MG provides an unparalleled level of mutational resolution compared to any cell line to date.
Nipbl and Mediator Cooperatively Regulate Gene Expression to Control Limb Development
Akihiko Muto,Shingo Ikeda,Martha E. Lopez-Burks,Yutaka Kikuchi equal contributor,Anne L. Calof equal contributor ,Arthur D. Lander equal contributor ,Thomas F. Schilling equal contributor
PLOS Genetics , 2014, DOI: doi/10.1371/journal.pgen.1004671
Abstract: Haploinsufficiency for Nipbl, a cohesin loading protein, causes Cornelia de Lange Syndrome (CdLS), the most common “cohesinopathy”. It has been proposed that the effects of Nipbl-haploinsufficiency result from disruption of long-range communication between DNA elements. Here we use zebrafish and mouse models of CdLS to examine how transcriptional changes caused by Nipbl deficiency give rise to limb defects, a common condition in individuals with CdLS. In the zebrafish pectoral fin (forelimb), knockdown of Nipbl expression led to size reductions and patterning defects that were preceded by dysregulated expression of key early limb development genes, including fgfs, shha, hand2 and multiple hox genes. In limb buds of Nipbl-haploinsufficient mice, transcriptome analysis revealed many similar gene expression changes, as well as altered expression of additional classes of genes that play roles in limb development. In both species, the pattern of dysregulation of hox-gene expression depended on genomic location within the Hox clusters. In view of studies suggesting that Nipbl colocalizes with the mediator complex, which facilitates enhancer-promoter communication, we also examined zebrafish deficient for the Med12 Mediator subunit, and found they resembled Nipbl-deficient fish in both morphology and gene expression. Moreover, combined partial reduction of both Nipbl and Med12 had a strongly synergistic effect, consistent with both molecules acting in a common pathway. In addition, three-dimensional fluorescent in situ hybridization revealed that Nipbl and Med12 are required to bring regions containing long-range enhancers into close proximity with the zebrafish hoxda cluster. These data demonstrate a crucial role for Nipbl in limb development, and support the view that its actions on multiple gene pathways result from its influence, together with Mediator, on regulation of long-range chromosomal interactions.
Crossing the Line: Selection and Evolution of Virulence Traits
Nat F Brown equal contributor,Mark E Wickham equal contributor,Brian K Coombes,B. Brett Finlay
PLOS Pathogens , 2006, DOI: 10.1371/journal.ppat.0020042
Abstract: The evolution of pathogens presents a paradox. Pathogenic species are often absolutely dependent on their host species for their propagation through evolutionary time, yet the pathogenic lifestyle requires that the host be damaged during this dependence. It is clear that pathogenic strategies are successful in evolutionary terms because a diverse array of pathogens exists in nature. Pathogens also evolve using a broad range of molecular mechanisms to acquire and modulate existing virulence traits in order to achieve this success. Detailing the benefit of enhanced selection derived through virulence and understanding the mechanisms through which virulence evolves are important to understanding the natural world and both have implications for human health.
Is Paromomycin an Effective and Safe Treatment against Cutaneous Leishmaniasis? A Meta-Analysis of 14 Randomized Controlled Trials
Dae Hyun Kim equal contributor,Hye Jin Chung equal contributor,Joachim Bleys,Reza F. Ghohestani
PLOS Neglected Tropical Diseases , 2009, DOI: 10.1371/journal.pntd.0000381
Abstract: Background High cost, poor compliance, and systemic toxicity have limited the use of pentavalent antimony compounds (SbV), the treatment of choice for cutaneous leishmaniasis (CL). Paromomycin (PR) has been developed as an alternative to SbV, but existing data are conflicting. Methodology/Principal Findings We searched PubMed, Scopus, and Cochrane Central Register of Controlled Trials, without language restriction, through August 2007, to identify randomized controlled trials that compared the efficacy or safety between PR and placebo or SbV. Primary outcome was clinical cure, defined as complete healing, disappearance, or reepithelialization of all lesions. Data were extracted independently by two investigators, and pooled using a random-effects model. Fourteen trials including 1,221 patients were included. In placebo-controlled trials, topical PR appeared to have therapeutic activity against the old world and new world CL, with increased local reactions, when used with methylbenzethonium chloride (MBCL) compared to when used alone (risk ratio [RR] for clinical cure, 2.58 versus 1.01: RR for local reactions, 1.60 versus 1.07). In SbV-controlled trials, the efficacy of topical PR was not significantly different from that of intralesional SbV in the old world CL (RR, 0.70; 95% confidence interval, 0.26–1.89), whereas topical PR was inferior to parenteral SbV in treating the new world CL (0.67; 0.54–0.82). No significant difference in efficacy was found between parenteral PR and parenteral SbV in the new world CL (0.88; 0.56–1.38). Systemic side effects were fewer with topical or parenteral PR than parenteral SbV. Conclusions/Significance Topical PR with MBCL could be a therapeutic alternative to SbV in selected cases of the old world CL. Development of new formulations with better efficacy and tolerability remains to be an area of future research.
Statins in Patients with Chronic Kidney Disease: Evidence from Systematic Reviews and Randomized Clinical Trials
Sankar D Navaneethan equal contributor ,Francesca Pansini,Giovanni F. M Strippoli equal contributor
PLOS Medicine , 2006, DOI: 10.1371/journal.pmed.0030123
Functional Specialization of the Plant miR396 Regulatory Network through Distinct MicroRNA–Target Interactions
Juan M. Debernardi equal contributor,Ramiro E. Rodriguez equal contributor,Martin A. Mecchia,Javier F. Palatnik
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1002419
Abstract: MicroRNAs (miRNAs) are ~21 nt small RNAs that regulate gene expression in animals and plants. They can be grouped into families comprising different genes encoding similar or identical mature miRNAs. Several miRNA families are deeply conserved in plant lineages and regulate key aspects of plant development, hormone signaling, and stress response. The ancient miRNA miR396 regulates conserved targets belonging to the GROWTH-REGULATING FACTOR (GRF) family of transcription factors, which are known to control cell proliferation in Arabidopsis leaves. In this work, we characterized the regulation of an additional target for miR396, the transcription factor bHLH74, that is necessary for Arabidopsis normal development. bHLH74 homologs with a miR396 target site could only be detected in the sister families Brassicaceae and Cleomaceae. Still, bHLH74 repression by miR396 is required for margin and vein pattern formation of Arabidopsis leaves. MiR396 contributes to the spatio-temporal regulation of GRF and bHLH74 expression during leaf development. Furthermore, a survey of miR396 sequences in different species showed variations in the 5′ portion of the miRNA, a region known to be important for miRNA activity. Analysis of different miR396 variants in Arabidopsis thaliana revealed that they have an enhanced activity toward GRF transcription factors. The interaction between the GRF target site and miR396 has a bulge between positions 7 and 8 of the miRNA. Our data indicate that such bulge modulates the strength of the miR396-mediated repression and that this modulation is essential to shape the precise spatio-temporal pattern of GRF2 expression. The results show that ancient miRNAs can regulate conserved targets with varied efficiency in different species, and we further propose that they could acquire new targets whose control might also be biologically relevant.
Targeted Deficiency of the Transcriptional Activator Hnf1α Alters Subnuclear Positioning of Its Genomic Targets
Reini F. Luco equal contributor,Miguel A. Maestro equal contributor,Nicolas Sadoni,Daniele Zink,Jorge Ferrer
PLOS Genetics , 2008, DOI: 10.1371/journal.pgen.1000079
Abstract: DNA binding transcriptional activators play a central role in gene-selective regulation. In part, this is mediated by targeting local covalent modifications of histone tails. Transcriptional regulation has also been associated with the positioning of genes within the nucleus. We have now examined the role of a transcriptional activator in regulating the positioning of target genes. This was carried out with primary β-cells and hepatocytes freshly isolated from mice lacking Hnf1α, an activator encoded by the most frequently mutated gene in human monogenic diabetes (MODY3). We show that in Hnf1a?/? cells inactive endogenous Hnf1α-target genes exhibit increased trimethylated histone H3-Lys27 and reduced methylated H3-Lys4. Inactive Hnf1α-targets in Hnf1a?/? cells are also preferentially located in peripheral subnuclear domains enriched in trimethylated H3-Lys27, whereas active targets in wild-type cells are positioned in more central domains enriched in methylated H3-Lys4 and RNA polymerase II. We demonstrate that this differential positioning involves the decondensation of target chromatin, and show that it is spatially restricted rather than a reflection of non-specific changes in the nuclear organization of Hnf1a-deficient cells. This study, therefore, provides genetic evidence that a single transcriptional activator can influence the subnuclear location of its endogenous genomic targets in primary cells, and links activator-dependent changes in local chromatin structure to the spatial organization of the genome. We have also revealed a defect in subnuclear gene positioning in a model of a human transcription factor disease.
A Map of Recent Positive Selection in the Human Genome
Benjamin F Voight equal contributor,Sridhar Kudaravalli equal contributor,Xiaoquan Wen,Jonathan K Pritchard
PLOS Biology , 2006, DOI: 10.1371/journal.pbio.0040072
Abstract: The identification of signals of very recent positive selection provides information about the adaptation of modern humans to local conditions. We report here on a genome-wide scan for signals of very recent positive selection in favor of variants that have not yet reached fixation. We describe a new analytical method for scanning single nucleotide polymorphism (SNP) data for signals of recent selection, and apply this to data from the International HapMap Project. In all three continental groups we find widespread signals of recent positive selection. Most signals are region-specific, though a significant excess are shared across groups. Contrary to some earlier low resolution studies that suggested a paucity of recent selection in sub-Saharan Africans, we find that by some measures our strongest signals of selection are from the Yoruba population. Finally, since these signals indicate the existence of genetic variants that have substantially different fitnesses, they must indicate loci that are the source of significant phenotypic variation. Though the relevant phenotypes are generally not known, such loci should be of particular interest in mapping studies of complex traits. For this purpose we have developed a set of SNPs that can be used to tag the strongest ~250 signals of recent selection in each population.
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