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1.
Phys Rev Lett ; 132(2): 026003, 2024 Jan 12.
Article in English | MEDLINE | ID: mdl-38277584

ABSTRACT

The hexatic phase is an intermediate stage in the melting process of a 2D crystal due to topological defects. Recently, this exotic phase was experimentally identified in the vortex lattice of 2D weakly disordered superconducting MoGe by scanning tunneling microscopic measurements. Here, we study this vortex state by the Nernst effect, which is an effective and sensitive tool to detect vortex motion, especially in the superconducting fluctuation regime. We find a surprising Nernst sign reversal at the melting transition of the hexatic phase. We propose that they are a consequence of vortex dislocations in the hexatic state which diffuse preferably from the cold to hot.

2.
Osteoporos Int ; 33(1): 1-12, 2022 Jan.
Article in English | MEDLINE | ID: mdl-34432115

ABSTRACT

The study was conducted to illustrate the effect of Romosozumab in postmenopausal osteoporosis patients. Romosozumab decreased the incidence of vertebral, nonvertebral, and clinical fractures significantly. In addition, decreased incidence of falls and increased bone mineral density at lumbar spine, total hip, and femoral neck was observed. Romosozumab is a monoclonal antibody that acts against the sclerostin pathway leading to enhanced bone formation and reduced bone resorption in patients with osteoporosis. Electronic search was performed on Medline (via PubMed), The Cochrane Central Register of Controlled Trials, and clinicaltrials.gov, till May 2020, for RCTs evaluating the effectiveness of Romosozumab in postmenopausal osteoporosis. RCTs evaluating the effect of Romosozumab on fractures and bone mineral density in postmenopausal osteoporosis patients. Meta-analysis was performed by Cochrane review manager 5 (RevMan) version 5.3. Cochrane risk of bias 2.0 tool and GRADE pro-GDT were applied for methodological quality and overall evidence quality, respectively. One hundred seventy-nine studies were screened, and 10 eligible studies were included in the analysis, with a total of 6137 patients in romosozumab group and 5732 patients in control group. Romosozumab significantly reduced the incidence of vertebral fractures [OR = 0.43 (95%CI = 0.35-0.52), High-quality evidence], nonvertebral fractures [OR = 0.78 (95%CI = 0.66-0.92), High quality], and clinical fractures [OR = 0.70 (95%CI = 0.60-0.82), High quality] at 24 months. Significant reduction in incidence risk of falls [OR = 0.87 (95%CI = 0.78-0.96), High quality] was observed with romosozumab. Bone mineral density was significantly increased in the romosozumab treated groups at lumbar spine [MD = 12.66 (95%CI = 12.66-12.67), High quality], total hip [MD = 5.69 (95%CI = 5.68 - 5.69), Moderate quality], and femoral neck [MD = 5.18 (95%CI = 5.18-5.19), Moderate quality] at 12 months. The total adverse events [RR = 0.98(95%CI = 0.96-1.01), Moderate quality] and serious adverse events [RR = 0.98(95%CI = 0.88-1.08), Moderate quality] with romosozumab were comparable to the control group. The current analysis with evidence on efficacy and safety of Romosozumab, authors opine to recommend the use of Romosozumab treatment for post-menopausal osteoporosis.Systematic review registration: PROSPERO registration number: CRD42019112196.


Subject(s)
Bone Density Conservation Agents , Osteoporosis, Postmenopausal , Antibodies, Monoclonal/adverse effects , Bone Density , Bone Density Conservation Agents/therapeutic use , Female , Humans , Osteoporosis, Postmenopausal/drug therapy
3.
Lett Appl Microbiol ; 75(2): 442-449, 2022 Aug.
Article in English | MEDLINE | ID: mdl-35616177

ABSTRACT

Actinobacillus pleuropneumoniae is the primary aetiological agent of contagious porcine pleuropneumonia associated with serious economic impact on pig husbandry worldwide. Diagnosis of the disease by existing techniques including isolation and identification of bacteria followed by serotyping, serological techniques, conventional PCR, real-time PCR and LAMP assays are cumbersome, time-consuming, costly and not suitable for rapid field application. A novel isothermal polymerase chain reaction (PSR) technique is standardized for all the reagents, incubation time and incubation temperature against A. pleuropneumoniae. The sensitivity of the assay was determined against various dilutions of purified DNA and total bacterial count. The specificity of the assay was determined against 11 closely related bacterial isolates. The relative sensitivity and specificity were compared with bacterial isolation, conventional PCR and real-time PCR assays. The PSR assay for specific detection was standardized at 64°C for 30 min of incubation in a water bath. The result was visible by the naked eye after centrifugation of the reaction mixture or after incorporation of SYBR Green dye as yellowish-green fluorescence. The technique was found to be 100% specific and equally sensitive with real-time PCR and 10 times more sensitive than conventional PCR. The PSR assay could be applicable in the detection of the organisms in porcine nasal swabs spiked with A. pleuropneumoniae. This is the first-ever report on the development of PSR for specific detection of A. pleuropneumoniae and can be applied for early diagnosis at the field level.


Subject(s)
Actinobacillus Infections , Actinobacillus pleuropneumoniae , Mycoplasma , Pleuropneumonia , Swine Diseases , Actinobacillus Infections/diagnosis , Actinobacillus Infections/microbiology , Actinobacillus Infections/veterinary , Actinobacillus pleuropneumoniae/genetics , Animals , Mycoplasma/genetics , Pleuropneumonia/diagnosis , Pleuropneumonia/microbiology , Pleuropneumonia/veterinary , Real-Time Polymerase Chain Reaction/veterinary , Swine , Swine Diseases/diagnosis , Swine Diseases/microbiology
4.
Ann Oncol ; 31(7): 930-941, 2020 07.
Article in English | MEDLINE | ID: mdl-32289380

ABSTRACT

BACKGROUND: We have shown previously in multivariable analysis that black men had 19% lower risk of death than white men with metastatic castration-resistant prostate cancer (mCRPC) treated with a docetaxel and prednisone (DP)-based regimen. The primary goal of this analysis was to compare progression-free survival (PFS), biochemical PFS, ≥50% decline in prostate-specific antigen (PSA) from baseline and objective response rate (ORR) in white, black and Asian men with mCRPC treated with a DP-based regimen. PATIENTS AND METHODS: Individual patient data from 8820 mCRPC men randomized on nine phase III trials to a DP-containing regimen were combined. Race used in the analysis was based on self-report. End points were PFS, biochemical PSA, ≥50% decline in PSA from baseline and ORR. The proportional hazards and the logistic regression models were employed to assess the prognostic importance of race in predicting outcomes adjusting for established prognostic factors. RESULTS: Of 8820 patients, 7528 (85%) were white, 500 (6%) were black, 424 were Asian (5%) and 368 (4%) had race unspecified. Median PFS were 8.3 [95% confidence interval (CI) 8.2-8.5], 8.2 (95% CI 7.4-8.8) and 8.3 (95% CI 7.6-8.8) months in white, black and Asian men, respectively. Median PSA PFS were 9.9 (95% CI 9.7-10.4), 8.5 (95% CI 8.0-10.3) and 11.1 (95% CI 9.9-12.5) months in white, black and Asian men, respectively. CONCLUSIONS: We observed no differences in clinical outcomes by race and ethnic groups in men with mCRPC enrolled on these phase III clinical trials with DP.


Subject(s)
Prostatic Neoplasms, Castration-Resistant , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Disease-Free Survival , Docetaxel/therapeutic use , Ethnicity , Humans , Male , Prednisone/therapeutic use , Prostate-Specific Antigen , Prostatic Neoplasms, Castration-Resistant/drug therapy , Retrospective Studies , Treatment Outcome
5.
J Appl Microbiol ; 128(1): 265-279, 2020 Jan.
Article in English | MEDLINE | ID: mdl-31574191

ABSTRACT

AIMS: Many physiological and microbial characteristics influence the biocontrol performance of the biological control agents (BCAs) in agricultural fields. To implement effective biocontrol, the contribution of specific genes, mechanisms and traits to the biocontrol performance of BCAs need to be characterized and explored in greater detail. METHODS AND RESULTS: In this study, a transposon (Tn) mutant library using the BCA Pseudomonas fluorescens NBC275 (Pf275) was generated to explore genes and bacterial characteristics involved in antifungal activity and biocontrol performance. Among the Tn mutants, 205 strains showing variations in antifungal activity compared to wild-type (WT) were selected and further analysed for biocontrol efficacy against gray mold in pepper fruits. The genes involved in pyoverdine biosynthesis (pvdI and pvdD) and chitin-binding protein (gbpA) played essential roles in the antifungal activity and biocontrol capacity of Pf275. In addition, a mutation in phlD completely abolished the antifungal activity and significantly suppressed the biocontrol ability of the strain. Genes affecting antifungal activity of Pf275 significantly influenced swimming motility, which was identified as an important trait for the biocontrol ability of the bacterial strain. CONCLUSIONS: Overall, our results suggest that antifungal compound production, siderophore biosynthesis and swimming motility synergistically contribute to Pf275 biocontrol performance. The utility of this library was demonstrated by identifying genes for antagonism and biocontrol ability in this BCA strain. The functional roles of many genes identified as contributing to antagonism and in vivo biocontrol activity require further study. SIGNIFICANCE AND IMPACT OF THIS STUDY: Genes contributing to antifungal activity and biocontrol performance of P. fluorescens were identified and highlighted by Tn mutagenesis, which will give insight to improve the biocontrol performance of this BCA.


Subject(s)
Antibiosis/genetics , Biological Control Agents , Genes, Bacterial , Pseudomonas fluorescens/genetics , Antifungal Agents/metabolism , Biological Control Agents/metabolism , Fungi/metabolism , Locomotion/genetics , Mutation , Plant Diseases/microbiology , Siderophores/genetics , Siderophores/metabolism
6.
Dis Esophagus ; 31(3)2018 Mar 01.
Article in English | MEDLINE | ID: mdl-29087474

ABSTRACT

The purpose of this study was to assess the oncological outcomes of a large multicenter series of left thoracoabdominal esophagectomies, and compare these to the more widely utilized Ivor-Lewis esophagectomy. With ethics approval and an established study protocol, anonymized data from five centers were merged into a structured database. The study exposure was operative approach (ILE or LTE). The primary outcome measure was time to death. Secondary outcome measures included time to tumor recurrence, positive surgical resection margins, lymph node yield, postoperative death, and hospital length of stay. Cox proportional hazards models provided hazard ratios (HR) with 95% confidence intervals (CI) adjusting for age, pathological tumor stage, tumor grade, lymphovascular invasion, and neoadjuvant treatment. Among 1228 patients (598 ILE; 630 LTE), most (86%) had adenocarcinoma (AC) and were male (81%). Comparing ILE and LTE for AC patients, no difference was seen in terms of time to death (HR 0.904 95%CI 0.749-1.1090) or time to recurrence (HR 0.973 95%CI 0.768-1.232). The risk of a positive resection margin was also similar (OR 1.022 95%CI 0.731-1.429). Median lymph node yield did not differ between approaches (LTE 21; ILE 21; P = 0.426). In-hospital mortality was 2.4%, significantly lower in the LTE group (LTE 1.3%; ILE 3.6%; P = 0.004). Median hospital stay was 11 days in the LTE group and 14 days in the ILE group (P < 0.0001). In conclusion, this is the largest series of left thoracoabdominal esophagectomies to be submitted for publication and the only one to compare two different transthoracic esophagectomy strategies. It demonstrates oncological equivalence between operative approaches but possible short- term advantages to the left thoracoabdominal esophagectomy.


Subject(s)
Adenocarcinoma/surgery , Esophageal Neoplasms/surgery , Esophagectomy/mortality , Postoperative Complications/etiology , Abdomen/surgery , Adenocarcinoma/mortality , Adult , Aged , Aged, 80 and over , Databases, Factual , Esophageal Neoplasms/mortality , Esophagectomy/methods , Esophagus/surgery , Female , Hospital Mortality , Humans , Length of Stay/statistics & numerical data , Male , Middle Aged , Neoplasm Recurrence, Local/etiology , Neoplasm Recurrence, Local/mortality , Postoperative Complications/mortality , Proportional Hazards Models , Thoracic Cavity/surgery , Time Factors , Treatment Outcome
7.
Acta Virol ; 62(1): 58-62, 2018.
Article in English | MEDLINE | ID: mdl-29521104

ABSTRACT

Hepatitis A virus (HAV) which causes liver disease is recognized by Toll-like receptors (TLRs) through the viral nucleic acid, initiating the host defense response. The study aims to analyze the role of TLR4 rs11536889 polymorphism in the pathogenesis of hepatitis A cases from Assam. There was significant correlation between TLR4 SNP G/C (rs11536889) and between acute viral hepatitis (AVH) A cases and controls. The correlation of the 3 different genotypes GG, GC and CC of TLR4 rs11536889 with the TLR4 mRNA expression level in all the HAV cases groups have been found to be statistically significant (p <0.001). TLR4 expression was most significantly upregulated in the acute HAV cases, HAV with cholestasis cases and even the HAV caused fulminant hepatitis failure (FHF) cases with the CC genotype of TLR4 rs11536889. The upregulation is mostly seen in the cases with the CC genotype of TLR4 rs11536889 and thus indicates that the mutant variant of TLR4 rs11536899 (CC) may have an effect on the expression of TLR4 at the transcription level. Our study did not show any significant association between AVH and HAV caused FHF (p = 0.32, OR = 0; p = 0.59, OR = 2.06 at 95% CI) among the genotypes GG, GC and CC. Our data suggest that TLR4 gene polymorphism rs11536889 may play a prominent role in HAV disease susceptibility and TLR4 expression in population from Assam.


Subject(s)
Hepatitis A/metabolism , Toll-Like Receptor 4/metabolism , Adult , Female , Hepatitis A/epidemiology , Humans , India/epidemiology , Male , Polymorphism, Genetic , Toll-Like Receptor 4/genetics , Young Adult
8.
J Viral Hepat ; 24(5): 397-403, 2017 05.
Article in English | MEDLINE | ID: mdl-27925355

ABSTRACT

Chronic hepatitis C virus (HCV) infection is characterized by high interindividual variability in response to pegylated interferon and ribavirin. A genetic polymorphism on chromosome 19 (rs12979860) upstream of interferon-λ3 (IFNλ3) is associated with a twofold change in sustained virologic response rate after 48 weeks of treatment with pegylated interferon/ribavirin in HCV genotype 1 (GT1) treatment-naïve patients. We conducted epigenetic analysis on the IFNλ3 promoter to investigate whether DNA methylation is associated with response to HCV therapy. DNA samples from HCV GT1-infected subjects receiving an interferon-free paritaprevir-containing combination regimen (N=540) and from HCV-uninfected, healthy controls (N=124) were analysed for IFNλ3 methylation levels. Methylation was strongly associated with rs12979860 allele status whether adjusting for HCV status (r=65.0%, 95% CI: [60.2%, 69.5%]), or not (r=64.4%), both with P<2.2×10-16 . In HCV GT1-infected subjects, C/C genotypes had significantly lower methylation levels relative to C/T or T/T genotypes (P<1×10-14 ), with each T allele resulting in a nine-unit increase in mean methylation level. Methylation levels did not correlate with response in subjects treated for 12 or 24 weeks. However, non-C/C subjects with higher methylation levels were more likely to relapse when treatment duration was 8 weeks. This analysis suggests that methylation status of the IFNλ3 promoter region may be a useful parameter that identifies patients more likely to relapse following HCV therapy; however, continuing therapy for a sufficient duration can overcome this difference. These findings may provide mechanistic insight into the role of IFNλ3 genetic variants in HCV treatment response.


Subject(s)
Antiviral Agents/therapeutic use , DNA Methylation , Epigenesis, Genetic , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/pathology , Interleukins/genetics , Promoter Regions, Genetic , Alleles , Cyclopropanes , Drug Therapy, Combination , Female , Genetic Markers , Humans , Interferons , Lactams, Macrocyclic , Macrocyclic Compounds/therapeutic use , Male , Polymorphism, Single Nucleotide , Proline/analogs & derivatives , Recurrence , Sulfonamides , Treatment Failure
9.
Eur J Clin Microbiol Infect Dis ; 36(11): 2273-2279, 2017 Nov.
Article in English | MEDLINE | ID: mdl-28756561

ABSTRACT

In India, dengue endemic areas overlap with chikungunya-affected areas and both the viruses are transmitted by same vector, Aedes aegypti - thereby increasing opportunity of co-infection by both viruses. Present study was carried out to understand the DENV-CHIKV infection dynamics during recent outbreaks in eastern India (West Bengal state) and its implication on disease manifestations. Blood was collected from 326 symptomatic febrile patients. Patients' serum was subjected to serological diagnosis for presence of anti-dengue-IgM, anti-chikungunya-IgM antibodies and dengue-NS1 antigen by ELISA. Viral RNA was extracted, and presence of dengue virus (DENV) and chikungunya virus (CHIKV) genome, their viral load (VL), and serotype among infected patients' plasma was determined by real-time qRT-PCR. Statistical analysis was performed by using EPI INFO software. DENV and CHIKV were detected in 54% and 33% of symptomatic patients respectively, among whom 23% were harboring both viruses. WHO classified warning signs were detected among 64% DENV patients and 61% DENV-CHIKV double-infected patients. Patients with warning signs always had much higher DEN VL than those without warning signs. Hemorrhagic manifestation and abdominal pain was found in significantly higher frequency among patients with high dengue VL (>10,000 copies/ml). DENV2 was the most predominant serotype among monotypic dengue patients, whereas DENV2-DENV4 combination was most prevalent among patients infected with dual dengue serotypes. This study indicated that DENV-CHIKV double infection and high dengue VL contributed towards severe disease manifestations among infected patients. DENV2 and DENV2-DENV4 combination were the most prevalent serotype(s) found in current outbreak.


Subject(s)
Chikungunya Fever/epidemiology , Chikungunya virus/immunology , Coinfection/virology , Dengue Virus/classification , Dengue Virus/immunology , Dengue/epidemiology , Adolescent , Adult , Antibodies, Viral/blood , Chikungunya Fever/complications , Chikungunya Fever/virology , Chikungunya virus/classification , Child , Child, Preschool , Dengue/complications , Dengue/virology , Disease Outbreaks , Glycoproteins/blood , Humans , Immunoglobulin M/blood , India/epidemiology , Infant , Infant, Newborn , Serogroup , Viral Nonstructural Proteins/blood , Young Adult
10.
Epidemiol Infect ; 145(11): 2212-2220, 2017 08.
Article in English | MEDLINE | ID: mdl-28712383

ABSTRACT

A total of 45 strains of Vibrio cholerae O1 isolated from 10 different places in India where they were associated with cases of cholera between the years 2007 and 2008 were examined by molecular methods. With the help of phenotypic and genotypic tests the strains were confirmed to be O1 El Tor biotype strains with classical ctxB gene. Polymerase chain reaction (PCR) analysis by double - mismatch amplification mutation assay PCR showed 16 of these strains carried the ctxB-7 allele reported in Haitian strains. Sequencing of the ctxB gene in all the 45 strains revealed that in 16 strains the histidine at the 20th amino acid position had been replaced by asparagine and this single nucleotide polymorphism did not affect cholera toxin production as revealed by beads enzyme-linked immunosorbent assay. This study shows that the new ctxB gene sequence was circulating in different places in India. Seven representatives of these 45 strains analysed by pulsed - field gel electrophoresis showed four distinct Not I digested profiles showing that multiple clones were causing cholera in 2007 and 2008.


Subject(s)
Cholera Toxin/genetics , Vibrio cholerae O1/classification , Vibrio cholerae O1/genetics , Bacterial Typing Techniques , Electrophoresis, Gel, Pulsed-Field , Enzyme-Linked Immunosorbent Assay , Genotype , Haiti , India , Sequence Analysis, DNA
11.
Lett Appl Microbiol ; 65(1): 2-10, 2017 Jul.
Article in English | MEDLINE | ID: mdl-28421612

ABSTRACT

As virulence of many pathogenic bacteria is regulated by the phenomenon of quorum sensing (QS), the present study aimed to find the QS-inhibiting (QS-I) property (if any) in 61 Indian medicinal plants. The presence of QS-I compound in the leaf extract was evaluated by its ability to inhibit production of pigment in Chromobacterium violaceum MTCC 2656 (violacein) and Pseudomonas aeruginosa MTCC 2297 (pyocyanin) or swarming of P. aeruginosa MTCC 2297. Extracts of three plants, Astilbe rivularis, Fragaria nubicola and Osbeckia nepalensis, have shown a dose-dependent inhibition of violacein production with no negative effect on bacterial growth. Inhibition of pyocyanin pigment production and swarming motility in P. aeruginosa MTCC 2297 was also shown. Based on the results obtained by gas chromatography-mass spectroscopy (GC-MS) and thin-layer chromatography-direct bioautography (TLC-DB), it was concluded that triterpenes and flavonoid compounds found in the three plant extracts could have QS-I activity. SIGNIFICANCE AND IMPACT OF THE STUDY: A novel alternative prospect to prevent bacterial infections without inhibiting the growth is to apply chemicals that inhibit quorum sensing mechanism of the pathogens. Antiquorum property of 61 medicinal plants was evaluated by the ability of their leaf extract(s) to inhibit production of pigment (violacein in Chromobacterium violaceum MTCC 2656, pyocyanin in Pseudomonas aeruginosa MTCC 2297) or swarming in P. aeruginosa MTCC 2297. The most prospective plants (for the development of quorum sensing inhibitor), showing inhibition of violacein production without affecting bacterial growth, were Astilbe rivularis, Fragaria nubicola and Osbeckia nepalensis.


Subject(s)
Chromobacterium/drug effects , Flavonoids/pharmacology , Indoles/metabolism , Pseudomonas aeruginosa/drug effects , Pyocyanine/biosynthesis , Quorum Sensing/drug effects , Triterpenes/pharmacology , Anti-Bacterial Agents/pharmacology , Fragaria/chemistry , Medicine, Traditional , Melastomataceae/chemistry , Plant Extracts/pharmacology , Plant Leaves/chemistry , Plants, Medicinal/chemistry , Prospective Studies , Saxifragaceae/chemistry
12.
Exp Appl Acarol ; 71(3): 291-301, 2017 Mar.
Article in English | MEDLINE | ID: mdl-28251410

ABSTRACT

Detection of resistance levels against amitraz and malathion in Rhipicephalus (Boophilus) microplus collected from four districts of Jammu region (India) was carried out using the adult immersion test. The regression graphs of probit mortality of ticks plotted against log values of concentration of drugs were utilised for the determination of slope of mortality, lethal concentration for 50% (LC50), 95% (LC95) and resistance factor (RF). On the basis of the data generated on variables (mortality, egg mass weight, reproductive index and percentage inhibition of oviposition) the resistance level was categorised as I, II, III and IV. Out of these four districts, resistance to amitraz was detected at level I in Udhampur (RF = 2.81), Jammu (RF = 2.53) and Samba isolates (RF = 2.24) whereas Rajouri isolate was found susceptible (RF = 1.0). Resistance to malathion was detected at level I in Udhampur (RF = 4.01) and Jammu isolates (RF = 1.76) whereas Rajouri (RF = 0.472) and Samba (RF = 0.199) isolates were found susceptible. The data generated on amitraz and malathion resistance status will help in formulating a tick control strategy in the region.


Subject(s)
Acaricides/pharmacology , Insecticide Resistance , Malathion/pharmacology , Rhipicephalus/drug effects , Toluidines/pharmacology , Animals , Female , India
14.
J Viral Hepat ; 23(2): 96-104, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26436610

ABSTRACT

Circulating microRNAs (miRNA) have been intensely investigated as biomarkers in disease and therapy. Several studies have identified miR-122 as an important regulator of HCV replication. The effect of new therapies that directly target the HCV replication life cycle on circulating microRNA levels has not been elucidated. We performed expression profiling of circulating miRNA in serum in subjects treated with HCV direct-acting antiviral agents (DAAs). Serum miRNA levels were evaluated from two studies in HCV GT1-infected treatment-naïve subjects and prior nonresponders to pegylated interferon (pegIFN) and ribavirin (RBV) who received paritaprevir/ritonavir + dasabuvir + RBV for 12 weeks, and in treatment-naïve genotype (GT)1-3-infected subjects who received paritaprevir/ritonavir + ombitasvir ± RBV for 12 weeks. Over 100 different miRNA species were detected in serum. Of these, levels of miR-122 showed the most consistent change in response to treatment across all HCV genotypes. In all subjects, miR-122 showed an average four-fold reduction between baseline and week 2, and remained below baseline through post-treatment week 12 in subjects who achieved sustained virological response. In contrast, in subjects who did not achieve SVR, miR-122 levels began to return to baseline levels after the second week of treatment. The change in miR-122 levels was similar across genotypes, and was comparable with or without RBV. This is the first report comparing expression levels of circulating miRNA in HCV GT1-3 subjects treated with IFN-free combinations of DAAs. The results suggest that serum levels of miR-122 are reduced following treatment in subjects who achieve SVR, and correlate with HCV RNA levels across genotypes.


Subject(s)
Antiviral Agents/therapeutic use , Hepacivirus/drug effects , Hepatitis C, Chronic/blood , Hepatitis C, Chronic/drug therapy , MicroRNAs/blood , 2-Naphthylamine , Anilides/therapeutic use , Biomarkers/blood , Carbamates/therapeutic use , Cyclopropanes , Drug Therapy, Combination , Humans , Lactams, Macrocyclic , Macrocyclic Compounds/therapeutic use , MicroRNAs/genetics , Proline/analogs & derivatives , Sulfonamides/therapeutic use , Uracil/analogs & derivatives , Uracil/therapeutic use , Valine , Virus Replication/genetics
15.
Br J Clin Pharmacol ; 81(5): 929-40, 2016 May.
Article in English | MEDLINE | ID: mdl-26710243

ABSTRACT

AIMS: Paritaprevir is a direct acting antiviral agent for use as part of a multidrug hepatitis C virus infection treatment regimen. To characterize the pharmacokinetics, safety, and tolerability of paritaprevir and determine an optimal dosing regimen for subsequent evaluations, clinical studies were conducted with paritaprevir alone or with ritonavir, a cytochrome P450 3A4 inhibitor anticipated to increase paritaprevir exposure. METHODS: Two phase 1, double-blind, placebo-controlled, parallel group studies were conducted in healthy volunteers (NCT00850044 and NCT00931281). Single dose study participants (n = 87) were randomized to one time administration of either paritaprevir or placebo, or paritaprevir with ritonavir or placebo. Participants (n = 38) enrolled in the multiple dose study received paritaprevir with ritonavir or placebo once or twice daily for 14 days. Pharmacokinetics, safety and tolerability were assessed throughout the study treatment periods. RESULTS: After single or multiple dose administration, paritaprevir displayed non-linear pharmacokinetics, with maximum plasma concentration and area under the plasma concentration-time curve increasing in a greater than dose proportional manner. Concomitant administration of 100 mg ritonavir increased paritaprevir exposure from a 300 mg dose approximately 30- to 50-fold and extended paritaprevir half-life. The tolerability of paritaprevir was similar with or without ritonavir. Asymptomatic, transient increases in bilirubin were observed but were not associated with abnormalities in other liver function tests. CONCLUSIONS: Paritaprevir exhibits non-linear pharmacokinetics with greater than dose proportional increases in exposure after single or multiple dosing. Co-administration with ritonavir increases paritaprevir exposure and half-life without adversely influencing tolerability.


Subject(s)
Antiviral Agents/pharmacokinetics , Cytochrome P-450 CYP3A Inhibitors/pharmacokinetics , Hepatitis C, Chronic/drug therapy , Macrocyclic Compounds/pharmacokinetics , Ritonavir/pharmacokinetics , Adult , Antiviral Agents/adverse effects , Bilirubin/blood , Cyclopropanes , Cytochrome P-450 CYP3A Inhibitors/administration & dosage , Cytochrome P-450 CYP3A Inhibitors/adverse effects , Double-Blind Method , Drug Interactions , Drug Therapy, Combination , Female , Half-Life , Healthy Volunteers , Humans , Lactams, Macrocyclic , Macrocyclic Compounds/adverse effects , Macrocyclic Compounds/therapeutic use , Male , Middle Aged , Proline/analogs & derivatives , Ritonavir/administration & dosage , Ritonavir/adverse effects , Sulfonamides , Young Adult
16.
Am J Transplant ; 15(5): 1313-22, 2015 May.
Article in English | MEDLINE | ID: mdl-25708713

ABSTRACT

ABT-450, ombitasvir, and dasabuvir are direct-acting antiviral agents (DAAs) that have been developed for combination treatment of chronic hepatitis C virus (HCV) infection. Because these DAAs have metabolic and transporter profiles that overlap with cyclosporine and tacrolimus disposition, there is potential for drug interactions. Two Phase 1 studies assessed effects of ABT-450 (150 mg coadministered with ritonavir 100 mg once daily), ombitasvir (25 mg once daily), and dasabuvir (400 mg twice daily) on the pharmacokinetics, safety, and tolerability of a single dose of cyclosporine (30 mg) or tacrolimus (2 mg) in healthy volunteers (N = 12 per study). In the presence of steady-state concentrations of all 3 DAAs, dose-normalized cyclosporine concentration at 24 hours (C24), and area under the concentration-time curve from time 0 to infinity (AUC(∞)) were 15.8-fold and 5.8-fold, respectively, and dose-normalized tacrolimus C24 and AUC(∞) were 17-fold and 57-fold, respectively, of either agent alone. Cyclosporine and tacrolimus half-lives increased from 7 to 25 h and 32 to 232 h, respectively. There were no major safety or tolerability issues in these studies. The results suggest that cyclosporine and tacrolimus doses and dosing frequency should be reduced in HCV-infected posttransplant patients being treated with this 3-DAA regimen.


Subject(s)
Anilides/administration & dosage , Antiviral Agents/administration & dosage , Carbamates/administration & dosage , Cyclosporine/administration & dosage , Hepatitis C/drug therapy , Macrocyclic Compounds/administration & dosage , Sulfonamides/administration & dosage , Tacrolimus/administration & dosage , Uracil/analogs & derivatives , 2-Naphthylamine , Adolescent , Adult , Anilides/pharmacokinetics , Antiviral Agents/pharmacokinetics , Area Under Curve , Carbamates/pharmacokinetics , Cyclopropanes , Cyclosporine/pharmacokinetics , Drug Administration Schedule , Female , Healthy Volunteers , Hepacivirus/drug effects , Humans , Lactams, Macrocyclic , Macrocyclic Compounds/pharmacokinetics , Male , Middle Aged , Proline/analogs & derivatives , Sulfonamides/pharmacokinetics , Tacrolimus/pharmacokinetics , Uracil/administration & dosage , Uracil/pharmacokinetics , Valine , Young Adult
17.
Acta Neurol Scand ; 132(3): 203-11, 2015 Sep.
Article in English | MEDLINE | ID: mdl-25689886

ABSTRACT

BACKGROUND: Disability-adjusted life year (DALY) is a time-based measure of disease burden incorporating both disability and mortality. Our study aimed to determine the DALY lost from epilepsy in an Indian metropolis. METHODS: A population-based prospective study on epilepsy was conducted over 5 years (2003-8) in Kolkata, India, on randomly selected 100,802 subjects (males 53,209, females 47,593) to assess prevalence as well as to capture incident cases of epilepsy and those incident cases that died. Standard case definitions were used. The data were used to estimate years of life lost (YLL) due to premature mortality, years of life lived with disability (YLD), and DALY, utilizing the prevalence-based Global Burden of Disease (GBD) 2010 approach. Age- and gender-specific figures were computed. RESULTS: During 2003-2004, a total of 476 subjects with active epilepsy were detected and the age-adjusted prevalence rate was 4.71 per 1000. Over 5 years, there were 197 incident cases of epilepsy of whom 26 died. The age-adjusted annual incidence rate of epilepsy was 38.3 per 100,000. The all-cause standardized mortality rate (SMR) of epilepsy was 2.4. The burden of epilepsy in the year 2007-8 revealed the overall YLL was 755 per 100,000, and the overall YLD ranged from 14.45 to 31.0 per 100,000 persons depending on the clinical severity of the epilepsy. Both YLL and YLD values were higher in males than in females. The overall DALY lost due to epilepsy in 2007-8 was found to be 846.96 (males 1183.04, females 463.81) per 100,000. CONCLUSIONS: This is the first study in India to determine the DALY of epilepsy using GBD 2010. The results reveal a substantial burden of epilepsy in our setting. Similar such studies are needed in other parts of India in both urban and rural settings.


Subject(s)
Cost of Illness , Epilepsy/epidemiology , Adult , Aged , Asian People , Female , Humans , India/epidemiology , Male , Middle Aged , Prevalence , Prospective Studies , Quality-Adjusted Life Years , Rural Population
18.
Exp Appl Acarol ; 67(1): 147-57, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26071101

ABSTRACT

Detection of resistance levels against deltamethrin and cypermethrin in Rhipicephalus (Boophilus) microplus collected from Jammu (India) was carried out using larval packet test (LPT). The results showed the presence of resistance level II and I against deltamethrin and cypermethrin, respectively. Adult immersion test (AIT) and LPT were used to evaluate the in vitro efficacy of ethanolic and aqueous floral extracts of Calendula officinalis against synthetic pyrethroid resistant adults and larvae of R. (B.) microplus. Four concentrations (1.25, 2.5, 5 and 10 %) of each extract with four replications for each concentration were used in both the bioassays. A concentration dependent mortality was observed and it was more marked with ethanolic extract. In AIT, the LC50 values for ethanolic and aqueous extracts were calculated as 9.9 and 12.9 %, respectively. The egg weight of the live ticks treated with different concentrations of the ethanolic and aqueous extracts was significantly lower than that of control ticks; consequently, the reproductive index and the percent inhibition of oviposition values of the treated ticks were reduced. The complete inhibition of hatching was recorded at 10 % of ethanolic extract. The 10 % extracts caused 100 % mortality of larvae after 24 h. In LPT, the LC50 values for ethanolic and aqueous extracts were determined to be 2.6 and 3.2 %, respectively. It can be concluded that the ethanolic extract of C. officinalis had better acaricidal properties against adults and larvae of R. (B.) microplus than the aqueous extract.


Subject(s)
Acaricides/pharmacology , Calendula/chemistry , Plant Extracts/pharmacology , Rhipicephalus/drug effects , Animals , Female , Flowers/chemistry , India , Larva/drug effects , Nitriles/pharmacology , Pyrethrins/pharmacology , Rhipicephalus/growth & development
19.
J Obstet Gynaecol ; 35(4): 362-7, 2015 May.
Article in English | MEDLINE | ID: mdl-25384080

ABSTRACT

A total of 200 women planned for labour induction were randomised to receive high-dose oxytocin (6 mU/min with similar increments every 45 min) or intermediate-dose oxytocin (3 mU/min with similar increments every 45 min). Oxytocin solution was prepared with 30 units in 500 ml saline with which the infusion rate in ml/h is numerically equal to oxytocin in mU/min. We observed that the caesarean rate (18% vs 6%, p = 0.009), contraction abnormalities (35% vs 14%, p = 0.0005) and neonatal bilirubin levels (7.99 ± 2.70 vs 6.80 ± 2.65, p = 0.002) were higher with high-dose than with intermediate-dose. The induction-delivery interval (IDI) was similar (10 h 13 min with high-dose and 11 h 5 min with intermediate-dose; p = 0.237, NS). Nulliparous women benefited more with intermediate-dose as the caesarean rate was higher with high-dose (24.6% vs 7.9%, p = 0.011). Although the caesarean rate was higher in multiparous women with high-dose oxytocin, it was statistically not significant (5.7% vs 2.7%; p = 0.609). Oxytocin regimens for labour induction are usually high-dose (4-6 mU/min) or low-dose (1-1.5 mU/min). The former is associated with more contraction abnormalities and the latter with prolonged IDI; both result in an increased caesarean rate. In order to offset these disadvantages, an intermediate- dose regimen was selected. The increment interval of 45 min was selected in accordance with the pharmacokinetics of oxytocin. We observed a lower caesarean rate when compared with the high-dose regimen, without any increase in the IDI. Hence, we propose that the intermediate-dose oxytocin regimen should be preferred to the high-dose regimen for labour induction.


Subject(s)
Labor, Induced , Oxytocin , Uterine Contraction/drug effects , Adult , Cesarean Section/methods , Cesarean Section/statistics & numerical data , Dose-Response Relationship, Drug , Drug Monitoring/methods , Female , Humans , Labor, Induced/adverse effects , Labor, Induced/methods , Oxytocics/administration & dosage , Oxytocics/pharmacokinetics , Oxytocin/administration & dosage , Oxytocin/pharmacokinetics , Pregnancy , Pregnancy Outcome , Treatment Outcome
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