bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characteristics of Genetic Hitchhiking around Dihydrofolate Reductase Gene Associated with Pyrimethamine Resistance in
Plasmodium falciparum
Isolates from India
Authors: Lumb Vanshika , Das Manoj K. , Singh Neeru , Dev Vas , Wajihullah  , Sharma Yagya D. 
Published: September 2009

ABSTRACT

Sulfadoxine-pyrimethamine (SP) resistance in
Plasmodium falciparum
has been widespread across continents, causing the major hurdle of controlling malaria. Resistance is encoded mainly by point mutations in
P. falciparum
dihydrofolate reductase (
pfdhfr
) and dihydropteroate synthase (
pfdhps
) target genes. To study the origin and evolution of pyrimethamine resistance on the Indian subcontinent, microsatellite markers flanking the
pfdhfr
gene were mapped. Here we describe the characteristics of genetic hitchhiking around the
pfdhfr
gene among 190
P. falciparum
isolates. These isolates were collected from five different geographical regions of India (Uttar Pradesh, Madhya Pradesh, Assam, Orissa, and Andaman and Nicobar Islands) where malarial transmission rates and levels of drug resistance vary across regions. Among the isolates, we observed a significant reduction in genetic variation in the ±20-kb vicinity of the mutant
pfdhfr
alleles due to hitchhiking. This reduction in genetic diversity was more prominent around quadruple
pfdhfr
alleles (heterozygosity [
H
e
] = 0.23) than around double (
H
e
= 0.365) and single (
H
e
= 0.465) mutant alleles. Asymmetry in the selective sweep flanking the
pfdhfr
alleles was observed with regional isolates, emphasizing the drug usage with the parasite population. All the
pfdhfr
alleles share a single microsatellite haplotype and seem to have originated from a single progenitor similar to that of Southeast Asian (Thailand)
pfdhfr
mutants. Results of the present study also indicate that the emergence of drug-resistant alleles is a recent phenomenon in India compared to Southeast Asian countries.
Atomic Force Microscopy Investigation of the Morphology and Topography of Colistin-Heteroresistant
Acinetobacter baumannii
Strains as a Function of Growth Phase and in Response to Colistin Treatment
Authors: Soon Rachel L. , Nation Roger L. , Hartley Patrick G. , Larson Ian , Li Jian 
Published: September 2009

ABSTRACT

The prevalence of infections caused by multidrug-resistant gram-negative
Acinetobacter baumannii
strains and the lack of novel antibiotics under development are posing a global dilemma, forcing a resurgence of the last-line antibiotic colistin. Our aim was to use atomic force microscopy (AFM) to investigate the morphology and topography of paired colistin-susceptible and -resistant cells from colistin-heteroresistant
A. baumannii
strains as a function of bacterial growth phase and colistin exposure. An optimal AFM bacterial sample preparation protocol was established and applied to examine three paired strains. Images revealed rod-shaped colistin-susceptible cells (1.65 ± 0.27 μm by 0.98 ± 0.07 μm) at mid-logarithmic phase, in contrast to spherical colistin-resistant cells (1.03 ± 0.09 μm); the latter were also more diverse in appearance and exhibited a rougher surface topography (7.05 ± 1.3 nm versus 11.4 ± 2.5 nm for susceptible versus resistant, respectively). Cellular elongation up to ∼18 μm at stationary phase was more commonly observed in susceptible strains, although these “worm-like” cells were also observed occasionally in the resistant population. The effects of colistin exposure on the cell surface of colistin-susceptible and -resistant cells were found to be similar; topographical changes were minor in response to 0.5 μg/ml colistin; however, at 4 μg/ml colistin, a significant degree of surface disruption was detected. At 32 μg/ml colistin, cellular clumping and surface smoothening were evident. Our study has demonstrated for the first time substantial morphological and topographical differences between colistin-susceptible and -resistant cells from heteroresistant
A. baumannii
strains. These results contribute to an understanding of colistin action and resistance in regard to this problematic pathogen.
Correlation of In Vitro Activity, Serum Levels, and In Vivo Efficacy of Posaconazole against
Rhizopus microsporus
in a Murine Disseminated Infection
Authors: Rodríguez M. Mar , Pastor F. Javier , Calvo Enrique , Salas Valentina , Sutton Deanna A. , Guarro Josep 
Published: September 2009

ABSTRACT

A broth microdilution method was used to evaluate the in vitro activities of seven antifungal agents against 15 clinical strains of
Rhizopus microsporus
. Amphotericin B (AMB) and posaconazole (POS) were the most active drugs. In a model of disseminated
R. microsporus
infection in immunosuppressed mice, we studied the efficacy of POS administered once or twice daily against four of the strains previously tested in vitro and compared it with that of liposomal AMB (LAMB). LAMB was the most effective treatment for the two strains with intermediate susceptibility to POS. For the two POS-susceptible strains, LAMB and POS at 20 mg/kg of body weight twice a day orally showed similar efficacies. The in vivo efficacy of POS administered twice a day orally correlated with the in vitro susceptibility data and the serum drug concentrations.
Impact of Antifungal Prophylaxis on Colonization and Azole Susceptibility of
Candida
Species
Authors: Mann Paul A. , McNicholas Paul M. , Chau Andrew S. , Patel Reena , Mendrick Cara , Ullmann Andrew J. , Cornely Oliver A. , Patino Hernando , Black Todd A. 
Published: September 2009

ABSTRACT

Two large studies compared posaconazole and fluconazole or itraconazole for prophylaxis in subjects undergoing allogeneic hematopoietic stem cell transplantation or subjects with acute myelogenous leukemia. To assess the impact of prophylaxis on colonization and the development of resistance in
Saccharomyces
yeasts, identification and susceptibility testing were performed with yeasts cultured at regular intervals from mouth, throat, and stool samples. Prior to therapy, 34 to 50% of the subjects were colonized with yeasts. For all three drugs, the number of positive
Candida albicans
cultures decreased during drug therapy. In contrast, the proportion of subjects with positive
C. glabrata
cultures increased by two- and fourfold in the posaconazole and itraconazole arms, respectively. Likewise, in the fluconazole arm the proportion of subjects with positive
C. krusei
cultures increased twofold.
C. glabrata
was the species that most frequently exhibited decreases in susceptibility, and this trend did not differ significantly between the prophylactic regimens. For the subset of subjects from whom colonizing
C. glabrata
isolates were recovered at the baseline and the end of treatment, approximately 40% of the isolates exhibited more than fourfold increases in MICs during therapy. Molecular typing of the
C. albicans
and
C. glabrata
isolates confirmed that the majority of the baseline and end-of-treatment isolates were closely related, suggesting that they were persistent colonizers and not newly acquired. Overall breakthrough infections by
Candida
species were very rare (∼1%), and
C. glabrata
was the colonizing species that was the most frequently associated with breakthrough infections.
Spread of
bla
CTX-M-14
Is Driven Mainly by IncK Plasmids Disseminated among
Escherichia coli
Phylogroups A, B1, and D in Spain
Authors: Valverde Aránzazu , Cantón Rafael , Garcillán-Barcia M. Pilar , Novais Ângela , Galán Juan Carlos , Alvarado Andrés , de la Cruz Fernando , Baquero Fernando , Coque Teresa M. 
Published: September 2009

ABSTRACT

Since its first description in 2000, CTX-M-14 has become one of the most widespread extended-spectrum β-lactamases in Spain. In the present
Escherichia coli
multilevel population genetic study involving the characterization of phylogroups, clones, plasmids, and genetic platforms, 61 isolates from 16 hospitalized patients and 40 outpatients and healthy volunteers recovered from 2000 to 2005 were analyzed. Clonal relatedness (XbaI pulsed-field gel electrophoresis [PFGE] type, phylogenetic group, multilocus sequence type [MLST]) was established by standard methods. Analysis of transferred plasmids (I-
Ceu
I; S1 nuclease; restriction fragment length polymorphism analysis; and analysis of RNA interference, replicase, and relaxase) was performed by PCR, sequencing, and hybridization. The genetic environment of
bla
CTX-M-14
was characterized by PCR on the basis of known associated structures (IS
Ecp1
, IS
903
, IS
CR1
). The isolates were mainly recovered from patients in the community (73.8%; 45/61) with urinary tract infections (62.2%; 28/45). They were clonally unrelated by PFGE and corresponded to phylogenetic groups A (36.1%), D (34.4%), and B1 (29.5%). MLST revealed a high degree of sequence type (ST) diversity among phylogroup D isolates and the overrepresentation of the ST10 complex among phylogroup A isolates and ST359/ST155 among phylogroup B1 isolates. Two variants of
bla
CTX-M
-14
previously designated
bla
CTX-M-14a
(
n
= 59/61) and
bla
CTX-M-14b
(
n
= 2/61) were detected.
bla
CTX-M-14a
was associated with either IS
Ecp1
within IncK plasmids (
n
= 27), IS
CR1
linked to an IncHI2 plasmid (
n
= 1), or IS
CR1
linked to IncI-like plasmids (
n
= 3). The
bla
CTX-M-14b
identified was associated with an IS
CR1
element located in an IncHI2 plasmid (
n
= 1) or with IS
Ecp1
located in IncK (
n
= 1). The CTX-M-14-producing
E. coli
isolates in our geographic area are frequent causes of community-acquired urinary tract infections. The increase in the incidence of such isolates is mostly due to the dissemination of IncK plasmids among
E. coli
isolates of phylogroups A, B1, and D.
Cellular Targeting of Engineered Heterologous Antigens Is a Determinant Factor for Bovine Herpesvirus 4-Based Vaccine Vector Development
Authors: Donofrio Gaetano , Franceschi Valentina , Capocefalo Antonio , Taddei Simone , Sartori Chiara , Bonomini Sabrina , Cavirani Sandro , Cabassi Clotilde S. , Flammini Cesidio F. 
Published: October 2009

ABSTRACT
In a previous study, an apathogenic strain of bovine herpesvirus 4 (BoHV-4) cloned as a bacterial artificial chromosome and expressing a chimeric peptide (gE2/gD) as a secreted form was described. Recombinant virus-inoculated animals produced antibodies against bovine viral diarrhea virus (BVDV) gE2 and BoHV-1 gD. However, neutralizing antibodies were produced only against BVDV, not against BoHV-1. In the present work a recombinant BoHV-4 expressing a membrane-linked form of gE2/gD chimeric peptide was constructed, and inoculated rabbits produced serum-neutralizing antibodies against both BVDV and BoHV-1. Protein cell sorting and targeting are a very important issue when immunodominant antigens are engineered for recombinant virus vaccine development.
MyD88-Deficient Mice Exhibit Decreased Parasite-Induced Immune Responses but Reduced Disease Severity in a Murine Model of Neurocysticercosis
Authors: Mishra Bibhuti B. , Gundra Uma Mahesh , Wong Kondi , Teale Judy M. 
Published: September 2009

ABSTRACTThe symptomatic phase of neurocysticercosis (NCC), a parasitic disease of the central nervous system (CNS) in humans, is characterized by inflammatory responses leading to neuropathology and, in some cases, death. In an animal model of NCC in which mice were intracranially inoculated with the parasiteMesocestoides corti, the infection in mice lacking the myeloid differentiation primary response gene 88 (MyD88−/−) resulted in decreased disease severity and improved survival compared with that in wild-type (WT) mice. The CNS of MyD88−/−mice was more quiescent, with decreased microgliosis and tissue damage. These mice exhibited substantially reduced primary and secondary microglial nodule formations and lacked severe astrogliotic reactions, which were seen in WT mice. Significantly reduced numbers of CD11b+myeloid cells, αβ T cells, γδ T cells, and B cells were present in the brains of MyD88−/−mice in comparison with those of WT mice. This decrease in cellular infiltration correlated with a decrease in blood-brain barrier permeability, as measured by reduced fibrinogen extravasation. Comparisons of cytokine expression indicated a significant decrease in the CNS levels of several inflammatory mediators, such as tumor necrosis factor alpha, gamma interferon, CCL2, and interleukin-6, during the course of infection in MyD88−/−mice. Collectively, these findings suggest that MyD88 plays a prominent role in the development of the hyperinflammatory response, which in turn contributes to neuropathology and disease severity in NCC.
Vaccination with the ML0276 Antigen Reduces Local Inflammation but Not Bacterial Burden during Experimental
M
ycobacterium
leprae
Infection
Authors: Raman Vanitha S. , O'Donnell Joanne , Bailor H. Remy , Goto Wakako , Lahiri Ramanuj , Gillis Thomas P. , Reed Steven G. , Duthie Malcolm S. 
Published: September 2009

ABSTRACT

Leprosy elimination has been a goal of the WHO for the past 15 years. Widespread BCG vaccination and multidrug therapy have dramatically reduced worldwide leprosy prevalence, but new case detection rates have remained relatively constant. These data suggest that additional control strategies, such as a subunit vaccine, are required to block transmission and to improve leprosy control. We recently identified several
M
ycobacterium
leprae
antigens that stimulate gamma interferon (IFN-γ) secretion upon incubation with blood from paucibacillary leprosy patients, a group who limit
M. leprae
growth and dissemination. In this study, we demonstrate that
M. leprae
-specific mouse T-cell lines recognize several of these antigens, with the ML0276 protein stimulating the most IFN-γ secretion. We then examined if the ML0276 protein could be used in a subunit vaccine to provide protection against experimental
M. leprae
infection. Our data demonstrate that combining ML0276 with either a Toll-like receptor 4 (TLR4) (EM005), TLR7 (imiquimod), or TLR9 (CpG DNA) agonist during immunization induces Th1 responses that limit local inflammation upon experimental
M. leprae
infection. Our data indicate that only the ML0276/EM005 regimen is able to elicit a response that is transferable to recipient mice. Despite the potent Th1 response induced by this regimen, it could not provide protection in terms of limiting bacterial growth. We conclude that EM005 is the most potent adjuvant for stimulating a Th1 response and indicate that while a subunit vaccine containing the ML0276 protein may be useful for the prevention of immune pathology during leprosy, it will not control bacterial burden and is therefore unlikely to interrupt disease transmission.
How-to guide on biomarkers: biomarker definitions, validation and applications with examples from cardiovascular disease
Authors: Puntmann V O 
Published: September 2009

Abstract
A biomarker is a characteristic that can be objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention. Many commonly used tests in clinical practice can serve as biomarkers. The majority have been identified on the basis of insight or underlying physiology or biological mechanisms. With increasing knowledge and practical experience, some of these tests have evolved into a measurable end point in clinical research, applied as an indicator of change, for the better or worse. The traditional identification of biomarkers as an observational side product of clinical practice is increasingly turning into an industrialised process of biomarker discovery, supported by standardised paradigms of biomarker validation and translation from bench to bedside. The potential utility of biomarkers in clinical studies, investigating either new treatments or new strategies of clinical management, is capitalising on recent advances in technology, from molecular sciences to powerful imaging, bearing the promise of expediting the discovery of new treatments. In the active search for new biomarkers, many potential candidates can be considered side by side, allowing many failures but a few great winners. Biomarker discovery is an ongoing process, with translation being tested de novo in every single study, providing us with the opportunity to revise our knowledge of the complex scheme of human physiology and pathophysiology. In predicting what Nature has set in place, advances in technology may be only the first step. This review provides an introduction to the field of biomarker discovery and translation. It deals with evolving nomenclature, basic principles of the validation process, and, drawing on examples in cardiovascular medicine, their significance for clinical application.
A gene-based risk score for lung cancer susceptibility in smokers and ex-smokers
Authors: Young R P , Hopkins R J , Hay B A , Epton M J , Mills G D , Black P N , Gardner H D , Sullivan R , Gamble G D 
Published: September 2009

Abstract

Background
Epidemiological and family studies suggest that lung cancer results from the combined effects of age, smoking and genetic factors. Chronic obstructive pulmonary disease (COPD) is also an independent risk factor for lung cancer and coexists in 40–60% of lung cancer cases.

Methods
In a two-stage case–control association study, genetic markers associated with either susceptibility or protection against lung cancer were identified. In a test cohort of 439 Caucasian smokers or ex-smokers, consisting of healthy smokers and lung cancer cases, 157 candidate single nucleotide polymorphisms (SNPs) were screened. From this, 30 SNPs were identified, the genotypes (codominant or recessive model) of which were associated with either the healthy smokers (protective) or lung cancer (susceptibility) phenotype. After genotyping of this 30-SNP panel in a second validation cohort of 491 subjects and using the same protective and susceptibility genotypes from our test cohort, a 20-SNP panel was selected on the basis of independent univariate analyses.

Results
Using multivariate logistic regression, including the 20 SNPs, it was also found that age, history of COPD, family history of lung cancer and gender were significantly and independently associated with lung cancer.

Conclusions
When numeric scores were assigned to both the SNP and demographic data, and sequentially combined by a simple algorithm in a risk model, the composite score was found to be linearly related to lung cancer risk with a bimodal distribution. Genetic data may therefore be combined with other risk variables from smokers or ex-smokers to identify individuals who are most susceptible to developing lung cancer.
Quantification of the relationship between glycemia and β-cell mass adaptation in vivo
Authors: Atkinson Laura L. , Topp Brian G. , Au Jenny , Vinerian Horatiu V. , Dhatt Narinder , Finegood Diane T. 
Published: September 2009

β-cell mass dynamics play an important role in the adaptation to obesity, as well as in the pathogenesis of type 2 diabetes. Here we used a 24-hour modified hyperglycemic clamp protocol to investigate the effect of increasing glucose concentrations (15, 20, 25, or 35 mmol/L) on β-cell mass and rates of β-cell replication, death, and neogenesis in 6-week-old Sprague Dawley rats (n = 40). During the first 4 h of glucose infusion, plasma insulin levels rose to an approximate steady state in each group, but by the end of 24 h, there was no difference in insulin levels between any of the groups. There was also no difference in β-cell mass between groups. Mean β-cell replication rates displayed a linear relationship to mean plasma glucose levels in all hyperglycemic animals (r2 = 0.98, p < 0.05). Relative to the uninfused basal control animals, replication rates were significantly reduced in the 15 mmol/L glucose group. The percentage of TUNEL-positive β-cells was not different between groups. There was also no significant difference in markers of neogenesis. Thus, these data demonstrate that hyperglycemia for 24 h had no effect on β-cell mass, death, or neogenesis in 6-week-old Sprague Dawley rats. We demonstrate a linear relationship, however, between hyperglycemia and β-cell replication rates in vivo.
Wet and dry extraction of coconut oil: impact on lipid metabolic and antioxidant status in cholesterol coadministered rats
Authors: Nevin K. Govindan , Rajamohan Thankappan 
Published: September 2009

Because coconut oil extracted by wet process (virgin coconut oil, VCO) is gaining popularity among consumers, this study was conducted to evaluate VCO compared with coconut oil extracted by dry process (copra oil, CO) for their influence on lipid parameters, lipid peroxidation, and antioxidant status in rats coadministered with cholesterol. VCO, CO, and cholesterol were fed in a semi-synthetic diet to 24 male Sprague–Dawley rats for 45 days. After the experimental period, lipid and lipid peroxide levels and antioxidant enzyme activities were observed. Chemical composition and antioxidant properties of the polyphenolic fraction from VCO and CO were also analyzed. The results showed that lipid and lipid peroxide levels were lower in VCO-fed animals than in animals fed either CO or cholesterol alone. Antioxidant enzyme activities in VCO-fed animals were comparable with those in control animals. Although the fatty acid profiles of both oils were similar, a significantly higher level of unsaponifiable components was observed in VCO. Polyphenols from VCO also showed significant radical-scavenging activity compared with those from CO. This study clearly indicates the potential benefits of VCO over CO in maintaining lipid metabolism and antioxidant status. These effects may be attributed in part to the presence of biologically active minor unsaponifiable components.
Effects of cadmium on cardiac metallothionein induction and ischemia–reperfusion injury in rats
Authors: Devaux Sylvie , Maupoil Véronique , Berthelot Alain 
Published: September 2009

Myocardial ischemia–reperfusion injury is associated with an imbalance between the formation and the scavenging of reactive oxygen species. In this context, the protective role of the antioxidant metallothionein, a thiol-rich protein that is induced in different organs in response to heavy metals and oxidative conditions, has mainly been investigated in metallothionein-knockout mice or metallothionein-overexpressing mice. The aim of this study was to evaluate whether the administration of cadmium has a protective effect against cardiac ischemia–reperfusion injury and whether this is associated with induction of in vivo cardiac metallothionein. Forty-eight hours after an injection of 0, 1, or 2 mg/kg cadmium, isolated perfused rat hearts were submitted to 30 min of total global ischemia and 30 min of reperfusion.   The ischemia–reperfusion sequence was associated with a significant decrease in cardiac metallothionein levels. Pretreatment with cadmium at a dose of 2 mg/kg (i) prevented this decrease and (ii) improved the postischemic recuperation of the coronary flow, the ventricular developed pressure, and therefore, the global postischemic functional recovery. These results showed that pretreatment of rats with 2 mg/kg cadmium induced cardioprotection against ischemia–reperfusion injuries, perhaps through an in vivo metallothionein induction that may be related to a metal activation of antioxidant systems.