scholarly journals Blocking antibodies against integrin-α3, integrin-αM, and integrin-αMβ2 de-differentiate myofibroblasts and reverse lung and kidney fibroses in a mouse model

2021 ◽  
Author(s):  
MICHAEL WHITE ◽  
melis ozkan ◽  
Michal Raczy ◽  
Jorge Emiliano Gomez Medellin ◽  
Kyle M Koss ◽  
...  
Keyword(s):  
United States ◽  
Cell Adhesion ◽  
Mouse Model ◽  
The United States ◽  
Myofibroblast Differentiation ◽  
Α3 Integrin ◽  
Blocking Antibodies ◽  
Lung And Kidney

Fibrosis is involved in 45% of deaths in the United States, and no treatment exists to reverse the progression of the disease. Myofibroblasts are key to the progression and maintenance of fibrosis. We investigated features of cell adhesion necessary for monocytes to differentiate into myofibroblasts, seeking to identify pathways key to myofibroblast differentiation. Blocking antibodies against integrins α3, αM, and αMβ2 de-differentiate myofibroblasts in vitro, lower the pro-fibrotic secretome of myofibroblasts, and reverse fibrosis in vivo. Blocking key integrins may be an effective therapeutic for the treatment and reversal of fibrosis.

scholarly journals USA300 and USA500 Clonal Lineages of Staphylococcus aureus Do Not Produce a Capsular Polysaccharide Due to Conserved Mutations in the cap5 Locus

mBio ◽  
2015 ◽  
Vol 6 (2) ◽  
Author(s):  
Susan Boyle-Vavra ◽  
Xue Li ◽  
Md Tauqeer Alam ◽  
Timothy D. Read ◽  
Julia Sieth ◽  
...  
Keyword(s):  
United States ◽  
Staphylococcus Aureus ◽  
Capsular Polysaccharide ◽  
The United States ◽  
Whole Genome Sequence ◽  
Content Type ◽  
Capsule Production ◽  
Usa300 Strain

ABSTRACTThe surface capsular polysaccharide (CP) is a virulence factor that has been used as an antigen in several successful vaccines against bacterial pathogens. A vaccine has not yet been licensed againstStaphylococcus aureus, although two multicomponent vaccines that contain CP antigens are in clinical trials. In this study, we evaluated CP production in USA300 methicillin-resistantS. aureus(MRSA) isolates that have become the predominant community-associated MRSA clones in the United States. We found that all 167 USA300 MRSA and 50 USA300 methicillin-susceptibleS. aureus(MSSA) isolates were CP negative (CP−). Moreover, all 16 USA500 isolates, which have been postulated to be the progenitor lineage of USA300, were also CP−. Whole-genome sequence analysis of 146 CP−USA300 MRSA isolates revealed they all carry acap5locus with 4 conserved mutations compared with strain Newman. Genetic complementation experiments revealed that three of these mutations (in thecap5promoter,cap5Dnucleotide 994, andcap5Enucleotide 223) ablated CP production in USA300 and that Cap5E75 Asp, located in the coenzyme-binding domain, is essential for capsule production. All but three USA300 MSSA isolates had the same fourcap5mutations found in USA300 MRSA isolates. Most isolates with a USA500 pulsotype carried three of these four USA300-specific mutations, suggesting the fourth mutation occurred in the USA300 lineage. Phylogenetic analysis of thecaploci of our USA300 isolates as well as publicly available genomes from 41 other sequence types revealed that the USA300-specificcap5mutations arose sequentially inS. aureusin a common ancestor of USA300 and USA500 isolates.IMPORTANCEThe USA300 MRSA clone emerged as a community-associated pathogen in the United States nearly 20 years ago. Since then, it has rapidly disseminated and now causes health care-associated infections. This study shows that the CP-negative (CP−) phenotype has persisted among USA300 isolates and is a universal and characteristic trait of this highly successful MRSA lineage. It is important to note that a vaccine consisting solely of CP antigens would not likely demonstrate high efficacy in the U.S. population, where about half of MRSA isolates comprise USA300. Moreover, conversion of a USA300 strain to a CP-positive (CP+) phenotype is unlikelyin vivoorin vitrosince it would require the reversion of 3 mutations. We have also established that USA300 MSSA isolates and USA500 isolates are CP−and provide new insight into the evolution of the USA300 and USA500 lineages.

scholarly journals Effects of Dietary Supplementation with the Solanaceae Plant Alkaloid Anatabine on Joint Pain and Stiffness: Results from an Internet-Based Survey Study

2013 ◽  
Vol 6 ◽  
pp. CMAMD.S13001 ◽  
Author(s):  
Ryan K. Lanier ◽  
Kainen D. Gibson ◽  
Amy E. Cohen ◽  
Maria Varga
Keyword(s):  
United States ◽  
Dietary Supplement ◽  
Joint Pain ◽  
Dietary Supplementation ◽  
The United States ◽  
Substantial Improvement ◽  
Survey Study ◽  
Plant Family

Anatabine is a Solanaceae plant family alkaloid marketed in the United States as a dietary supplement. It has demonstrated anti-inflammatory effects in vivo and in vitro, and may be useful for musculoskeletal aches and pains. The purpose of this internet-based survey study was to provide more information about anatabine users who report benefits for joint pain or stiffness. Of the 282 survey respondents, 232 (82%) reported a benefit from anatabine supplementation for one or more joint pain conditions, most commonly the knee, wrists/hands/fingers, shoulder, and back, most often due to osteoarthritis or injury to the joint. Mean scores of joint pain and stiffness were significantly ( P < 0.0001) reduced after starting anatabine supplementation, and for most respondents joint pain was virtually eliminated. Around 90% of all individuals rated the effect of anatabine supplementation as good or excellent for joint pain, stiffness, functionality, and overall effects. These results provide evidence that anatabine supplementation can lead to substantial improvement of musculoskeletal aches, pains, and stiffness, and can provide benefits in some individuals for various medical conditions in multiple joint locations.

scholarly journals Immunoglobulin Attenuates Streptokinase-Mediated Virulence inStreptococcus dysgalactiae Subspeciesequisimilis Necrotizing Fasciitis

2017 ◽  
Vol 217 (2) ◽  
pp. 270-279 ◽  
Author(s):  
Federica Andreoni ◽  
Fabio Ugolini ◽  
Nadia Keller ◽  
Andrina Neff ◽  
Victor Nizet ◽  
...  
Keyword(s):  
Mortality Rate ◽  
Mouse Model ◽  
Necrotizing Fasciitis ◽  
Protective Role ◽  
Specific Antibodies ◽  
Blocking Antibodies ◽  
First Time ◽  
Very High

Abstract Background Necrotizing fasciitis (NF) retains a very high mortality rate despite prompt and adequate antibiotic treatment and surgical debridement. Necrotizing fasciitis has recently been associated withStreptococcus dysgalactiae subspeciesequisimilis (SDSE). Methods We investigated the causes of a very severe clinical manifestation of SDSE-NF by assessing both host and pathogen factors. Results We found a lack of streptokinase-function blocking antibodies in the patient resulting in increased streptokinase-mediated fibrinolysis and bacterial spread. At the same time, the clinical SDSE isolate produced very high levels of streptokinase. Exogenous immunoglobulin Gs (ex-IgGs) efficiently blocked streptokinase-mediated fibrinolysis in vitro, indicating a protective role against the action of streptokinase. In vivo, SDSE infection severity was also attenuated by ex-IgGs in a NF mouse model. Conclusions These findings illustrate for the first time that the lack of specific antibodies against streptococcal virulence factors, such as streptokinase, may contribute to NF disease severity. This can be counteracted by ex-IgGs.

scholarly journals Pathogenesis and Transmission of Genetically Diverse Swine-Origin H3N2 Variant Influenza A Viruses from Multiple Lineages Isolated in the United States, 2011–2016

2018 ◽  
Vol 92 (16) ◽  
Author(s):  
Xiangjie Sun ◽  
Joanna A. Pulit-Penaloza ◽  
Jessica A. Belser ◽  
Claudia Pappas ◽  
Melissa B. Pearce ◽  
...  
Keyword(s):  
United States ◽  
Respiratory Tract ◽  
Influenza A ◽  
Seasonal Influenza ◽  
The United States ◽  
Influenza Viruses ◽  
Upper Respiratory Tract ◽  
Pandemic Preparedness

ABSTRACTWhile several swine-origin influenza A H3N2 variant (H3N2v) viruses isolated from humans prior to 2011 have been previously characterized for their virulence and transmissibility in ferrets, the recent genetic and antigenic divergence of H3N2v viruses warrants an updated assessment of their pandemic potential. Here, four contemporary H3N2v viruses isolated during 2011 to 2016 were evaluated for their replicative ability in bothin vitroandin vivoin mammalian models as well as their transmissibility among ferrets. We found that all four H3N2v viruses possessed similar or enhanced replication capacities in a human bronchial epithelium cell line (Calu-3) compared to a human seasonal influenza virus, suggestive of strong fitness in human respiratory tract cells. The majority of H3N2v viruses examined in our study were mildly virulent in mice and capable of replicating in mouse lungs with different degrees of efficiency. In ferrets, all four H3N2v viruses caused moderate morbidity and exhibited comparable titers in the upper respiratory tract, but only 2 of the 4 viruses replicated in the lower respiratory tract in this model. Furthermore, despite efficient transmission among cohoused ferrets, recently isolated H3N2v viruses displayed considerable variance in their ability to transmit by respiratory droplets. The lack of a full understanding of the molecular correlates of virulence and transmission underscores the need for close genotypic and phenotypic monitoring of H3N2v viruses and the importance of continued surveillance to improve pandemic preparedness.IMPORTANCESwine-origin influenza viruses of the H3N2 subtype, with the hemagglutinin (HA) and neuraminidase (NA) derived from historic human seasonal influenza viruses, continue to cross species barriers and cause human infections, posing an indelible threat to public health. To help us better understand the potential risk associated with swine-origin H3N2v viruses that emerged in the United States during the 2011-2016 influenza seasons, we use bothin vitroandin vivomodels to characterize the abilities of these viruses to replicate, cause disease, and transmit in mammalian hosts. The efficient respiratory droplet transmission exhibited by some of the H3N2v viruses in the ferret model combined with the existing evidence of low immunity against such viruses in young children and older adults highlight their pandemic potential. Extensive surveillance and risk assessment of H3N2v viruses should continue to be an essential component of our pandemic preparedness strategy.

scholarly journals Pharmacodynamic Evaluation of the Activities of Six Parenteral Vancomycin Products Available in the United States

2014 ◽  
Vol 59 (1) ◽  
pp. 622-632 ◽  
Author(s):  
Arnold Louie ◽  
Michael T. Boyne ◽  
Vikram Patel ◽  
Clayton Huntley ◽  
Weiguo Liu ◽  
...  
Keyword(s):  
United States ◽  
Drug Exposure ◽  
The United States ◽  
Mouse Serum ◽  
Infection Model ◽  
Population Pharmacokinetic ◽  
Bacterial Killing ◽  
The Impact

ABSTRACTA recent report found that generic parenteral vancomycin products may not havein vivoefficacies equivalent to those of the innovator in a neutropenic murine thigh infection model despite having similarin vitromicrobiological activities and murine serum pharmacokinetics. We compared thein vitroandin vivoactivities of six of the parenteral vancomycin products available in the United States. Thein vitroassessments for the potencies of the vancomycin products included MIC/minimal bactericidal concentration (MBC) determinations, quantifying the impact of human and murine serum on the MIC values, and time-kill studies. Also, the potencies of the vancomycin products were quantified with a biological assay, and the human and mouse serum protein binding rates for the vancomycin products were measured. Thein vivostudies included dose-ranging experiments with the 6 vancomycin products for three isolates ofStaphylococcus aureusin a neutropenic mouse thigh infection model. The pharmacokinetics of the vancomycin products were assessed in infected mice by population pharmacokinetic modeling. No differences were seen across the vancomycin products with regard to anyin vitroevaluation. Inhibitory sigmoid maximal bacterial kill (Emax) modeling of the relationship between vancomycin dosage and the killing of the bacteria in micein vivoyielded similarEmaxand EC50(drug exposure driving one-halfEmax) values for bacterial killing. Further, there were no differences in the pharmacokinetic clearances of the 6 vancomycin products from infected mice. There were no important pharmacodynamic differences in thein vitroorin vivoactivities among the six vancomycin products evaluated.

scholarly journals Host Cell Responses to Genotypically Similar Helicobacter pylori Isolates from United States and Japan

2002 ◽  
Vol 9 (1) ◽  
pp. 167-175 ◽  
Author(s):  
Takafumi Ando ◽  
Richard M. Peek ◽  
Yong-Chan Lee ◽  
Uma Krishna ◽  
Kazuo Kusugami ◽  
...  
Keyword(s):  
United States ◽  
Helicobacter Pylori ◽  
Tyrosine Phosphorylation ◽  
Dna Fragmentation ◽  
Signal Sequence ◽  
The United States ◽  
Ags Cells ◽  
H Pylori

ABSTRACT Associations of Helicobacter pylori genotypes with disease differ between Western countries and Asia. Therefore, we directly compared histopathological and in vitro responses to clinical isolates with similar genotypes. Sixty-three cagA + vacAs1/m1 H. pylori isolates (United States, n = 24; Japan, n = 39) and eight cagA-negative vacAs2/m2 strains were incubated with AGS cells, and supernatants were assayed for interleukin-8 (IL-8) and for DNA fragmentation. CagA tyrosine phosphorylation in AGS cells and the sequence of the putative HP0638 (oipA) signal sequence region were determined for 22 representative strains. HP0638 and/or cag island mutant strains were created and examined in IL-8 and CagA tyrosine phosphorylation assays. Levels of IL-8 induction and DNA fragmentation were similar in the U.S. and Japanese cagA + vacAs1/m1 isolates. All 10 of the isolates with the highest IL-8 induction and 8 of the 10 isolates with the lowest IL-8 induction had an in-frame oipA open reading frame, and all 10 of the isolates with the highest IL-8 induction and 7 of the 10 isolates with the lowest IL-8 induction induced CagA tyrosine phosphorylation in AGS cells. Eight isolates from gastric ulcer patients induced significantly more apoptosis in vitro, and more severe gastritis and atrophy in vivo, than other Japanese isolates. Disruption of HP0638 did not affect IL-8 induction or CagA tyrosine phosphorylation. Thus, H. pylori cagA + vacAs1/m1 isolates from the United States and Japan induce similar IL-8 and apoptosis levels. Inactivation of HP0638 does not alter epithelial responses mediated by the cag island in vitro. Assessment of apoptosis in vitro identified a group of H. pylori isolates that induce more severe gastric inflammation and atrophy.

scholarly journals VCAM1-α4β1 integrin interaction mediates interstitial tissue reconstruction in 3-D re-aggregate culture of dissociated prepubertal mouse testicular cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kazuko Abe ◽  
Shigeyuki Kon ◽  
Hiroki Kameyama ◽  
JiDong Zhang ◽  
Ken-ichirou Morohashi ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Leydig Cells ◽  
Interstitial Tissue ◽  
Testicular Cells ◽  
Aggregate Culture ◽  
Tissue Reconstruction ◽  
Blocking Antibodies ◽  
Cell To Cell Adhesion

AbstractRoles of interstitial tissue in morphogenesis of testicular structures remain less well understood. To analyze the roles of CD34+ cells in the reconstruction of interstitial tissue containing Leydig cells (LCs), and testicular structures, we used 3D-reaggregate culture of dissociated testicular cells from prepubertal mouse. After a week of culture, adult Leydig cells (ALCs) were preferentially incorporated within CD34+ cell-aggregates, but fetal LCs (FLCs) were not. Immunofluorescence studies showed that integrins α4, α9 and β1, and VCAM1, one of the ligands for integrins α4β1 and α9β1, are expressed mainly in CD34+ cells and ALCs, but not in FLCs. Addition of function-blocking antibodies against each integrin and VCAM1 to the culture disturbed the reconstruction of testicular structures. Antibodies against α4 and β1 integrins and VCAM1 robustly inhibited cell-to-cell adhesion between testicular cells and between CD34+ cells. Cell-adhesion assays indicated that CD34+ cells adhere to VCAM1 through the interaction with α4β1 integrin. Live cell imaging showed that CD34+ cells adhered around ALC-aggregates. CD34+ cells on the dish moved toward the aggregates, extending filopodia, and entered into them, which was disturbed by VCAM1 antibody. These results indicate that VCAM1-α4β1 integrin interaction plays pivotal roles in formation of testicular interstitial tissues in vitro and also in vivo.

scholarly journals rpoS-Regulated Core Genes Involved in the Competitive Fitness of Salmonella enterica Serovar Kentucky in the Intestines of Chickens

2014 ◽  
Vol 81 (2) ◽  
pp. 502-514 ◽  
Author(s):  
Ying Cheng ◽  
Adriana Ayres Pedroso ◽  
Steffen Porwollik ◽  
Michael McClelland ◽  
Margie D. Lee ◽  
...  
Keyword(s):  
United States ◽  
Salmonella Enterica ◽  
The United States ◽  
Differential Regulation ◽  
Metabolic Adaptation ◽  
Content Type ◽  
Metabolic Genes ◽  
Core Genes

ABSTRACTSalmonella entericaserovar Kentucky has become the most frequently isolated serovar from poultry in the United States over the past decade. Despite its prevalence in poultry, it causes few human illnesses in the United States. The dominance ofS. Kentucky in poultry does not appear to be due to single introduction of a clonal strain, and its reduced virulence appears to correlate with the absence of virulence genesgrvA,sseI,sopE, andsodC1. S. Kentucky's prevalence in poultry is possibly attributable to its metabolic adaptation to the chicken cecum. While there were no difference in the growth rate ofS. Kentucky andS. Typhimurium grown microaerophilically in cecal contents,S. Kentucky persisted longer when chickens were coinfected withS. Typhimurium. Thein vivoadvantage thatS. Kentucky has overS. Typhimurium appears to be due to differential regulation of coreSalmonellagenes via the stationary-phase sigma factorrpoS. Microarray analysis ofSalmonellagrown in cecal contentsin vitroidentified several metabolic genes and motility and adherence genes that are differentially activated inS. Kentucky. The contributions of four of these operons (mgl,prp,nar, andcsg) toSalmonellacolonization in chickens were assessed. Deletion ofmglandcsgreducedS. Kentucky persistence in competition studies in chickens infected with wild-type or mutant strains. Subtle mutations affecting differential regulation of coreSalmonellagenes appear to be important inSalmonella's adaptation to its animal host and especially forS. Kentucky's emergence as the dominant serovar in poultry.

Coagulation Disorders Caused by Hydroxyethyl Starch

1997 ◽  
Vol 78 (03) ◽  
pp. 0974-0983 ◽  
Author(s):  
Johannes Treib ◽  
Anton Haass ◽  
Gerhard Pindur
Keyword(s):  
United States ◽  
Factor Viii ◽  
Hydroxyethyl Starch ◽  
Von Willebrand Factor ◽  
The United States ◽  
Degree Of Substitution ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryInitially, hydroxyethyl starch (HES) was only characterized by its in vitro molecular weight (MW). This is not sufficient because HES is degraded in vivo. One relevant parameter that predicts the rate of enzymatic breakdown is the degree of substitution, a measure of the average number of hydroxyethyl groups per glucose unit. The higher this degree of substitution, the slower the break-down. In addition, because the glucose units can be substituted at carbon 2,3 and 6, different substitution patterns are possible. They are classified by their C2/C6 hydroxyethylation ratio. A higher C2/C6 ratio results in less metabolism of the starch in vivo and results in a larger in vivo MW. This in turn affects therapy, because the larger the in vivo MW, the longer is the duration of the volume effect of HES.Of particular importance is the fact that HES with a high in vivo MW affects factor VIII/von Willebrand factor which can lead to an acquired von Willebrand syndrome. During a 10-day volume therapy with a medium-MW HES 200, a form that is difficult to metabolize, we observed an 80% drop in factor VIII/von Willebrand factor. Therapy with a medium-MW HES 200, a form that is easily degraded, and therapy with a low-MW HES 70 did not result in a relevant decline of factor VIII/von Willebrand factor.This explains why hemorrhagic complications have been observed repeatedly in the United States after therapy with HES infusions, some of them lethal. In the United States high-MW HES 480 which is difficult to degrade is most frequently used and results in a larger in vivo MW and subsequent decrease in factor VIII/von Willebrand factor levels. In Europe, medium-MW HES 200 that is easily degraded and low-MW HES 70 are preferred. In the future, HES should be characterized by the in vivo, not the in vitro MW.

In vitro and in vivo activities of AM-1155, a new fluoroquinolone, against Chlamydia spp.

1997 ◽  
Vol 41 (6) ◽  
pp. 1331-1334 ◽  
Author(s):  
N Miyashita ◽  
Y Niki ◽  
T Kishimoto ◽  
M Nakajima ◽  
T Matsushima
Keyword(s):  
United States ◽  
Body Weight ◽  
Survival Rate ◽  
Chlamydia Pneumoniae ◽  
The United States ◽  
Chlamydia Psittaci ◽  
Wild Type ◽  
Type Strains

The in vitro and in vivo activities of AM-1155, a new quinolone, against Chlamydia spp. were investigated. The MIC of AM-1155 for 10 standard strains of different Chlamydia spp. and 25 wild-type strains of Chlamydia pneumoniae isolated in Japan, which were morphologically different from clinical isolates from the United States, ranged from 0.063 to 0.125 microg/ml. Its activity was almost the same as those of sparfloxacin and tosufloxacin and was 4 and 16 times superior to those of levofloxacin and ciprofloxacin, respectively, but lower than those of clarithromycin and minocycline (range for each, 0.016 to 0.031 microg/ml). The minimal chlamydiacidal concentration of AM-1155 ranged from 0.063 to 0.125 microg/ml, while those of clarithromycin and minocycline ranged from 0.016 to 0.031 microg/ml and 0.016 to 0.063 microg/ml, respectively. The therapeutic effect of a 7-day course of AM-1155 at doses of 5 and 10 mg/kg of body weight administered orally twice daily to mice with experimental Chlamydia psittaci pneumonia was excellent, with a 100% survival rate at 21 days after infection. The efficacy was equal to those of clarithromycin and minocycline and higher than those of ciprofloxacin and ofloxacin.

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