Publications by authors named "J W Martinson"

163 Publications

Development of omics biomarkers for estrogen exposure using mRNA, miRNA and piRNAs.

Aquat Toxicol 2021 Mar 12;235:105807. Epub 2021 Mar 12.

US Environmental Protection Agency, Office of Research and Development, 26 W. Martin Luther King Dr., Cincinnati, OH 45268, United States. Electronic address:

The number of chemicals requiring risk evaluation exceeds our capacity to provide the underlying data using traditional methodology. This has led to an increased focus on the development of novel approach methodologies. This work aimed to expand the panel of gene expression-based biomarkers to include responses to estrogens, to identify training strategies that maximize the range of applicable concentrations, and to evaluate the potential for two classes of small non-coding RNAs (sncRNAs), microRNA (miRNA) and piwi-interacting RNA (piRNA), as biomarkers. To this end larval Pimephales promelas (96 hpf +/- 1h) were exposed to 5 concentrations of 17α- ethinylestradiol (0.12, 1.25, 2.5, 5.0, 10.0 ng/L) for 48 h. For mRNA-based biomarker development, RNA-seq was conducted across all concentrations. For sncRNA biomarkers, small RNA libraries were prepared only for the control and 10.0 ng/L EE2 treatment. In order to develop an mRNA classifier that remained accurate over the range of exposure concentrations, three different training strategies were employed that focused on 10 ng/L, 2.5 ng/L or a combination of both. Classifiers were tested against an independent test set of individuals exposed to the same concentrations used in training and subsequently against concentrations not included in model training. Both random forest (RF) and logistic regression with elastic net regularizations (glmnet) models trained on 10 ng/L EE2 performed poorly when applied to lower concentrations. RF models trained with either the 2.5 ng/L or combination (2.5 + 10 ng/L) treatments were able to accurately discriminate exposed vs. non-exposed across all but the lowest concentrations. glmnet models were unable to accurately classify below 5 ng/L. With the exception of the 10 ng/L treatment, few mRNA differentially expressed genes (DEG) were observed, however, there was marked overlap of DEGs across treatments. Overlapping DEGs have well established linkages to estrogen and several of the 81 DEGs identified in the 10 ng/L treatment have been previously utilized as estrogenic biomarkers (vitellogenin, estrogen receptor-β). Following multiple test correction, no sncRNAs were found to be differentially expressed, however, both miRNA and piRNA classifiers were able to accurately discriminate control and 10 ng/L exposed organisms with AUCs of 0.83 and 1.0 respectively. We have developed a highly discriminative estrogenic mRNA biomarker that is accurate over a range of concentrations likely to be found in real-world exposures. We have demonstrated that both miRNA and piRNA are responsive to estrogenic exposure, suggesting the need to further investigate their regulatory roles in the estrogenic response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.aquatox.2021.105807DOI Listing
March 2021

DNA methylation and expression of estrogen receptor alpha in fathead minnows exposed to 17α-ethynylestradiol.

Aquat Toxicol 2021 Apr 23;233:105788. Epub 2021 Feb 23.

US Environmental Protection Agency, Office of Research and Development, Cincinnati, OH, 45268, United States. Electronic address:

The gene expression response thought to underlie the negative apical effects resulting from estrogen exposure have been thoroughly described in fish. Although epigenetics are believed to play a critical role translating environmental exposures into the development of adverse apical effects, they remain poorly characterized in fish species. This study investigated alterations of DNA methylation of estrogen receptor alpha (esr1) in brain and liver tissues from 8 to 10 month old male fathead minnows (Pimephales promelas) after a 2d exposure to either 2.5 ng/L or 10 ng/L 17α-ethynylestradiol (EE2). Changes in the patterns of methylation were evaluated using targeted deep sequencing of bisulfite treated DNA in the 5' region of esr1. Methylation and gene expression were assessed at 2d of exposure and after a 7 and 14d depuration period. After 2d EE2 exposure, males exhibited significant demethylation in the 5' upstream region of esr1 in liver tissue, which was inversely correlated to gene expression. This methylation pattern reflected what was seen in females. No gene body methylation (GBM) was observed for liver of exposed males. Differential methylation was observed for a single upstream CpG site in the liver after the 14d depuration. A less pronounced methylation response was observed in the upstream region in brain tissue, however, several CpGs were necessarily excluded from the analysis. In contrast to the liver, a significant GBM response was observed across the entire gene body, which was sustained until at least 7d post-exposure. No differential expression was observed in the brain, limiting functional interpretation of methylation changes. The identification of EE2-dependent changes in methylation levels strongly suggests the importance of epigenetic mechanisms as a mediator of the organismal response to environmental exposures and the need for further characterization of the epigenome. Further, differential methylation following depuration indicates estrogenic effects persist well after the active exposure, which has implications for the risk posed by repeated exposures..
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.aquatox.2021.105788DOI Listing
April 2021

Characteristics of Patients With Chronic Hepatitis B Virus Infection With Genotype E Predominance in Burkina Faso.

Hepatol Commun 2020 Dec 15;4(12):1781-1792. Epub 2020 Sep 15.

Division of Gastroenterology and Hepatology Mayo Clinic Rochester MN.

Hepatitis B virus (HBV) genotype E (HBV-E) accounts for the majority of chronic hepatitis B (CHB) infections in West Africa. We aimed to determine factors associated with HBV-E-induced hepatocellular carcinoma (HCC) in West Africa. Data on patients from Burkina Faso who were hepatitis B surface antigen positive (HBsAg+) and had CHB were analyzed. HBV viral load and hepatitis B e antigen (HBeAg) status were measured in 3,885 individuals with CHB without HCC (CHB HCC-) and 59 individuals with CHB with HCC (CHB HCC+). HBV genotyping was performed for 364 subjects with CHB HCC- and 41 subjects with CHB HCC+. Overall, 2.5% of the CHB HCC- group was HBeAg+ compared with 0% of the CHB HCC+ group. Of the 364 patients who were CHB HCC- with available genotyping, the frequencies of HBV genotypes E and C/E were 70.3% and 12.9%, respectively. Age (odds ratio [OR] for older age, 1.08; 95% confidence interval [CI], 1.06-1.10 per 1-year increase in age), male sex (OR, 2.03; 95% CI, 1.11-3.69), and HBV viremia (OR, 1.48; 95% CI, 1.31-1.67 per 1 log10 IU/mL) were each associated with HCC diagnosis. Patients with genotype E had a lower HBeAg prevalence (6.3% vs. 14.9%), lower HBV viral load, and higher prevalence of cirrhosis (14.5% vs. 4.8%) than patients with genotype C/E. HBV-E is the most common circulating strain (70.3%) in West African patients. HCC was associated with older age, male sex, and high HBV viral load. It is expected that these results will further inform guidance on clinical management of HBV infection in West Africa.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hep4.1595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706297PMC
December 2020

HLA tapasin independence: broader peptide repertoire and HIV control.

Proc Natl Acad Sci U S A 2020 11 23;117(45):28232-28238. Epub 2020 Oct 23.

Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702;

Human leukocyte antigen (HLA) class I allotypes vary in their ability to present peptides in the absence of tapasin, an essential component of the peptide loading complex. We quantified tapasin dependence of all allotypes that are common in European and African Americans ( = 97), which revealed a broad continuum of values. Ex vivo examination of cytotoxic T cell responses to the entire HIV-1 proteome from infected subjects indicates that tapasin-dependent allotypes present a more limited set of distinct peptides than do tapasin-independent allotypes, data supported by computational predictions. This suggests that variation in tapasin dependence may impact the strength of the immune responses by altering peptide repertoire size. In support of this model, we observed that individuals carrying genotypes characterized by greater tapasin independence progress more slowly to AIDS and maintain lower viral loads, presumably due to increased breadth of peptide presentation. Thus, tapasin dependence level, like zygosity, may serve as a means to restrict or expand breadth of the HLA-I peptide repertoire across humans, ultimately influencing immune responses to pathogens and vaccines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.2013554117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668082PMC
November 2020

Measuring Lateral Screw Protuberance Is a Clinically Accurate Method for Quantifying Femoral Neck Shortening.

J Orthop Trauma 2020 11;34(11):600-605

Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD.

Objectives: The purpose of this study is to compare the reliability and accuracy of the screw protuberance method (SPM) and overlay method (OM) for measuring femoral neck shortening on anterior-posterior (AP) radiographs. The secondary aim is to investigate the changes in reliability and accuracy with varying femoral rotation.

Methods: Radio-opaque femur sawbone models were fitted with either 3 cancellous screws or a sliding hip screw implant. Anterior-posterior radiographs were obtained using C-arm fluoroscopy with femoral neck shortening up to 15 mm and with the femoral shaft in 30 degrees of internal rotation to 30 degrees of external rotation (ER). Four observers measured femoral neck shortening at 2 time points. Intraobserver and interobserver reliability were calculated using the intraclass coefficient. Accuracy was analyzed through a Bland-Altman agreement statistic stratified by femoral rotation.

Results: Both measurement techniques displayed excellent reliability, regardless of femoral rotation or implant. There was a significant difference in femoral neck shortening measurements with rotation for both the OM (P < 0.001) and SPM (P < 0.001). Both methods are accurate within 1 mm of the actual magnitude of shortening from 30-degree internal rotation to 15-degree ER. At 30-degree ER, shortening was underestimated by -2.10 mm using the OM (95% confidence interval, -2.43 to -1.76; P < 0.01) and by -1.64 mm using the SPM (95% confidence interval, -1.83 to -1.45; P < 0.01).

Conclusion: This study demonstrates that both the OM and SPM are accurate and reliable assessments for femoral neck shortening; however, both methods are sensitive to extreme ER. Given the simplicity of the SPM technique, it may have increased utility for pragmatic research studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/BOT.0000000000001806DOI Listing
November 2020

Residency in the Gut of Healthy Human Adults.

EcoSal Plus 2020 09;9(1)

Department of Microbiology and Immunology, Montana State University, Bozeman, MT, 59717.

is one of the most well-studied bacterial species, but several significant knowledge gaps remain regarding its ecology and natural history. Specifically, the most important factors influencing its life as a member of the healthy human gut microbiome are either underevaluated or currently unknown. Distinct population dynamics have been observed over the past century from a handful of temporal studies conducted in healthy human adults. Early studies using serology up to the most recent studies using genotyping and DNA sequencing approaches have all identified long-lived residents and short-lived transients. This review summarizes these discoveries and other studies that focused on the underlying mechanisms that lead to establishment and maintenance of residency in healthy human adults. Many fundamental knowledge gaps remain and are highlighted with the hope of facilitating future studies in this exciting research area.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/ecosalplus.ESP-0003-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523338PMC
September 2020

Metabarcoding quantifies differences in accumulation of ballast water borne biodiversity among three port systems in the United States.

Sci Total Environ 2020 Dec 3;749:141456. Epub 2020 Aug 3.

Smithsonian Environmental Research Center, Edgewater, MD 21037, USA.

Characterizing biodiversity conveyed in ships' ballast water (BW), a global driver of biological invasions, is critically important for understanding risks posed by this key vector and establishing baselines to evaluate changes associated with BW management. Here we employ high throughput sequence (HTS) metabarcoding of the 18S small subunit rRNA to test for and quantify differences in the accumulation of BW-borne biodiversity among three distinct recipient port systems in the United States. These systems were located on three different coasts (Pacific, Gulf, and Atlantic) and chosen to reflect distinct trade patterns and source port biogeography. Extensive sampling of BW tanks (n = 116) allowed detailed exploration of molecular diversity accumulation. Our results indicate that saturation of introduced zooplankton diversity may be achieved quickly, with fewer than 25 tanks needed to achieve 95% of the total extrapolated diversity, if source biogeography is relatively limited. However, as predicted, port systems with much broader source geographies require more extensive sampling to estimate diversity, which continues to accumulate after sampling >100 discharges. The ability to identify BW sources using molecular indicators was also found to depend on the breadth of source biogeography and the extent to which sources had been sampled. These findings have implications both for the effort required to fully understand introduced diversity and for projecting risks associated with future changes to maritime traffic that may increase source biogeography for many recipient ports. Our data also suggest that molecular diversity may not decline significantly with BW age, indicating either that some organisms survive longer than recognized in previous studies or that nucleic acids from dead organisms persist in BW tanks. We present evidence for detection of potentially invasive species in arriving BW but discuss important caveats that preclude strong inferences regarding the presence of living representatives of these species in BW tanks.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.scitotenv.2020.141456DOI Listing
December 2020

Radial versus femoral arterial access for trauma endovascular interventions: A noninferiority study.

J Trauma Acute Care Surg 2020 09;89(3):458-463

From the Department of Surgery (S.M.A.), Einstein Healthcare Network, Philadelphia, Pennsylvania; R Adams Cowley Shock Trauma Center (A.N.R., M.J.M., J.J.D., T.M.S., J.J.M.), University of Maryland Medical System; and University of Maryland School of Medicine (N.N.E., J.R.M.), Baltimore, Maryland.

Background: The majority of endovascular interventions for trauma are performed using transfemoral access (TFA). Transradial access (TRA) is a recently integrated alternative at the authors' institution. This noninferiority study compares the technical success and complication rate of TRA compared with TFA.

Methods: All patients undergoing emergent endovascular interventions between March 2016 and March 2019 were identified from a prospectively maintained database. Data were collected on access type, complications, and procedural success. A noninferiority margin was established from previous randomized trials for technical success (0.475) and complications (0.015).

Results: Over 3 years, 96 patients underwent TRA and 335 patients received TFA. The overall technical success rate was 98.1%, without significance based on access strategy (p = 0.078). All femoral arteries and 97.9% (n = 94) of radial arteries were accessed as intended. Complications occurred in 1.0% of TRA and 9.9% of TFA groups (p = 0.002). In the TFA group, complications included access site bleeding, hematoma, pseudoaneurysm, lower limb ischemia, and femoral artery thrombosis (n = 6, 14, 3, 3, and 4, respectively). In the TRA group, complications included radial artery thrombosis (n = 1). Transradial access procedural success and complication rate fell within the lower bound confidence interval of the noninferiority margin, demonstrated the noninferiority of TRA in this data set.

Conclusion: Transradial access in a cohort of trauma patients undergoing endovascular intervention does not appear to be inferior to TFA in relation to technical success and complications. For patients where groin access may be challenging, TRA is a useful, efficacious, and safe alternative. Longer-term study is required to fully characterize the advantages and disadvantages of TRA compared with TFA.

Level Of Evidence: Therapeutic V.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/TA.0000000000002740DOI Listing
September 2020

Tourniquets USA: A Review of the Current Literature for Commercially Available Alternative Tourniquets for Use in the Prehospital Civilian Environment.

J Spec Oper Med 2020 ;20(2):116-122

The American College of Surgeons' "Stop the Bleed" (STB) campaign emphasizes how to apply the Combat Application Tourniquet (CAT), a device adopted by the military to control extremity hemorrhage. However, multiple commercially available alternatives to the CAT exist, and it would be helpful for instructors to be knowledgeable about how these other models compare. A PubMed search from January 2012 to January 2020 cross-referenced with a Google search for "tourniquet" was performed for commercially available tourniquets that had been trialed against the CAT. Windlass-type models included the Special Operations Forces Tactical Tourniquet (SOFT-T), the SOFT-T Wide (SOFFT-W), the SAM-XT tourniquet, the Military Emergency Tourniquet (MET), and the Tactical Medical Tourniquet (TMT). Elastic-type tourniquets included were the Stretch, Wrap, And Tuck Tourniquet (SWAT-T), the Israeli Silicone Tourniquet (IST), and the Rapid Activation Tourniquet System (RATS). Ratchet-type tourniquets included were the Ratcheting Medical Tourniquet (RMT) and TX2/TX3 tourniquets, and pneumatic-type tourniquets were the Emergency and Military Tourniquet (EMT) and Tactical Pneumatic Tourniquet (TPT). This review aims to describe the literature surrounding these models so that instructors can help laypeople make more informed purchases, stop the bleed, and save a life.
View Article and Find Full Text PDF

Download full-text PDF

Source
July 2020

Cone-beam computed tomography for trauma.

J Trauma Acute Care Surg 2020 09;89(3):e34-e40

From the Saint Agnes Hospital (S.G.); Shock Trauma Center (J.R.M., D.R., T.S., J.M.), University of Maryland, Baltimore, Maryland.

Radiographic imaging is critical in helping guide treatment of critically injured patients. Cone-beam computed tomography is an axial imaging technique available from fixed imaging systems found in hybrid operating rooms. It can be used to provide focused studies of specific anatomical regions, where patients cannot undergo conventional multidetector computed tomography. This includes non-contrast-enhanced evaluation of the intracranial contents and vascular imaging throughout the body. There are a number of advantages and disadvantages to cone-beam computed tomography, but these are not widely discussed within the trauma literature. This narrative review article presents the initial practical experience of this novel imaging modality. LEVEL OF EVIDENCE: Review article, level III.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/TA.0000000000002748DOI Listing
September 2020

A Comparison of Transradial and Transfemoral Access for Splenic Angio-Embolisation in Trauma: A Single Centre Experience.

Eur J Vasc Endovasc Surg 2020 Mar 18;59(3):472-479. Epub 2019 Dec 18.

R Adams Cowley Shock Trauma Centre, University of Maryland Medical System, Baltimore, MD, USA. Electronic address:

Objective: The study compared transradial access (TRA) and transfemoral access (TFA) for splenic angio-embolisation (SAE), with a focus on technical success, intra-operative adjuncts, and complications.

Methods: This was a retrospective comparative study of all trauma patients undergoing SAE by TRA or TFA between February 2015 and February 2019 at a single institution. The medical records were queried for procedural and post-operative data, with comparisons made based on access site. Continuous variables were compared using a two tailed t test and categorical variables were compared using a chi square test.

Results: Over a four year period, there were 47 cases of SAE via TRA and 127 via TFA. Technical success was 95.7% during TRA and 98.4% during TFA (p = .30). Technical failures were a result of failed splenic artery cannulation after successful radial or femoral access. Time to splenic cannulation was shorter in the TRA group (19 min vs. 30 min; p = .008). Two or fewer catheters were used during TRA, whereas more than two catheters were needed during TFA (p < .001). There were no statistically significant differences in procedure length, fluoroscopy time, radiation dose, or contrast volume between groups. Nine patients (5.2%) developed access related complications, all in the TFA group (p = .12). Mortality rate was 2.3% (n = 4), with no statistical significance between groups (p = .71).

Conclusion: While TFA is the conventional strategy for SAE, TRA is a safe and efficacious modality for SAE in trauma patients. Although larger studies are needed to establish the full efficacy of TRA for SAE at the multi-institutional level, this single centre study demonstrates the legitimacy of an alternative means for SAE in the trauma population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejvs.2019.11.028DOI Listing
March 2020

Role of Killer cell immunoglobulin-like receptors (KIR) genes in stages of HIV-1 infection among patients from Burkina Faso.

Biomol Concepts 2019 Dec 19;10(1):226-236. Epub 2019 Dec 19.

Laboratory of Molecular Biology and Genetics (LABIOGENE), University Joseph Ki-Zerbo, Ouagadougou, Burkina Faso.

Objectives A cluster of specialized KIR genes of specialized KIR genes has been shown to be associated with susceptibility or resistance to viral infections in humans. Therefore, this pilot study, this pilot investigation sought to determine the frequencies of KIR genes human immunodeficiency virus type 1( HIV-1) patients and establish their potential clinical involvement in disease progression and staging. Methods HIV-1 infected and healthy individuals were selected for this study. Hepatitis B surface antigen (HBsAg), anti-HCV antibodies and anti-HIV-1/2 antibody/ antigen were screened using a 4th generation ELISA assay (Cobas e 411 Analyzer, Roche Diagnostics GmbH Mannheim, Germany). SSP-PCR was used to evaluate the frequencies of KIR genes. CD4+ T counts and HIV-1 viral load were measured in patients using respectively BD FACSCount and Abbott m2000rt instruments. Results We found a significant association between the frequencies of KIR2DL2 (OR=4.41; p < 0.001), KIR2DS2 (OR=4.76; p < 0.001), KIR2DS3 (OR=2.27; p=0.004), KIR2DS4 (OR=1.76; p=0.026), KIR3DS1 (OR=2.43; p=0.016) and HIV-1 infection; whilst the KIR3DL1 gene (OR= 0.39; p < 0.001) was associated with protection against HIV-1 infection. HIV-1 replication was found to be associated with the presence of KIR2DS2 (OR=6.08, p = 0.024). In contrary the pseudogene KIR2DP1 (OR=0.39; p=0.026) were linked to a protective status with the highest number of lymphocyte T CD4 counts. Conclusion Our data showed that KIR2DL2, KIR2DS2, KIR2DS3, KIR2DS4, and KIR3DS1 were significantly associated with HIV-1 infection whereas KIR3DL1 was associated with protection against HIV-1 infection. Further investigations are needed to fully comprehend the clinical significance of KIR genes in HIV disease progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1515/bmc-2019-0024DOI Listing
December 2019

Alterations in Oral Microbiota in HIV Are Related to Decreased Pulmonary Function.

Am J Respir Crit Care Med 2020 02;201(4):445-457

Division of Pulmonary, Allergy and Critical Care Medicine and.

Mechanisms of HIV-associated chronic obstructive pulmonary disease (COPD) are poorly understood. The oral microbiome shapes the lung microbiome, and gut dysbiosis can affect lung diseases; however, relationships of the oral and gut microbiome to COPD in HIV have not been explored. To examine alterations in the oral and gut microbiome associated with pulmonary disease in persons with HIV (PWH). Seventy-five PWH and 93 HIV-uninfected men from the MACS (Multicenter AIDS Cohort Study) performed pulmonary function testing. Sequencing of bacterial 16S ribosomal RNA in saliva and stool was performed. We used nonmetric multidimensional scaling, permutational multivariate ANOVA, and linear discriminant analysis to analyze communities by HIV and lung function. Oral microbiome composition differed by HIV and smoking status. Alterations of oral microbial communities were observed in PWH with abnormal lung function with increases in relative abundance of , , and . There were no significant associations between the oral microbiome and lung function in HIV-uninfected individuals. No associations with HIV status or lung function were seen with the gut microbiome. Alterations of oral microbiota in PWH were related to impaired pulmonary function and to systemic inflammation. These results suggest that the oral microbiome may serve as a biomarker of lung function in HIV and that its disruption may contribute to COPD pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.201905-1016OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049920PMC
February 2020

Human Immunodeficiency Virus (HIV) Infection and Use of Illicit Substances Promote Secretion of Semen Exosomes that Enhance Monocyte Adhesion and Induce Actin Reorganization and Chemotactic Migration.

Cells 2019 09 3;8(9). Epub 2019 Sep 3.

Department of Pharmacology, Stony Brook University School of Medicine, Stony Brook, NY 11794-8651, USA.

Semen exosomes (SE) from HIV-uninfected (HIV-) individuals potently inhibit HIV infection in vitro. However, morphological changes in target cells in response to SE have not been characterized or have the effect of HIV infection or the use of illicit substances, specifically psychostimulants, on the function of SE been elucidated. The objective of this study was to evaluate the effect of HIV infection, psychostimulant use, and both together on SE-mediated regulation of monocyte function. SE were isolated from semen of HIV- and HIV-infected (HIV+) antiretroviral therapy (ART)-naive participants who reported either using or not using psychostimulants. The SE samples were thus designated as HIV-Drug-, HIV-Drug+, HIV+Drug-, and HIV+Drug+. U937 monocytes were treated with different SEs and analyzed for changes in transcriptome, morphometrics, actin reorganization, adhesion, and chemotaxis. HIV infection and/or use of psychostimulants had minimal effects on the physical characteristics of SE. However, different SEs had diverse effects on the messenger RNA signature of monocytes and rapidly induced monocyte adhesion and spreading. SE from HIV infected or psychostimulants users but not HIV-Drug- SE, stimulated actin reorganization, leading to the formation of filopodia-like structures and membrane ruffles containing F-actin and vinculin that in some cases were colocalized. All SE stimulated monocyte chemotaxis to HIV secretome and activated the secretion of matrix metalloproteinases, a phenotype exacerbated by HIV infection and psychostimulant use. SE-directed regulation of cellular morphometrics and chemotaxis depended on the donor clinical status because HIV infection and psychostimulant use altered SE function. Although our inclusion criteria specified the use of cocaine, humans are poly-drug and alcohol users and our study participants used psychostimulants, marijuana, opiates, and alcohol. Thus, it is possible that the effects observed in this study may be due to one of these other substances or due to an interaction between different substances.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells8091027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770851PMC
September 2019

Telemedicine for Interfacility Nurse Handoffs.

Pediatr Crit Care Med 2019 09;20(9):832-840

All authors: Department of Pediatrics, University of California Davis, School of Medicine, Davis, CA.

Objective: To compare nurse preparedness and quality of patient handoff during interfacility transfers from a pretransfer emergency department to a PICU when conducted over telemedicine versus telephone.

Design: Cross-sectional nurse survey linked with patient electronic medical record data using multivariable, multilevel analysis.

Setting: Tertiary PICU within an academic children's hospital.

Participants: PICU nurses who received a patient handoff between October 2017 and July 2018.

Interventions: None.

Main Results And Measurements: Among 239 eligible transfers, 106 surveys were completed by 55 nurses (44% survey response rate). Telemedicine was used for 30 handoffs (28%), and telephone was used for 76 handoffs (72%). Patients were comparable with respect to age, sex, race, primary spoken language, and insurance, but handoffs conducted over telemedicine involved patients with higher illness severity as measured by the Pediatric Risk of Mortality III score (4.4 vs 1.9; p = 0.05). After adjusting for Pediatric Risk of Mortality III score, survey recall time, and residual clustering by nurse, receiving nurses reported higher preparedness (measured on a five-point adjectival scale) following telemedicine handoffs compared with telephone handoffs (3.4 vs 3.1; p = 0.02). There were no statistically significant differences in both bivariable and multivariable analyses of handoff quality as measured by the Handoff Clinical Evaluation Exercise. Handoffs using telemedicine were associated with increased number of Illness severity, Patient summary, Action list, Situation awareness and contingency planning, Synthesis by receiver components (3.3 vs 2.8; p = 0.04), but this difference was not significant in the adjusted analysis (3.1 vs 2.9; p = 0.55).

Conclusions: Telemedicine is feasible for nurse-to-nurse handoffs of critically ill patients between pretransfer and receiving facilities and may be associated with increased perceived and objective nurse preparedness upon patient arrival. Additional research is needed to demonstrate that telemedicine during nurse handoffs improves communication, decreases preventable adverse events, and impacts family and provider satisfaction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PCC.0000000000002011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726530PMC
September 2019

Rethinking gut microbiome residency and the Enterobacteriaceae in healthy human adults.

ISME J 2019 09 14;13(9):2306-2318. Epub 2019 May 14.

Department of Microbiology and Immunology, Montana, State University, Bozeman, MT, USA.

Longitudinal human gut microbiome datasets generated using community-level, sequence-based approaches often report a sub-set of long-lived "resident" taxa that rarely, if ever, are lost. This result contrasts with population-level turnover of resident clones on the order of months to years. We hypothesized that the disconnect between these results is due to a relative lack of simultaneous discrimination of the human gut microbiome at both the community and population-levels. Here, we present results of a small, longitudinal cohort study (n = 8 participants) of healthy human adults that identifies static and dynamic members of the gut microbiome at the clone level based on cultivation/genetic discrimination and at the operational taxonomic unit/amplified sequence variant levels based on 16S rRNA sequencing. We provide evidence that there is little "stability" within resident clonal populations of the common gut microbiome bacterial family, Enterobacteriaceae. Given that clones can vary substantially in genome content and that evolutionary processes operate on the population level, these results question the biological relevance of apparent stability at higher taxonomic levels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41396-019-0435-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776003PMC
September 2019

Vitamin D does not modulate immune-mediated bone loss during ART initiation.

Antivir Ther 2019 ;24(5):355-362

Department of Medicine, University of Alabama, Birmingham, AL, USA.

Background: Vitamin D (VitD) and calcium (Ca) supplementation attenuates antiretroviral therapy (ART)-associated bone loss, but it is unclear whether this effect is mediated through immunomodulation.

Methods: In this exploratory analysis of A5280, a 48-week, randomized, double-blind, placebo-controlled study of VitD/Ca supplementation with ART initiation, we characterized lymphocyte phenotypes and receptor activator of nuclear factor kappa-B ligand (RANKL) expression by median fluorescence intensity (MFI) at baseline and 48 weeks. Changes were evaluated within and between treatment groups by Wilcoxon signed rank and rank sum tests, respectively. Spearman correlations estimated relationships between cellular phenotypes and bone mineral density (BMD).

Results: Of 165 participants enrolled, 138 had samples for cellular phenotypes (64 VitD/Ca, 74 placebo). Markers of CD4, CD8 activation (CD38HLA-DR) declined (all P<0.001), but did not differ between arms. There was no decline in either %T-cells (CD4 and CD8) expressing RANKL or expression of RANKL by MFI. CD4 and CD8 activation markers were not correlated with BMD at baseline (r<0.15 and P>0.09 for all), but greater declines in CD4 activation correlated with greater declines in hip and spine BMD in both arms (0.25 ≤r ≤0.37, all P<0.05). A greater decline in CD8 activation was correlated with greater declines in both hip and spine BMD in the placebo arm only (hip r=0.31, P=0.009; spine r=0.25, P=0.035).

Conclusions: Reductions in T-cell activation are characteristic of ART initiation, but only correlated modestly with bone loss. VitD/Ca supplementation does not appear to mitigate bone loss through modulation of immune activation or expression of RANKL.

Trial Registration Number: NCT01403051.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3851/IMP3316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854279PMC
July 2020

Increasing Levels of Serum Heat Shock Protein 70 Precede the Development of AIDS-Defining Non-Hodgkin Lymphoma Among Carriers of HLA-B8-DR3.

J Acquir Immune Defic Syndr 2019 07;81(3):266-273

Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL.

Background: We hypothesized that carriage of presumably high Hsp70-producing gene variants on a specific human major histocompatibility complex haplotype, the 8.1 ancestral haplotype (8.1AH), may predispose HIV-infected individuals to AIDS-non-Hodgkin lymphoma (NHL).

Setting: We compared serum Hsp70 levels in the years preceding the diagnosis of AIDS-NHL in a matched case-control study (n = 151 pairs) nested in the Multicenter AIDS Cohort Study.

Methods: We tested the impact of 8.1AH-specific single-nucleotide polymorphism (SNP) and joint SNP-human leukocyte antigen extended haplotypes previously associated with AIDS-NHL in the Multicenter AIDS Cohort Study on the circulating Hsp70 levels in mixed linear models.

Results: We report elevated serum levels of Hsp70 in the 4 years preceding the diagnosis of AIDS-NHL in cases that carry 8.1AH, but not in noncarrier cases and not in carrier- or non-carrier-matched controls. The strongest predictor of higher serum Hsp70 was the haplotype A-G-A-C formed by SNPs rs537160(A) and rs1270942(G) in the complement factor CFB gene cluster, and rs2072633(A) and rs6467(C) in nearby RDBP and CYP21A2 located 70 Kb apart from the Hsp70 gene cluster. The association with A-G-A-C haplotype (beta = 0.718; standard error = 0.182; P = 0.0002) and with other 8.1AH-specific haplotypes including the high-producing tumor necrosis factor-alpha haplotype rs909253(G)-rs1800629(A) (beta = 0.308; standard error = 0.140; P = 0.032) were observed only with NHL identified as an AIDS-defining condition, but not as a post-AIDS condition, nor in combined AIDS and post-AIDS cases.

Conclusion: Our combined genetic and functional approach suggests that the altered level of Hsp70 is a correlate of 8.1AH-mediated AIDS-NHL. Further investigation of the Hsp70 gene cluster and nearby loci that are tagged by A-G-A-C could better elucidate the genetic determinants of the malignancy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/QAI.0000000000002027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587227PMC
July 2019

GlycA, a novel inflammatory marker, is associated with subclinical coronary disease.

AIDS 2019 03;33(3):547-557

Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins School of Medicine, Baltimore, Maryland.

Objective: GlycA, a novel NMR biomarker of inflammation, has been associated with incident cardiovascular disease (CVD) in the general population, but its association with CVD among HIV-infected individuals is unknown. We examined the associations between GlycA and subclinical coronary plaque among HIV-infected and HIV-uninfected men participating in Multicenter AIDS Cohort Study (MACS).

Design: Cross-sectional analysis of 935 men with plasma measurement of GlycA and noncontrast cardiac computed tomography (CT) and/or coronary CT angiography.

Methods: We used multivariable Poisson and linear regression to assess associations of GlycA with prevalent coronary atherosclerosis and plaque extent, respectively.

Results: Mean ± SD age was 54 ± 7 years; 31% were black; 63% HIV-infected. GlycA levels were higher in HIV-infected compared with HIV-uninfected men (397 ± 68 vs. 380 ± 60 μmol/l, P = 0.0001) and higher for men with detectable viral load vs. undetectable (413 ± 79 vs. 393 ± 65 μmol/l, P = 0.004). After adjusting for HIV serostatus, demographic and CVD risk factors, every 1SD increment in GlycA level was associated with a higher prevalence of coronary artery calcium (CAC >0) [prevalence ratio 1.09 (95% CI 1.03-1.15)] and coronary stenosis at least 50% [1.20 (1.02-1.41)]. These associations were not significantly altered after adjusting for traditional inflammatory biomarkers or differ by HIV serostatus. Among men with plaque, GlycA was positively associated with the extent of CAC and total plaque.

Conclusion: HIV infection was associated with higher GlycA levels. In both HIV-infected and HIV-uninfected individuals, GlycA was significantly associated with several measures of subclinical coronary atherosclerosis, independent of other CVD risk factors and inflammatory biomarkers. These findings suggest the potential role of GlycA in CVD risk stratification among HIV patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/QAD.0000000000002079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559349PMC
March 2019

Insights into the Interplay between KIR Gene Frequencies and Chronic HBV Infection in Burkina Faso.

Mediterr J Hematol Infect Dis 2018 1;10(1):e2018060. Epub 2018 Nov 1.

Laboratory of Molecular Biology and Genetics (LABIOGENE), University Ouaga I Prof. Joseph Ki-Zerbo, P.O. Box 7021, Ouagadougou 03, Burkina Faso.

Background/objective: Hepatitis B virus (HBV) infection is the leading risk factor for cirrhosis and hepatocellular carcinoma (HCC). The objective of this investigation was to assess the association between "Killer Cell Immunoglobulin-Like Receptor" (KIR) gene frequencies and chronic HBV infection.

Methods: Chronic HBV carriers and healthy patients were selected for this study. The viral load for HBV were performed, and SSP-PCR was used to characterize the frequencies of KIR genes.

Results: The study suggested that inhibitory genes KIR2DL2 (crude OR = 2.82; p < 0.001), KIR2DL3 (crude OR = 2.49; p < 0.001) and activator gene KIR2DS2 (crude OR = 3.95; p< 0.001) might be associated with chronic stages of HBV infection. Conversely the inhibitory genes KIR3DL1 (crude OR = 0.49; p = 0.0018) and KIR3DL2 (crude OR = 0.41; p = 0.005), the activator gene KIR2DS1 (crude OR = 0.48; p = 0.014) and the pseudo gene KIR2DP1 (crude OR = 0.49; p = 0.008) could be associated with immunity against HBV infection. Chronic HBV patients who are carriers for the KIR3DL3 gene (crude OR = 8; p = 0.048) were positive for HBeAg and patients who carried the KIR3DL2 gene (crude OR = 3.21; p = 0.012) had a high HBV viral load compared to the rest of the study population.

Conclusion: Our data showed evidence of a correlation between the risk of developing chronic HBV infection and certain KIR gene frequencies and also show that KIR3DL1, KIR3DL2, KIR2DS1 might confer a protective status against chronic HBV infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4084/MJHID.2018.060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223576PMC
November 2018

Genetic correlations among psychiatric and immune-related phenotypes based on genome-wide association data.

Am J Med Genet B Neuropsychiatr Genet 2018 10 16;177(7):641-657. Epub 2018 Oct 16.

Psychiatric Genetic Epidemiology & Neurobiology Laboratory (PsychGENe Lab), Departments of Psychiatry and Behavioral Sciences & Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, New York.

Individuals with psychiatric disorders have elevated rates of autoimmune comorbidity and altered immune signaling. It is unclear whether these altered immunological states have a shared genetic basis with those psychiatric disorders. The present study sought to use existing summary-level data from previous genome-wide association studies to determine if commonly varying single nucleotide polymorphisms are shared between psychiatric and immune-related phenotypes. We estimated heritability and examined pair-wise genetic correlations using the linkage disequilibrium score regression (LDSC) and heritability estimation from summary statistics methods. Using LDSC, we observed significant genetic correlations between immune-related disorders and several psychiatric disorders, including anorexia nervosa, attention deficit-hyperactivity disorder, bipolar disorder, major depression, obsessive compulsive disorder, schizophrenia, smoking behavior, and Tourette syndrome. Loci significantly mediating genetic correlations were identified for schizophrenia when analytically paired with Crohn's disease, primary biliary cirrhosis, systemic lupus erythematosus, and ulcerative colitis. We report significantly correlated loci and highlight those containing genome-wide associations and candidate genes for respective disorders. We also used the LDSC method to characterize genetic correlations among the immune-related phenotypes. We discuss our findings in the context of relevant genetic and epidemiological literature, as well as the limitations and caveats of the study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.b.32652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6230304PMC
October 2018

Ballast Water Exchange and Invasion Risk Posed by Intracoastal Vessel Traffic: An Evaluation Using High Throughput Sequencing.

Environ Sci Technol 2018 09 21;52(17):9926-9936. Epub 2018 Aug 21.

Smithsonian Environmental Research Center , Edgewater , Maryland 21037 United States.

Ballast water remains a potent vector of non-native aquatic species introductions, despite increased global efforts to reduce risk of ballast water mediated invasions. This is particularly true of intracoastal vessel traffic, whose characteristics may limit the feasibility and efficacy of management through ballast water exchange (BWE). Here we utilize high throughput sequencing (HTS) to assess biological communities associated with ballast water being delivered to Valdez, Alaska from multiple source ports along the Pacific Coast of the United States. Our analyses indicate that BWE has a significant but modest effect on ballast water assemblages. Although overall richness was not reduced with exchange, we detected losses of some common benthic coastal taxa (e.g., decapods, mollusks, bryozoans, cnidaria) and gains of open ocean taxa (e.g., certain copepods, diatoms, and dinoflagellates), including some potentially toxic species. HTS-based metabarcoding identified significantly differentiated biodiversity signatures from individual source ports; this signal persisted, though weakened, in vessels undergoing BWE, indicating incomplete faunal turnover associated with management. Our analysis also enabled identification of taxa that may be of particular concern if established in Alaskan waters. While these results reveal a clear effect of BWE on diversity in intracoastal transit, they also indicate continued introduction risk of non-native and harmful taxa.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.est.8b02108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944436PMC
September 2018

Polymorphism rs1385129 Within Glut1 Gene Is Linked to Poor CD4+ T Cell Recovery in Antiretroviral-Treated HIV+ Individuals.

Front Immunol 2018 17;9:900. Epub 2018 May 17.

Centre for Biomedical Research, Burnet Institute, Melbourne, VIC, Australia.

Untreated HIV infection is associated with progressive CD4+ T cell depletion, which is generally recovered with combination antiretroviral therapy (cART). However, a significant proportion of cART-treated individuals have poor CD4+ T cell reconstitution. We investigated associations between HIV disease progression and CD4+ T cell glucose transporter-1 (Glut1) expression. We also investigated the association between these variables and specific single nucleotide polymorphisms (SNPs) within the Glut1 regulatory gene AKT (rs1130214, rs2494732, rs1130233, and rs3730358) and in the Glut1-expressing gene SLC2A1 (rs1385129 and rs841853) and antisense RNA 1 region SLC2A1-AS1 (rs710218). High CD4+Glut1+ T cell percentage is associated with rapid CD4+ T cell decline in HIV-positive treatment-naïve individuals and poor T cell recovery in HIV-positive individuals on cART. Evidence suggests that poor CD4+ T cell recovery in treated HIV-positive individuals is linked to the homozygous genotype (GG) associated with SLC2A1 SNP rs1385129 when compared to those with a recessive allele (GA/AA) (odds ratio = 4.67;  = 0.04). Furthermore, poor response to therapy is less likely among Australian participants when compared against American participants (odds ratio: 0.12;  = 0.01) despite there being no difference in prevalence of a specific genotype for any of the SNPs analyzed between nationalities. Finally, CD4+Glut1+ T cell percentage is elevated among those with a homozygous dominant genotype for SNPs rs1385129 (GG) and rs710218 (AA) when compared to those with a recessive allele (GA/AA and AT/TT respectively) ( < 0.04). The heterozygous genotype associated with AKT SNP 1130214 (GT) had a higher CD4+Glut1+ T cell percentage when compared to the dominant homozygous genotype (GG) ( = 0.0068). The frequency of circulating CD4+Glut1+ T cells and the rs1385129 SLC2A1 SNP may predict the rate of HIV disease progression and CD4+ T cell recovery in untreated and treated infection, respectively.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2018.00900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966582PMC
July 2019

The Role of Mitochondrial DNA Variation in Age-Related Decline in Gait Speed Among Older Men Living With Human Immunodeficiency Virus.

Clin Infect Dis 2018 08;67(5):778-784

Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland.

Background: Age-related gait speed decline is accelerated in men with human immunodeficiency virus (HIV). Mitochondrial genetic variation is associated with frailty and mortality in the general population and may provide insight into mechanisms of functional decline in people aging with HIV.

Methods: Gait speed was assessed semiannually in the Multicenter AIDS Cohort Study. Mitochondrial DNA (mtDNA) haplogroups were extracted from genome-wide genotyping data, classifying men aged ≥50 years into 5 groups: mtDNA haplogroup H, J, T, Uk, and other. Differences in gait speed by haplogroups were assessed as rate of gait speed decline per year, probability of slow gait speed (<1.0 m/s), and hazard of slow gait using multivariable linear mixed-effects models, mixed-effects logistic regression models, and the Andersen-Gill model, controlling for hepatitis C virus infection, previous AIDS diagnosis, thymidine analogues exposure, education, body composition, smoking, and peripheral neuropathy. Age was further controlled for in the mixed-effects logistic regression models.

Results: A total of 455 HIV-positive white men aged ≥50 years contributed 3283 person-years of follow-up. Among them, 70% had achieved HIV viral suppression. In fully adjusted models, individuals with haplogroup J had more rapid decline in gait speed (adjusted slopes, 0.018 m/s/year vs 0.011 m/s/year, pinteraction = 0.012) and increased risk of developing slow gait (adjusted odds ratio, 2.97; 95% confidence interval, 1.24-7.08) compared to those with other haplogroups.

Conclusions: Among older, HIV-infected men, mtDNA haplogroup J was an independent risk factor for more rapid age-related gait speed decline.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciy151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6093993PMC
August 2018

Frailty and subclinical coronary atherosclerosis: The Multicenter AIDS Cohort Study (MACS).

Atherosclerosis 2017 Nov 26;266:240-247. Epub 2017 Aug 26.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins School of Medicine, Baltimore, MD, USA. Electronic address:

Background And Aims: Frailty and cardiovascular disease share many risk factors. We evaluated whether frailty is independently associated with subclinical coronary atherosclerosis and whether any relationships differ by HIV-serostatus.

Methods: We studied 976 [62% HIV-infected] male participants of the Multicenter AIDS Cohort Study who underwent assessment of frailty and non-contrast cardiac CT scanning; of these, 747 men also underwent coronary CT angiography (CCTA). Frailty was defined as having ≥3 of 5 of the following: weakness, slowness, weight loss, exhaustion, and low physical activity. Coronary artery calcium (CAC) was assessed by non-contrast CT, and total plaque score (TPS), mixed plaque score (MPS), and non-calcified plaque score (NCPS) by CCTA. Multivariable-adjusted regression was used to assess the cross-sectional associations between frailty and subclinical coronary atherosclerosis.

Results: Mean (SD) age of participants was 54 (7) years; 31% were black. Frailty existed in 7.5% and 14.3% of HIV-uninfected and HIV-infected men, respectively. After adjustment for demographics, frailty was significantly associated with prevalence of any CAC (CAC>0), any plaque (TPS>0), and mixed plaque (MPS>0) in HIV-uninfected but not in HIV-infected men (p-interaction<0.05 for all). Among HIV-uninfected men, after adjustment for cardiovascular risk factors, frailty was significantly associated only with CAC>0 [Prevalence Ratio 1.27 (95%CI 1.02, 1.59)] and TPS>0 [1.19 (1.06, 1.35)]. No association was found for NCPS.

Conclusions: Frailty was independently associated with subclinical coronary atherosclerosis among HIV-uninfected men, but not among HIV-infected men. Further work is needed to ascertain mechanisms underlying these differences and whether interventions that improve frailty (i.e. strength training) can improve cardiovascular outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.atherosclerosis.2017.08.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5671901PMC
November 2017

HLA-B*14:02-Restricted Env-Specific CD8 T-Cell Activity Has Highly Potent Antiviral Efficacy Associated with Immune Control of HIV Infection.

J Virol 2017 11 27;91(22). Epub 2017 Oct 27.

Department of Paediatrics, University of Oxford, Oxford, United Kingdom.

Immune control of human immunodeficiency virus type 1 (HIV) infection is typically associated with effective Gag-specific CD8 T-cell responses. We here focus on HLA-B*14, which protects against HIV disease progression, but the immunodominant HLA-B*14-restricted anti-HIV response is Env specific (ERYLKDQQL, HLA-B*14-EL9). A subdominant HLA-B*14-restricted response targets Gag (DRYFKTLRA, HLA-B*14-DA9). Using HLA-B*14/peptide-saporin-conjugated tetramers, we show that HLA-B*14-EL9 is substantially more potent at inhibiting viral replication than HLA-B*14-DA9. HLA-B*14-EL9 also has significantly higher functional avidity ( < 0.0001) and drives stronger selection pressure on the virus than HLA-B*14-DA9. However, these differences were HLA-B*14 subtype specific, applying only to HLA-B*14:02 and not to HLA-B*14:01. Furthermore, the HLA-B*14-associated protection against HIV disease progression is significantly greater for HLA-B*14:02 than for HLA-B*14:01, consistent with the superior antiviral efficacy of the HLA-B*14-EL9 response. Thus, although Gag-specific CD8 T-cell responses may usually have greater anti-HIV efficacy, factors independent of protein specificity, including functional avidity of individual responses, are also critically important to immune control of HIV. In HIV infection, although cytotoxic T lymphocytes (CTL) play a potentially critical role in eradication of viral reservoirs, the features that constitute an effective response remain poorly defined. We focus on HLA-B*14, unique among HLAs associated with control of HIV in that the dominant CTL response is Env specific, not Gag specific. We demonstrate that Env-specific HLA-B*14-restricted activity is substantially more efficacious than the subdominant HLA-B*14-restricted Gag response. Env immunodominance over Gag and strong Env-mediated selection pressure on HIV are observed only in subjects expressing HLA-B*14:02, and not HLA-B*14:01. This reflects the increased functional avidity of the Env response over Gag, substantially more marked for HLA-B*14:02. Finally, we show that HLA-B*14:02 is significantly more strongly associated with viremic control than HLA-B*14:01. These findings indicate that, although Gag-specific CTL may usually have greater anti-HIV efficacy than Env responses, factors independent of protein specificity, including functional avidity, may carry greater weight in mediating effective control of HIV.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/JVI.00544-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5660483PMC
November 2017

Sensitivity and accuracy of high-throughput metabarcoding methods for early detection of invasive fish species.

Sci Rep 2017 04 13;7:46393. Epub 2017 Apr 13.

Systems Exposure Division, National Exposure Research Laboratory, Office of Research and Development, Environmental Protection Agency, Cincinnati, OH, 45268, United States of America.

High-throughput DNA metabarcoding has gained recognition as a potentially powerful tool for biomonitoring, including early detection of aquatic invasive species (AIS). DNA based techniques are advancing, but our understanding of the limits to detection for metabarcoding complex samples is inadequate. For detecting AIS at an early stage of invasion when the species is rare, accuracy at low detection limits is key. To evaluate the utility of metabarcoding in future fish community monitoring programs, we conducted several experiments to determine the sensitivity and accuracy of routine metabarcoding methods. Experimental mixes used larval fish tissue from multiple "common" species spiked with varying proportions of tissue from an additional "rare" species. Pyrosequencing of genetic marker, COI (cytochrome c oxidase subunit I) and subsequent sequence data analysis provided experimental evidence of low-level detection of the target "rare" species at biomass percentages as low as 0.02% of total sample biomass. Limits to detection varied interspecifically and were susceptible to amplification bias. Moreover, results showed some data processing methods can skew sequence-based biodiversity measurements from corresponding relative biomass abundances and increase false absences. We suggest caution in interpreting presence/absence and relative abundance in larval fish assemblages until metabarcoding methods are optimized for accuracy and precision.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep46393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5390320PMC
April 2017

Increased glucose transporter-1 expression on intermediate monocytes from HIV-infected women with subclinical cardiovascular disease.

AIDS 2017 01;31(2):199-205

aDepartment of Microbiology, University of the West Indies, Mona, Kingston, Jamaica bDepartment of Epidemiology and Population Health cDepartment of Medicine, Albert Einstein College of Medicine, Bronx, New York dDepartment of Pathology, SUNY Downstate Medical Center, New York City, New York eDivision of Infectious Diseases, Georgetown University, Washington, D.C fDepartment of Medicine, University of Southern California, Los Angeles gDepartment of Medicine, University of California, San Francisco, California hDepartment of Epidemiology, Johns Hopkins University, Baltimore, Maryland iDivision of Infectious Diseases, University of North Carolina, Chapel Hill, North Carolina jDepartment of Medicine, Emory University, Atlanta, Georgia kDivision of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida lDivision of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama mDepartment of Immunology and Microbiology, Rush University Medical Center, Chicago, Illinois, USA nCentre for Biomedical Research, Burnet Institute oDepartment of Infectious Diseases, Monash University pDepartment of Microbiology and Immunology, University of Melbourne, Melbourne, Victoria, Australia.

Objective: People living with HIV (PLWH) have chronic immune activation and increased cardiovascular disease (CVD) risk. Activation of monocytes and T lymphocytes causes upregulation of glucose transporter-1 (GLUT1) for efficient function. PLWH have an increased percentage of GLUT1-expressing monocytes and T lymphocytes, but it is unclear if these cells are associated with CVD. We evaluated the expression of GLUT1 and CD38 on monocyte and T lymphocyte populations from HIV-infected women with subclinical CVD.

Methods: Participants with more than 75th percentile (n = 15) and less than 25th percentile (n = 15) age-adjusted intima-media thickness (IMT) at the right common carotid artery and bifurcation were identified from the Women's Interagency HIV Study. Groups were matched by age, race/ethnicity, smoking status, and CD4 cell count. All women were receiving suppressive antiretroviral therapy except for one high and one low IMT participant. Monocyte and T lymphocyte populations were evaluated for GLUT1 and CD38 expression using flow cytometry.

Results: Intermediate monocytes from high IMT women had significantly increased expression of GLUT1 (310 MFI vs. 210 MFI, P = 0.024) (66.4% vs. 48.5%, P = 0.031) and CD38 (339 MFI vs. 211 MFI, P = 0.002) (10.5% vs. 3.8%, P = 0.0002) compared with women with low IMT. High and low IMT participants showed no differences in GLUT1 or CD38 expression on classical monocytes, nonclassical monocytes, CD4 and CD8 T lymphocytes.

Conclusion: GLUT1-expressing intermediate monocytes are elevated in HIV-infected women with subclinical CVD. These cells may contribute to development of CVD in PLWH and could be a novel target to limit inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/QAD.0000000000001320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5393043PMC
January 2017

MicroRNA-related polymorphisms and non-Hodgkin lymphoma susceptibility in the Multicenter AIDS Cohort Study.

Cancer Epidemiol 2016 Dec 1;45:47-57. Epub 2016 Oct 1.

Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles (UCLA), Box 951772, 71-267 CHS, Los Angeles, CA 90095-1772, USA; Department of Medicine and Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, 8700 Beverly Blvd, West Hollywood, CA 90048, USA.

Background: MicroRNAs, small non-coding RNAs involved in gene regulation, are implicated in lymphomagenesis. We evaluated whether genetic variations in microRNA coding regions, binding sites, or biogenesis genes (collectively referred to as miRNA-SNPs) were associated with risk of AIDS-associated non-Hodgkin lymphoma (AIDS-NHL), and serum levels of four lymphoma-related microRNAs.

Methods: Twenty-five miRNA-SNPs were genotyped in 180 AIDS-NHL cases and 529 HIV-infected matched controls from the Multicenter AIDS Cohort Study (MACS), and real-time polymerase chain reaction was used to quantify serum microRNA levels. Adjusted odds ratios (ORs) estimated using conditional logistic regression evaluated associations between miRNA-SNPs and AIDS-NHL risk. A semi-Bayes shrinkage approach was employed to reduce likelihood of false-positive associations. Adjusted mean ratios (MR) calculated using linear regression assessed associations between miRNA-SNPs and serum microRNA levels.

Results: DDX20 rs197412, a non-synonymous miRNA biogenesis gene SNP, was associated with AIDS-NHL risk (OR=1.34 per minor allele; 95% CI: 1.02-1.75), and higher miRNA-222 serum levels nearing statistical significance (MR=1.21 per minor allele; 95% CI: 0.98-1.49). MiRNA-196a2 rs11614913 was associated with decreased central nervous system (CNS) AIDS-NHL (CT vs. CC OR=0.52; 95% CI: 0.27-0.99). The minor allele of HIF1A rs2057482, which creates a miRNA-196a2 binding site, was associated with systemic AIDS-NHL risk (OR=1.73 per minor allele; 95% CI: 1.12-2.67), and decreased CNS AIDS-NHL risk (OR=0.49 per minor allele; 95% CI: 0.25-0.94).

Conclusions: This study suggests that a few miRNA-SNPs are associated with AIDS-NHL risk and may modulate miRNA expression. These results support a role for miRNA in AIDS-NHL and may highlight pathways to be targeted for risk stratification or therapeutics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.canep.2016.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127653PMC
December 2016

Genetic basis for rapidly evolved tolerance in the wild: adaptation to toxic pollutants by an estuarine fish species.

Mol Ecol 2016 11 20;25(21):5467-5482. Epub 2016 Oct 20.

U.S. Environmental Protection Agency, Office of Research and Development, National Exposure Research Laboratory, Ecological Exposure Research Division, 26 W. Martin Luther King Dr., Cincinnati, OH, 45268, USA.

Atlantic killifish (Fundulus heteroclitus) residing in some urban and industrialized estuaries of the US eastern seaboard demonstrate recently evolved and extreme tolerance to toxic aryl hydrocarbon pollutants, characterized as dioxin-like compounds (DLCs). Here, we provide an unusually comprehensive accounting (69%) through quantitative trait locus (QTL) analysis of the genetic basis for DLC tolerance in killifish inhabiting an urban estuary contaminated with PCB congeners, the most toxic of which are DLCs. Consistent with mechanistic knowledge of DLC toxicity in fish and other vertebrates, the aryl hydrocarbon receptor (ahr2) region accounts for 17% of trait variation; however, QTL on independent linkage groups and their interactions have even greater explanatory power (44%). QTL interpreted within the context of recently available Fundulus genomic resources and shared synteny among fish species suggest adaptation via interacting components of a complex stress response network. Some QTL were also enriched in other killifish populations characterized as DLC-tolerant and residing in distant urban estuaries contaminated with unique mixtures of pollutants. Together, our results suggest that DLC tolerance in killifish represents an emerging example of parallel contemporary evolution that has been driven by intense human-mediated selection on natural populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/mec.13848DOI Listing
November 2016