This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.It has not been determined whether implementation of combined prevention programming for persons who inject drugs reduce racial/ethnic disparities in HIV infection. We examine racial/ethnic disparities in New York City among persons who inject drugs after implementation of the New York City Condom Social Marketing Program in 2007. Quantitative interviews and HIV testing were conducted among persons who inject drugs entering Mount Sinai Beth Israel drug treatment (2007-2014). 703 persons who inject drugs who began injecting after implementation of large-scale syringe exchange were included in the analyses. Factors independently associated with being HIV seropositive were identified and a published model was used to estimate HIV infections due to sexual transmission. Overall HIV prevalence was 4%; Whites 1%, African-Americans 17%, and Hispanics 4%. Adjusted odds ratios were 21.0 (95% CI 5.7, 77.5) for African-Americans to Whites and 4.5 (95% CI 1.3, 16.3) for Hispanics to Whites. There was an overall significant trend towards reduced HIV prevalence over time (adjusted odd ratio = 0.7 per year, 95% confidence interval (0.6-0.8). An estimated 75% or more of the HIV infections were due to sexual transmission. Racial/ethnic disparities among persons who inject drugs were not significantly different from previous disparities. Reducing these persistent disparities may require new interventions (treatment as prevention, pre-exposure prophylaxis) for all racial/ethnic groups.
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Matthew C. L. Keith;
Xian-Liang Tang;
Yukichi Tokita;
Qian-hong Li;
Shahab Ghafghazi;
Joseph Moore;
Kyung U. Hong;
Brandon Elmore;
Alok Amraotkar;
Brian L. Ganzel;
Kendra Grubb;
Michael P. Flaherty;
Gregory Hunt;
Bathri Vajravelu;
Marcin Wysoczynski;
Roberto Bolli
Background: There is mounting interest in using c-kit positive human cardiac stem cells (c-kit<sup>pos</sup> hCSCs) to repair infarcted myocardium in patients with ischemic cardiomyopathy. A recent phase I clinical trial (SCIPIO) has shown that intracoronary infusion of 1 million hCSCs is safe. Higher doses of CSCs may provide superior reparative ability; however, it is unknown if doses >1 million cells are safe. To address this issue, we examined the effects of 20 million hCSCs in pigs. Methods: Right atrial appendage samples were obtained from patients undergoing cardiac surgery. The tissue was processed by an established protocol with eventual immunomagnetic sorting to obtain in vitro expanded hCSCs. A cumulative dose of 20 million cells was given intracoronarily to pigs without stop flow. Safety was assessed by measurement of serial biomarkers (cardiac: troponin I and CK-MB, renal: creatinine and BUN, and hepatic: AST, ALT, and alkaline phosphatase) and echocardiography pre- and post-infusion. hCSC retention 30 days after infusion was quantified by PCR for human genomic DNA. All personnel were blinded as to group assignment. Results: Compared with vehicle-treated controls (n=5), pigs that received 20 million hCSCs (n=9) showed no significant change in cardiac function or end organ damage (assessed by organ specific biomarkers) that could be attributed to hCSCs (P>0.05 in all cases). No hCSCs could be detected in left ventricular samples 30 days after infusion. Conclusions: Intracoronary infusion of 20 million c-kit positive hCSCs in pigs (equivalent to ∼40 million hCSCs in humans) does not cause acute cardiac injury, impairment of cardiac function, or liver and renal injury. These results have immediate translational value and lay the groundwork for using doses of CSCs >1 million in future clinical trials. Further studies are needed to ascertain whether administration of >1 million hCSCs is associated with greater efficacy in patients with ischemic cardiomyopathy.
Background: The pathomechanisms of atherosclerosis and vascular remodelling are under intense research. Only a few in vivo tools to study these processes longitudinally in animal experiments are available. Here, we evaluated the potential of micro-CT technology. Methods: Lumen areas of the common carotid arteries (CCA) in the ApoE<sup>-/-</sup> partial carotid artery ligation mouse model were compared between in vivo and ex vivo micro-CT technique and serial histology in a total of 28 animals. AuroVist-15 nm nanoparticles were used as in vivo blood pool contrast agent in a Skyscan 1176 micro-CT at resolution of 18 μmeter voxel size and a mean x-ray dose of 0.5 Gy. For ex vivo imaging, animals were perfused with MicroFil and imaged at 9 μmeter voxel size. Lumen area was evaluated at postoperative days 7, 14, and 28 first by micro-CT followed by histology. Results: In vivo micro-CT and histology revealed lumen loss starting at day 14. The lumen profile highly correlated (r = 0.79, P<0.0001) between this two methods but absolute lumen values obtained by histology were lower than those obtained by micro-CT. Comparison of in vivo and ex vivo micro-CT imaging revealed excellent correlation (r = 0.83, P<0.01). Post mortem micro-CT yielded a higher resolution than in vivo micro-CT but there was no statistical difference of lumen measurements in the partial carotid artery ligation model. Conclusion: These data demonstrate that in vivo micro-CT is a feasible and accurate technique with low animal stress to image remodeling processes in the murine carotid artery.
Autophagy, an ancient homeostasis mechanism for macromolecule degradation, performs an important role in host defense by facilitating pathogen elimination. To counteract this host defense strategy, bacterial pathogens have evolved a variety of mechanisms to avoid or otherwise dysregulate autophagy by phagocytic cells so as to enhance their survival during infection. Neisseria gonorrhoeae is a strictly human pathogen that causes the sexually transmitted infection, gonorrhea. Phosphoethanolamine (PEA) addition to the 4' position of the lipid A (PEA-lipid A) moiety of the lipooligosaccharide (LOS) produced by gonococci performs a critical role in this pathogen's ability to evade innate defenses by conferring decreased susceptibility to cationic antimicrobial (or host-defense) peptides, complementmediated killing by human serum and intraleukocytic killing by human neutrophils compared to strains lacking this PEA decoration. Heretofore, however, it was not known if gonococci can evade autophagy and if so, whether PEA-lipid A contributes to this ability. Accordingly, by using murine macrophages and human macrophage-like phagocytic cell lines we investigated if PEA decoration of gonococcal lipid A modulates autophagy formation. We report that infection with PEA-lipid A-producing gonococci significantly reduced autophagy flux in murine and human macrophages and enhanced gonococcal survival during their association with macrophages compared to a PEA-deficient lipid A mutant. Our results provide further evidence that PEA-lipid A produced by gonococci is a critical component in the ability of this human pathogen to evade host defenses. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Caileen M. Brison;
Steven M. Mullen;
Michelle E. Wuerth;
Kira Podolsky;
Matthew Cook;
Jacob A. Herman;
Justin D. Walter;
Shannon Meeks;
P. Clint Spiegel
The factor VIII C2 domain is essential for binding to activated platelet surfaces as well as the cofactor activity of factor VIII in blood coagulation. Inhibitory antibodies against the C2 domain commonly develop following factor VIII replacement therapy for hemophilia A patients, or they may spontaneously arise in cases of acquired hemophilia. Porcine factor VIII is an effective therapeutic for hemophilia patients with inhibitor due to its low cross-reactivity; however, the molecular basis for this behavior is poorly understood. In this study, the X-ray crystal structure of the porcine factor VIII C2 domain was determined, and superposition of the human and porcine C2 domains demonstrates that most surface-exposed differences cluster on the face harboring the "non-classical" antibody epitopes. Furthermore, antibody-binding results illustrate that the "classical" 3E6 antibody can bind both the human and porcine C2 domains, although the inhibitory titer to human factor VIII is 41 Bethesda Units (BU)/mg IgG versus 0.8 BU/mg IgG to porcine factor VIII, while the non-classical G99 antibody does not bind to the porcine C2 domain nor inhibit porcine factor VIII activity. Further structural analysis of differences between the electrostatic surface potentials suggest that the C2 domain binds to the negatively charged phospholipid surfaces of activated platelets primarily through the 3E6 epitope region. In contrast, the G99 face, which contains residue 2227, should be distal to the membrane surface. Phospholipid binding assays indicate that both porcine and human factor VIII C2 domains bind with comparable affinities, and the human K2227A and K2227E mutants bind to phospholipid surfaces with similar affinities as well. Lastly, the G99 IgG bound to PS-immobilized factor VIII C2 domain with an apparent dissociation constant of 15.5 nM, whereas 3E6 antibody binding to PS-bound C2 domain was not observed.
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Hyman M. Scott;
Risha Irvin;
Leo Wilton;
Hong Van Tieu;
Chauncey Watson;
Manya Magnus;
Iris Chen;
Charlotte Gaydos;
Sophia Hussen;
Sharon Mannheimer;
Kenneth Mayer;
Nancy A. Hessol;
Susan Buchbinder
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background: Black men who have sex with men (MSM) have a high prevalence of bacterial sexually transmitted infections (STIs), and individual risk behavior does not fully explain the higher prevalence when compared with other MSM. Using the social-ecological framework, we evaluated individual, social and sexual network, and structural factors and their association with prevalent STIs among Black MSM. Methods: The HIV Prevention Trials Network 061 was a multi-site cohort study designed to determine the feasibility and acceptability of a multi-component intervention for Black MSM in six US cities. Baseline assessments included demographics, risk behavior, and social and sexual network questions collected information about the size, nature and connectedness of their sexual network. Logistic regression was used to estimate the odds of having any prevalent sexually transmitted infection (gonorrhea, chlamydia, or syphilis). Results: A total of 1,553 Black MSM were enrolled in this study. In multivariate analysis, older age (aOR = 0.57; 95% CI 0.49-0.66, p<0.001) was associated with a lower odds of having a prevalent STI. Compared with reporting one male sexual partner, having 2-3 partners (aOR = 1.74; 95% CI 1.08-2.81, p<0.024) or more than 4 partners (aOR = 2.29; 95% CI 1.43-3.66, p<0.001) was associated with prevalent STIs. Having both Black and non-Black sexual partners (aOR = 0.67; 95% CI 0.45-0.99, p = 0.042) was the only sexual network factor associated with prevalent STIs. Conclusions: Age and the number and racial composition of sexual partners were associated with prevalent STIs among Black MSM, while other sexual network factors were not. Further studies are needed to evaluate the effects of the individual, network, and structural factors on prevalent STIs among Black MSM to inform combination interventions to reduce STIs among these men.
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Andrew W. Bergen;
Martha Michel;
Denise Nishita;
Ruth Krasnow;
Harold S. Javitz;
Karen Conneely;
Christina N. Lessov-Schlaggar;
Hyman Hops;
Andy Z. X. Zhu;
James W. Baurley;
Jennifer B. McClure;
Sharon M. Hall;
Timothy B. Baker;
David V. Conti;
Neal L. Benowitz;
Caryn Lerman;
Rachel F. Tyndale;
Gary E. Swan
The Nicotine Metabolite Ratio (NMR, ratio of trans-3'-hydroxycotinine and cotinine), has previously been associated with CYP2A6 activity, response to smoking cessation treatments, and cigarette consumption. We searched for drug metabolizing enzyme and transporter (DMET) gene variation associated with the NMR and prospective abstinence in 2,946 participants of laboratory studies of nicotine metabolism and of clinical trials of smoking cessation therapies. Stage I was a meta-analysis of the association of 507 common single nucleotide polymorphisms (SNPs) at 173 DMET genes with the NMR in 449 participants of two laboratory studies. Nominally significant associations were identified in ten genes after adjustment for intragenic SNPs; CYP2A6 and two CYP2A6 SNPs attained experiment-wide significance adjusted for correlated SNPs (CYP2A6 P<inf>ACT</inf>=4.1E-7, rs4803381 P<inf>ACT</inf>=4.5E-5, rs1137115, P<inf>ACT</inf>=1.2E-3). Stage II was mega-regression analyses of 10 DMET SNPs with pretreatment NMR and prospective abstinence in up to 2,497 participants from eight trials. rs4803381 and rs1137115 SNPs were associated with pretreatment NMR at genome-wide significance. In post-hoc analyses of CYP2A6 SNPs, we observed nominally significant association with: abstinence in one pharmacotherapy arm; cigarette consumption among all trial participants; and lung cancer in four case:control studies. CYP2A6 minor alleles were associated with reduced NMR, CPD, and lung cancer risk. We confirmed the major role that CYP2A6 plays in nicotine metabolism, and made novel findings with respect to genome-wide significance and associations with CPD, abstinence and lung cancer risk. Additional multivariate analyses with patient variables and genetic modeling will improve prediction of nicotine metabolism, disease risk and smoking cessation treatment prognosis.
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Kaval Kaur;
Nai-Ying Zheng;
Kenneth Smith;
Min Huang;
Lie Li;
Noel T. Pauli;
Carole J. Henry Dunand;
Jane-Hwei Lee;
Michael Morrissey;
Yixuan Wu;
Michelle L. Joachims;
Melissa E. Munroe;
Denise Lau;
Xinyan Qu;
Florian Krammer;
Jens Wrammert;
Peter Palese;
Rafi Ahmed;
Judith A. James;
Patrick C. Wilson
Breakdown of B cell tolerance is a cardinal feature of systemic lupus erythematosus (SLE). Increased numbers of autoreactive mature naïve B cells have been described in SLE patients and autoantibodies have been shown to arise from autoreactive and non-autoreactive precursors. How these defects, in the regulation of B cell tolerance and selection, influence germinal center (GC) reactions that are directed towards foreign antigens has yet to be investigated. Here, we examined the characteristics of post-GC foreign antigen-specific B cells from SLE patients and healthy controls by analyzing monoclonal antibodies generated from plasmablasts induced specifically by influenza vaccination. We report that many of the SLE patients had anti-influenza antibodies with higher binding affinity and neutralization capacity than those from controls. Although overall frequencies of autoreactivity in the influenza-specific plasmablasts were similar for SLE patients and controls, the variable gene repertoire of influenza-specific plasmablasts from SLE patients was altered, with increased usage of JH6 and long heavy chain CDR3 segments. We found that high affinity anti-influenza antibodies generally characterize the plasmablast responses of SLE patients with low levels of autoreactivity; however, certain exceptions were noted. The high-avidity antibody responses in SLE patients may also be correlated with cytokines that are abnormally expressed in lupus. These findings provide insights into the effects of dysregulated immunity on the quality of antibody responses following influenza vaccination and further our understanding of the underlying abnormalities of lupus.
Objective: To examine the associations between occupation, sleep duration and sleep quality. Methods: The data for this study was extracted from data collected from the 2008 Chinese Suboptimal Health Study. Our study sample consisted of 18,316 Chinese subjects aged 18-65. Occupation and other relevant characteristics to sleep were collected. We used the Pittsburgh Sleep Quality Index (PSQI) to measure sleep quality and multiple logistic regression models to examine the association of occupation with shortened sleep duration and poor sleep quality. Results: Farmers had the longest sleep duration (mean=8.22 hours) while the civil servants had the shortest sleep duration (mean=7.85 hours). Farmers also had the best sleep quality (mean score=3.74) while professional workers had the worst sleep quality (mean score=4.87). Compared to civil servants, the OR of shortened sleep duration and poor sleep quality for blue collar workers is 1.39 (95%CI: 1.11-1.73) and 1.28 (95%-CI: 1.15-1.42), respectively, after adjusting for age, sex, marital status, education, area, smoking, drinking, pain, and health status. Conclusion: sleep duration and quality varied among different Chinese occupation populations. The blue collar workers are more likely to have shortened sleep duration and poor sleep quality.
Stone tools provide some of the most abundant, continuous, and high resolution evidence of behavioral change over human evolution, but their implications for cognitive evolution have remained unclear. We investigated the neurophysiological demands of stone toolmaking by training modern subjects in known Paleolithic methods ("Oldowan", "Acheulean") and collecting structural and functional brain imaging data as they made technical judgments (outcome prediction, strategic appropriateness) about planned actions on partially completed tools. Results show that this task affected neural activity and functional connectivity in dorsal prefrontal cortex, that effect magnitude correlated with the frequency of correct strategic judgments, and that the frequency of correct strategic judgments was predictive of success in Acheulean, but not Oldowan, toolmaking. This corroborates hypothesized cognitive control demands of Acheulean toolmaking, specifically including information monitoring and manipulation functions attributed to the "central executive" of working memory. More broadly, it develops empirical methods for assessing the differential cognitive demands of Paleolithic technologies, and expands the scope of evolutionary hypotheses that can be tested using the available archaeological record.