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1.  Admixture Analysis of Spontaneous Hepatitis C Virus Clearance in Individuals of African-Descent 
Genes and immunity  2014;15(4):241-246.
Hepatitis C virus (HCV) infects an estimated 3% of the global population with the majority of individuals (75–85%) failing to clear the virus without treatment, leading to chronic liver disease. Individuals of African-descent have lower rates of clearance compared to individuals of European-descent and this is not fully explained by social and environmental factors. This suggests that differences in genetic background may contribute to this difference in clinical outcome following HCV infection. Using 473 individuals and 792,721 SNPs from a genome-wide association study (GWAS), we estimated local African ancestry across the genome. Using admixture mapping and logistic regression we identified two regions of interest associated with spontaneous clearance of HCV (15q24, 20p12). A genome-wide significant variant was identified on chromosome 15 at the imputed SNP, rs55817928 (P=6.18×10−8) between the genes SCAPER and RCN. Each additional copy of the African ancestral C allele is associated with 2.4 times the odds of spontaneous clearance. Conditional analysis using this SNP in the logistic regression model explained one-third of the local ancestry association. Additionally, signals of selection in this area suggest positive selection due to some ancestral pathogen or environmental pressure in African, but not in European populations.
doi:10.1038/gene.2014.11
PMCID: PMC4308959  PMID: 24622687
Hepatitis C; Chronic Infection; Admixture; African Ancestry
2.  Hepatitis C Virus Infection Is Not An Independent Risk Factor For Obstructive Lung Disease 
COPD  2013;11(1):10-16.
Several epidemiological studies have suggested that hepatitis C virus (HCV) infection is associated with the presence of obstructive lung disease (OLD). However, there is a strong link between HCV infection and tobacco abuse, a major risk factor for the development of OLD. In this study we analyzed clinical, laboratory and spirometric data from 1068 study participants to assess whether HCV infection, viremia, or HCV-associated end organ damage were associated with OLD. Demographics, risk behavior, serologic status for HCV and HIV, and spirometric measurements were collected from a cross-sectional analysis of the Acquired Immunodeficiency Syndrome (AIDS) Linked to the IntraVenous Experience (ALIVE) study, an observational cohort of IDUs followed in Baltimore, MD since 1988. Of 1,068 participants, 890 (83%) were HCV positive and 174 (16%) met spirometric criteria for OLD. Factors independently associated with OLD were age and BMI. HCV infection, viral load and HCV-associated end organ damage were similar in participants with and without OLD. In summary, there was no independent association between markers of HCV exposure, chronicity, viremia, or HCV-associated end-organ damage with OLD. Our findings support the strong correlation between HCV status, injection drug use, and smoking. These data suggest that HCV may not be a sole contributor to the increased prevalence of OLD described in previous studies of HCV-infected individuals.
doi:10.3109/15412555.2013.800854
PMCID: PMC4302731  PMID: 23862666
chronic viral infections; injection drug users; HIV; Obstructive Lung Disease
3.  High Frequency of False-Positive Hepatitis C Virus Enzyme-Linked Immunosorbent Assay in Rakai, Uganda 
The prevalence of hepatitis C virus (HCV) infection in sub-Saharan Africa remains unclear. We tested 1000 individuals from Rakai, Uganda, with the Ortho version 3.0 HCV enzyme-linked immunosorbent assay. All serologically positive samples were tested for HCV RNA. Seventy-six of the 1000 (7.6%) participants were HCV antibody positive; none were confirmed by detection of HCV RNA.
doi:10.1093/cid/cit602
PMCID: PMC3840403  PMID: 24051866
hepatitis C virus; ELISA; Africa
4.  Inferring Viral Dynamics in Chronically HCV Infected Patients from the Spatial Distribution of Infected Hepatocytes 
PLoS Computational Biology  2014;10(11):e1003934.
Chronic liver infection by hepatitis C virus (HCV) is a major public health concern. Despite partly successful treatment options, several aspects of intrahepatic HCV infection dynamics are still poorly understood, including the preferred mode of viral propagation, as well as the proportion of infected hepatocytes. Answers to these questions have important implications for the development of therapeutic interventions. In this study, we present methods to analyze the spatial distribution of infected hepatocytes obtained by single cell laser capture microdissection from liver biopsy samples of patients chronically infected with HCV. By characterizing the internal structure of clusters of infected cells, we are able to evaluate hypotheses about intrahepatic infection dynamics. We found that individual clusters on biopsy samples range in size from infected cells. In addition, the HCV RNA content in a cluster declines from the cell that presumably founded the cluster to cells at the maximal cluster extension. These observations support the idea that HCV infection in the liver is seeded randomly (e.g. from the blood) and then spreads locally. Assuming that the amount of intracellular HCV RNA is a proxy for how long a cell has been infected, we estimate based on models of intracellular HCV RNA replication and accumulation that cells in clusters have been infected on average for less than a week. Further, we do not find a relationship between the cluster size and the estimated cluster expansion time. Our method represents a novel approach to make inferences about infection dynamics in solid tissues from static spatial data.
Author Summary
Around 170 million people worldwide are chronically infected with the hepatitis C virus (HCV). Although partly successful treatment options are available, several aspects of HCV infection dynamics within the liver are still poorly understood. How many hepatocytes are infected during chronic HCV infection? How does the virus propagate, and how do innate immune responses interfere with the spread of the virus? We developed mathematical and computational methods to study liver biopsy samples of patients chronically infected with HCV that were analyzed by single cell laser capture microdissection, to infer the spatial distribution of infected cells. With these methods, we find that infected cells on biopsy sections tend to occur in clusters comprising 4–50 hepatocytes, and, based on their amount of intracellular viral RNA, that these cells have been infected for less than a week. The observed HCV RNA profile within clusters of infected cells suggests that factors such as local immune responses could have shaped cluster expansion and intracellular viral replication. Our methods can be applied to various types of infections in order to infer infection dynamics from spatial data.
doi:10.1371/journal.pcbi.1003934
PMCID: PMC4230741  PMID: 25393308
5.  Genome-Wide Association Study of Hepatitis C Virus- and Cryoglobulin-Related Vasculitis 
Genes and immunity  2014;15(7):500-505.
Objectives
The host genetic basis of mixed cryoglobulin vasculitis is not well understood and has not been studied in large cohorts. A genome-wide association study was conducted among 356 HCV RNA positive individuals with cryoglobulin-related vasculitis and 447 ethnically-matched, HCV RNA positive controls.
Methods
All cases had both serum cryoglobulins as well as a vasculitis syndrome. A total of 899,641 markers from the Illumina HumanOmni1-Quad chip were analyzed using logistic regression adjusted for sex, as well as genetically-determined ancestry. Replication of select single nucleotide polymorphisms (SNPs) was conducted using 91 cases and 180 controls, adjusting for sex and country of origin.
Results
The most significant associations were identified on chromosome 6 near the NOTCH4 and MHC class II genes. A genome-wide significant association was detected on chromosome 6 at SNP rs9461776 (OR= 2.16, p=1.16E-07) between HLA-DRB1 and DQA1: this association was further replicated in additional independent samples (meta-analysis p=7.1×10−9).
Conclusions
A genome-wide significant association with cryoglobulin related vasculitis was identified with SNPs near NOTCH4 and MHC Class II genes. The two regions are correlated and it is difficult to disentangle which gene is responsible for the association with MC vasculitis in this extended MHC region.
doi:10.1038/gene.2014.41
PMCID: PMC4208981  PMID: 25030430
Genome-Wide Association Study; Cryoglobulinemia; Human Leukocyte Antigen; SNP
6.  Hepatitis C Virus Vaccines Among People Who Inject Drugs 
Most people who inject drugs (PWID) are infected with hepatitis C virus (HCV), and PWID have the highest risk of HCV infection of any risk group. The incidence of HCV infection is 5%–25% per year, demonstrating continued need for HCV infection prevention in PWID. Existing data in chimpanzees and PWID suggest that protective immunity against persistent HCV infection is achievable. Due to the high incidence of infection, PWID are both the most likely to benefit from a vaccine and a population in which vaccine efficacy could be tested. Challenges to testing a vaccine in PWID are significant. However, the first HCV vaccine trial in at-risk HCV-uninfected PWID was initiated in 2012. The results will likely guide future vaccine development and strategies for vaccination of this and other high-risk populations.
doi:10.1093/cid/cit329
PMCID: PMC3722079  PMID: 23884065
hepatitis C virus; viral hepatitis; injection drug users; vaccine; hepatitis
7.  Metabolic Changes in the Spinal Cord After Brachial Plexus Root Re-implantation 
Objective. To investigate metabolic changes within the spinal cord using proton magnetic resonance spectroscopy (1H-MRS) and determine their relationship with clinical function in patients with complete brachial plexus avulsion who underwent reimplantation of the ventral roots. Methods. Single-voxel 1H-MRS of the cord between C1 and C3 was performed in 10 patients with normal spinal cord on MRI, who underwent reimplantation of C5 to T1 ventral roots on average 5.5 years earlier, and 19 healthy controls. The ratios of the concentrations of the following main metabolites, with respect to total creatine levels, were obtained: total N-acetyl-aspartate, choline-containing compounds, creatine and phosphocreatine (Cr), and myo-inositol (m-Ins). Patient disability was assessed using upper limb scales. Differences in metabolite concentration ratios and their correlations with disability were investigated. Results. Patients showed increased m-Ins/Cr ratio compared with controls, which was associated with the level of function of the affected arm and time from injury. Conclusions. The finding of increased m-Ins/Cr in patients suggests that reactive gliosis, perhaps in response to the degeneration of avulsed fibers, may occur in the spinal cord above the site of injury and be relevant to motor dysfunction. However, this pathological process appears to diminish with time. These insights underline the need to integrate metabolic imaging with structural and functional magnetic resonance imaging to obtain a complete view of spinal cord plasticity. Last, this study provides the first steps toward identifying markers to serve as outcome measures for trials comparing strategies of plexus repair following avulsion injury.
doi:10.1177/1545968312457825
PMCID: PMC4107801  PMID: 22961264
spinal cord trauma; brachial plexus avulsion; magnetic resonance spectroscopy; brachial plexus reimplantation
8.  Curing hepatitis C with pills: a step toward global control 
Lancet  2010;376(9751):1441-1442.
doi:10.1016/S0140-6736(10)61497-3
PMCID: PMC4083467  PMID: 20951421
9.  Interleukin-28b: A Key Piece of the Hepatitis C Virus Recovery Puzzle 
Gastroenterology  2010;138(4):1240-1243.
doi:10.1053/j.gastro.2010.02.033
PMCID: PMC3805379  PMID: 20184973
10.  Genome wide association study of spontaneous resolution of hepatitis C virus infection 
Annals of internal medicine  2013;158(4):235-245.
Background
Hepatitis C virus (HCV) infections occur worldwide and either spontaneously resolve or persist and markedly increase the person’s lifetime risk of cirrhosis and hepatocellular carcinoma. Although HCV persistence occurs more often in persons of African ancestry and in persons with a genetic variant near IL28B, the genetic basis is not well understood.
Objective
To evaluate the host genetic basis for spontaneous resolution of HCV infection.
Design
Two-stage genome wide association study (GWAS).
Setting
13 international multicenter study sites.
Patients
919 individuals with serum HCV antibodies but no HCV RNA (spontaneous resolution) and 1482 individuals with serum HCV antibodies and RNA (persistence).
Measurements
Frequencies of 792,721 SNPs.
Results
Differences in allele frequencies between persons with spontaneous resolution and persistence were identified on chromosomes 19q13.13 and 6p21.32. On chromosome 19, allele frequency differences localized near IL28B and included rs12979860 (overall per-allele OR = 0.45, P = 2.17 × 10−30) and 10 additional SNPs spanning 55,000 bases. On chromosome 6, allele frequency differences localized near genes for class II human leukocyte antigens (HLA) and included rs4273729 (overall per-allele OR= 0.59, P = 1.71 × 10−16) near DQB1*03:01 and an additional 116 SNPs spanning 1,090,000 base pairs. The associations in chromosomes 19 and 6 were independent, additive, and explain an estimated 14.9% (95% CI: 8.5–22.6%) of the variation in HCV resolution in those of European-Ancestry, and 15.8% (95% CI:4.4–31.0%) in individuals of African-Ancestry. Replication of the chromosome 6 SNP, rs4272729 in an additional 746 individuals confirmed the findings (p=0.015).
Limitations
Epigenetic effects were not studied.
Conclusions
IL28B and HLA class II are independently associated with spontaneous resolution of HCV infection and SNPs marking IL28B and DQB1*03:01 may explain ~15% of spontaneous resolution of HCV infection.
doi:10.7326/0003-4819-158-4-201302190-00003
PMCID: PMC3638215  PMID: 23420232
11.  Use of Laser Capture Microdissection to Map Hepatitis C Virus–Positive Hepatocytes in Human Liver 
Gastroenterology  2013;145(6):1404-13.e1-10.
BACKGROUND & AIMS
Hepatitis C virus (HCV) predominantly infects hepatocytes, but many hepatocytes are not infected; studies have shown that HCV antigens cluster within the liver. We investigated spatial distribution and determinants of HCV replication in human liver samples.
METHODS
We analyzed liver samples from 4 patients with chronic HCV infection (genotype 1, Metavir scores 0–1) to estimate the proportion of infected hepatocytes and the amount of HCV viral RNA (vRNA) per cell. Single-cell laser capture microdissection was used to capture more than 1000 hepatocytes in grids, to preserve geometric relationships. HCV vRNA and interferon-induced transmembrane protein 3 (IFITM3) messenger RNA (the transcript of an interferon-stimulated gene) were measured in the same hepatocytes by quantitative polymerase chain reaction and assembled in maps to identify areas of high and low HCV replication.
RESULTS
Patients’ serum levels of HCV RNA ranged from 6.87 to 7.40 log10 IU/mL; the proportion of HCV-infected hepatocytes per person ranged from 21% to 45%, and the level of vRNA ranged from 1 to 50 IU/hepatocyte. Infection was not random; we identified clustering of HCV-positive hepatocytes using infected-neighbor analysis (P < .0005) and distance to the kth nearest neighbor compared with random distributions, obtained by bootstrap simulations (P < .02). Hepatocytes that expressed IFITM3 did not appear to cluster and were largely HCV negative.
CONCLUSIONS
We used single-cell laser capture and high-resolution analysis to show that in human liver HCV infects hepatocytes in nonrandom clusters, whereas expression of antiviral molecules is scattered among hepatocytes. These findings show that quantitative single-cell RNA measurements can be used to estimate the abundance of HCV vRNA per infected human hepatocyte and are consistent with cell–cell propagation of infection in the absence of clustered IFITM3.
doi:10.1053/j.gastro.2013.08.034
PMCID: PMC4005338  PMID: 23973767
ISG; Intrahepatic Infection; Virology; scLCM
12.  HIV, Age, and the Severity of Hepatitis C Virus–Related Liver Disease 
Annals of internal medicine  2013;158(9):658-666.
Background
Persons with HIV infection have been reported to develop age-related diseases at younger ages than those without HIV. Whether this finding is related to HIV infection or failure to control for other risk factors is unknown.
Objective
To investigate whether persons with HIV infection develop hepatitis C virus (HCV)–related liver disease at younger ages than similar persons without HIV.
Design
Comparison of the severity of liver fibrosis by age among persons who have HCV with and without HIV followed concurrently in the same protocol.
Setting
Observational cohort from Baltimore, Maryland, participating in the ALIVE (AIDS Linked to the IntraVenous Experience) study.
Participants
1176 current and former injection drug users with antibodies to HCV.
Measurements
Liver fibrosis assessed semiannually from 2006 to 2011 by elastography (FibroScan, Echosens, Paris, France) and using previously validated thresholds for clinically significant fibrosis and cirrhosis; concurrent assessment of medical history, alcohol and illicit drug use, HCV RNA levels, hepatitis B virus surface antigen level, body mass index, and (for those with HIV) CD4+ lymphocyte count and HIV RNA levels.
Results
Among 1176 participants with antibodies to HCV, the median age was 49 years and 34% were coinfected with HIV and HCV. Participants contributed 5634 valid liver fibrosis measurements. The prevalence of clinically significant fibrosis without cirrhosis (12.9% vs. 9.5%) and of cirrhosis (19.5% vs. 11.0%) was greater in persons coinfected with HIV and HCV than in those with only HCV (P < 0.001). Increasing age and HIV infection were independently associated with liver fibrosis, as were daily alcohol use, chronic hepatitis B virus infection, body mass index greater than 25 kg/m2, and greater plasma HCV RNA levels. When these factors were kept constant, persons with HIV had liver fibrosis measurements equal to those of persons without HIV, who were, on average, 9.2 years older.
Limitation
The process of liver fibrosis began before the study in most persons.
Conclusion
In this cohort, persons who have HCV with HIV have liver fibrosis stages similar to those without HIV who are nearly a decade older.
doi:10.7326/0003-4819-158-9-201305070-00604
PMCID: PMC3708651  PMID: 23440167
13.  Dairy sheep production research at the University of Wisconsin-Madison, USA – a review 
Commercial milking of sheep is a new agricultural industry in the United States starting approximately 30 yr ago. The industry is still small, but it is growing. The majority of the sheep milk is used in the production of specialty cheeses. The United States is the major importer of sheep milk cheeses with 50 to 60% of annual world exports coming to the United States during the past 20 yr. Therefore, there is considerable growth potential for the industry in the United States. The only dairy sheep research flock in North America is located at the Spooner Agricultural Research Station of the University of Wisconsin-Madison. The research program started in 1993 and has been multifaceted; dealing with several areas important to commercial dairy sheep farmers. The East Friesian and Lacaune dairy breeds were compared and introduced to the industry through the research program. Both dairy breeds produced significantly more milk than traditional meat-wool breeds found in the U.S., but the two breeds differed in their production traits. East Friesian-cross ewes produced more lambs and slightly more milk than Lacaune-cross ewes whereas Lacaune-cross ewes produced milk with a higher percentage of fat and protein than East Friesian-cross ewes. Lactation physiology studies have shown that ewes with active corpora lutea have increased milk yields, oxytocin release during milking is required to obtain normal fat percentages in the milk, large udder cisterns of dairy ewes can allow for increased milking intervals, and short daylengths during late pregnancy results in increased milk yield. In the nutrition area, legume-grass pastures and forages with a higher percentage of legume will result in increased milk production. Grazing ewes respond to additional supplementation with increased milk yield, but it is important to match the supplement to the quality of the grazing. Ewes on high quality legume-grass pastures that are high in rumen degradable protein respond with increased milk production to supplements high in energy and/or high in rumen undegraded protein.
doi:10.1186/2049-1891-5-22
PMCID: PMC4004524  PMID: 24739956
Dairy sheep; East Friesian; Grazing; Lacaune; Lactation physiology; Nitrogen efficiency; RDP; RUP; Supplementation
14.  Provisional Guidance on the Use of Hepatitis C Virus Protease Inhibitors for Treatment of Hepatitis C in HIV-Infected Persons 
In May 2011, hepatitis C virus (HCV) protease inhibitors (PIs) were approved by the US Food and Drug Administration to treat persons with genotype 1 chronic hepatitis C virus (HCV) infection, but not those dually infected with human immunodeficiency virus (HIV). Although critical safety and efficacy data are lacking, the availability of the drugs and substantial medical need justify the off-label use of HCV PIs in select HIV/HCV-coinfected persons. Pending results of ongoing investigations, this article represents provisional guidance on the use of HCV PIs in HIV-infected persons.
doi:10.1093/cid/cir882
PMCID: PMC3404695  PMID: 22173234
15.  Measuring biexponential transverse relaxation of the ASL signal at 9.4 T to estimate arterial oxygen saturation and the time of exchange of labeled blood water into cortical brain tissue 
The transverse decay of the arterial spin labeling (ASL) signal was measured at four inflow times in the rat brain cortex at 9.4 T. Biexponential T2 decay was observed that appears to derive from different T2 values associated with labeled water in the intravasculature (IV) and extravascular (EV) compartments. A two compartment biexponential model was used to assess the relative contribution of the IV and EV compartments to the ASL signal, without assuming a value for T2 of labeled blood water in the vessels. This novel methodology was applied to estimate the exchange time of blood water into EV tissue space and the oxygen saturation of blood on the arterial side of the vasculature. The mean exchange time of labeled blood water was estimated to be 370±40 ms. The oxygen saturation of the arterial side of the vasculature was significantly less than 100% (∼85%), which may have implications for quantitative functional magnetic resonance imaging studies where the arterial oxygen saturation is frequently assumed to be 100%.
doi:10.1038/jcbfm.2012.156
PMCID: PMC3564190  PMID: 23168531
arterial spin labeling; ASL; cerebral hemodynamics; exchange; functional MRI (fMRI); MRI
16.  Relationship of Liver Disease Stage and Antiviral Therapy With Liver-Related Events and Death in Adults Coinfected With HIV/HCV 
JAMA : the journal of the American Medical Association  2012;308(4):10.1001/jama.2012.7844.
Context
Human immunodeficiency virus (HIV) accelerates hepatitis C virus (HCV) disease progression; however, the effect of liver disease stage and antiviral therapy on the risk of clinical outcomes is incompletely understood.
Objective
To determine the incidence of end-stage liver disease (ESLD), hepatocellular carcinoma (HCC), or death according to baseline hepatic fibrosis and antiviral treatment for HIV/HCV coinfected individuals.
Design, Setting, and Participants
Prospective cohort of 638 coinfected adults (80% black, 66% men) receiving care at the Johns Hopkins HIV clinic and receiving a liver biopsy and who were prospectively monitored for clinical events between July 1993 and August 2011 (median follow-up, 5.82 years; interquartile range, 3.42–8.85 years). Histological specimens were scored for hepatic fibrosis stage according to the METAVIR scoring system.
Main Outcome Measure
Incidence of composite outcome of ESLD, HCC, or death.
Results
Patients experienced a graded increased risk in incidence of clinical outcomes based on baseline hepatic fibrosis stage (classification range, F0-F4): F0, 23.63 (95% CI, 16.80–33.24); F1, 36.33 (95% CI, 28.03–47.10); F2, 53.40 (95% CI, 33.65–84.76); F3, 56.14 (95% CI, 31.09–101.38); and F4, 79.43 (95% CI, 55.86–112.95) per 1000 person-years (P<.001). In multivariable negative binomial regression, fibrosis stages F2 through F4 and antiretroviral therapy were independently associated with composite ESLD, HCC, or all-cause mortality after adjustment for demographic characteristics, injection drug use, and CD4 cell count. Compared with F0, the incidence rate ratio (RR) for F2 was 2.31 (95% CI, 1.23–4.34; P=.009); F3, 3.18 (95% CI, 1.47–6.88; P=.003); and F4, 3.57 (95% CI, 2.06–6.19; P<.001). Human immunodeficiency virus treatment was associated with fewer clinical events (incidence RR, 0.27; 95% CI, 0.19–0.38; P<.001). For the 226 patients who underwent HCV treatment, the incidence of clinical events did not significantly differ between treatment nonresponders and untreated patients (incidence RR, 1.27; 95% CI, 0.86–1.86; P=.23). In contrast, no events were observed in the 51 patients with sustained virologic response (n= 36) and relapse (n= 15), including 19 with significant fibrosis.
Conclusion
In this cohort of patients with HIV/HCV coinfection, hepatic fibrosis stage was independently associated with a composite outcome of ESLD, HCC, or death.
doi:10.1001/jama.2012.7844
PMCID: PMC3807214  PMID: 22820790
17.  Limited Uptake of Hepatitis C Treatment among Injection Drug Users 
Journal of community health  2008;33(3):126-133.
We characterized HCV treatment knowledge, experience and barriers in a cohort of community-based injection drug users (IDUs) in Baltimore, MD. In 2005, a questionnaire on HCV treatment knowledge, experience and barriers was administered to HCV-infected IDUs. Self-reported treatment was confirmed from medical records. Of 597 participants, 71% were male, 95% African-American, 31% HIV co-infected and 94% were infected with HCV genotype 1; 70% were aware that treatment was available, but only 22% understood that HCV could be cured. Of 418 who had heard of treatment, 86 (21%) reported an evaluation by a provider that included a discussion of treatment of whom 30 refused treatment, 20 deferred and 36 reported initiating treatment (6% overall). The most common reasons for refusal were related to treatment-related perceptions and a low perceived need of treatment. Compared to those who had discussed treatment with their provider, those who had not were more likely to be injecting drugs, less likely to have health insurance, and less knowledgeable about treatment. Low HCV treatment effectiveness was observed in this IDU population. Comprehensive integrated care strategies that incorporate education, case-management and peer support are needed to improve care and treatment of HCV-infected IDUs.
doi:10.1007/s10900-007-9083-3
PMCID: PMC3800027  PMID: 18165889
Hepatitis C virus; Injection drug use; Antiviral therapy; Health care access
18.  Hepatic steatosis associated with increased central body fat by dual-energy X-ray absorptiometry and uncontrolled HIV in HIV/hepatitis C co-infected persons 
AIDS (London, England)  2010;24(6):811-817.
Objective
To evaluate the relationship between regional body composition and liver disease (fibrosis or steatosis) in HIV/HCV co-infected individuals.
Methods
Whole body dual-energy X-ray absorptiometry (DXA) was performed in 173 HIV/HCV co-infected persons within 12 months of a liver biopsy. Significant fibrosis was defined as a METAVIR stage greater than 1. Steatosis was graded as: 0, none; 1, steatosis involving less than 5% of hepatocytes; 2, 5–29%; 3, 30–60%; 4 greater than 60%, and was defined as more than 0. Poisson regression with robust variance was used to estimate prevalence ratios of the outcome measures.
Results
The population was 62% male and 84% black with a median body mass index of 25.2 kg/m2 (interquartile range 22.5, 29.3 kg/m2). No differences in regional body fat or fat distribution were observed in 42 patients with significant fibrosis compared to others with less fibrosis. However, the 77 individuals (45%) with steatosis had greater central fat than those without steatosis [prevalence ratio 1.04 per kg trunk fat; 95% confidence interval (CI) 1.04, 1.11], after adjusting for hepatic fibrosis (prevalence ratio 1.77; 95% CI 1.29, 2.42), uncontrolled HIV replication (viral load >400 copies/ml) (prevalence ratio 1.57; 95% CI 1.12, 2.22), age, sex, race and diabetes mellitus.
Conclusions
In HIV/HCV co-infected individuals, measures of regional body fat or fat distribution were not associated with hepatic fibrosis. In contrast, increased central adiposity by DXA, as well as concomitant fibrosis and uncontrolled HIV, were associated with hepatic steatosis. The extent to which weight loss and effective antiretroviral therapy can reduce the risk of steatosis deserves further investigation.
doi:10.1097/QAD.0b013e3283333651
PMCID: PMC3800050  PMID: 20186036
body composition; hepatic fibrosis; hepatitis C; HIV; steatosis
19.  Development of a high-resolution fat and CSF-suppressed optic nerve DTI protocol at 3T: application in multiple sclerosis 
Functional Neurology  2013;28(2):93-100.
Summary
Clinical trials of neuroprotective interventions in multiple sclerosis require outcome measures that reflect the disease pathology. Measures of neuroaxonal integrity in the anterior visual pathways are of particular interest in this context, however imaging of the optic nerve is technically challenging. We therefore developed a 3T optic nerve diffusion tensor imaging protocol incorporating fat and cerebrospinal fluid suppression and without parallel imaging. The sequence used a scheme with six diffusion-weighted directions, b=600smm−2 plus one b≈0 (b0) and 40 repetitions, averaged offline, giving an overall scan time of 30 minutes. A coronal oblique orientation was used with voxel size 1.17mm×1.17mm×4mm, We validated the sequence in 10 MS patients with a history of optic neuritis and 11 healthy controls: mean fractional anisotropy was reduced in the patients: 0.346(±0.159) versus 0.528(±0.123), p<0.001; radial diffusivity was increased: 0.940(±0.370)×10−6mm2s−1 compared to 0.670(± 0.221)×10−6mm2s−1 (p<0.01). No significant differences were seen for mean diffusivity or mean axial diffusivity.
PMCID: PMC3812733  PMID: 24125558
3T; diffusion; multiple sclerosis; optic nerve; optic neuritis
20.  Human Immunodeficiency Virus and Liver Disease Forum 2010: Conference Proceedings 
Hepatology (Baltimore, Md.)  2011;54(6):2245-2253.
Liver disease continues to represent a critical mediator of morbidity and mortality in those with human immunodeficiency virus (HIV) infection. The frequent presence and overlap of concomitant injurious processes, including hepatitis C virus and hepatitis B virus infections, hepatoxicity associated with antiretroviral therapeutic agents, alcohol, and other toxins, in the setting of immunosuppression lead to rapid fibrotic progression and early development of end-stage liver disease. This conference summary describes the proceedings of a state-of-the-art gathering of international experts designed to highlight the status of current research in epidemiology, natural history, pathogenesis, and treatment of HIV and liver disease.
doi:10.1002/hep.24651
PMCID: PMC3795389  PMID: 21898501
21.  A variant upstream of IFNL3 (IL28B) creating a novel interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus 
Nature genetics  2013;45(2):164-171.
SUMMARY
Chronic infection with hepatitis C virus (HCV) is a common cause of liver cirrhosis and cancer. We performed RNA-sequencing in primary human hepatocytes activated with synthetic dsRNA to mimic HCV infection. Upstream of IFNL3 (IL28B) on chromosome 19q13.13, we discovered a novel, transiently induced region that harbors dinucleotide variant ss469415590 (TT/ΔG), which is in high linkage disequilibrium with rs12979860, a genetic marker strongly associated with HCV clearance. ss469415590-ΔG is a frame-shift variant that creates a novel primate-specific gene, designated interferon lambda 4 (IFNL4), which encodes a protein of moderate similarity with IFNL3. Compared to rs12979860, ss469415590 is more strongly associated with HCV clearance in individuals of African ancestry, whereas it provides comparable information in Europeans and Asians. Transient over-expression of IFNL4 in a hepatoma cell line induced STAT1/STAT2 phosphorylation and expression of interferon-stimulated genes. Our findings provide new insights into the genetic regulation of HCV clearance and its clinical management.
doi:10.1038/ng.2521
PMCID: PMC3793390  PMID: 23291588
22.  Vitamin D deficiency and its relation to bone mineral density and liver fibrosis in HIV–HCV coinfection 
Antiviral therapy  2012;18(2):237-242.
Background
Fractures and cirrhosis are major causes of morbidity and mortality among HIV–HCV-coinfected individuals. It is not known whether vitamin D deficiency is associated with these outcomes.
Methods
Between 2005 and 2007, 116 HIV–HCV- coinfected individuals underwent dual-energy X-ray absorptiometry within 1 year of a liver biopsy. 25-Hydroxy-vitamin D (25OHD) and parathyroid hormone were measured from archived samples. Low bone mineral density (BMD) was defined as BMD≥2 standard deviations lower than age-, sex- and race-matched controls (Z-score ≤−2.0) at the total hip, femoral neck or lumbar spine. Histological fibrosis staging was assessed according to the METAVIR system (0 [no fibrosis] to 4 [cirrhosis]).
Results
The cohort was 87% African-American and 63% male. The median age (IQR) was 49.9 years (46.5–53.3). A total of 89% had a CD4+ T-cell count >200 cells/mm3 and 64% were receiving HAART. The median 25OHD was 19 ng/ ml (IQR 11.0–26.0). Hypovitaminosis D (25OHD≤15 ng/ml) was present in 41% and secondary hyperparathyroidism, defined by parathyroid hormone >65 pg/ml, was present in 24%. In total, 27% had low BMD (Z-score ≤−2) at the spine, femoral neck or total hip, and 39% had significant hepatic fibrosis (METAVIR≥2). In multivariate analysis, vitamin D deficiency was not associated with significant fibrosis or with BMD at any site.
Conclusions
Vitamin D deficiency was highly prevalent in this mostly African-American HIV–HCV-coinfected population, but was not related to BMD or liver disease severity. These data suggest that efforts to increase vitamin D levels in this population may not improve bone or liver outcomes.
doi:10.3851/IMP2264
PMCID: PMC3790468  PMID: 22910231
23.  Laser Captured Hepatocytes Show Association of BCHE Loss and Fibrosis Progression in Hepatitis C Infected Drug Users 
Hepatology (Baltimore, Md.)  2012;56(2):544-554.
Chronic hepatitis C virus (HCV) infection is complicated by hepatic fibrosis. Hypothesizing that early fibrogenic signals may originate in cells susceptible to HCV infection, hepatocyte gene expression was analyzed from persons with chronic HCV at different stages of liver fibrosis. Four HCV-infected subjects with pre-cirrhotic liver fibrosis (Ishak fibrosis 3–5) were matched for age, race, and gender to five HCV-infected subjects with no evidence of fibrosis (Ishak fibrosis 0). Hepatocytes from each subject were isolated from liver biopsies using laser capture microdissection. Transcriptome profiling was performed on hepatocyte RNA using hybridization arrays. We found that hepatocytes in pre-cirrhotic fibrosis were depleted for genes involved in small molecule and drug metabolism, especially butyrylcholinesterase (BCHE), a gene involved in the metabolism of drugs of abuse. Differential expression of BCHE was validated in the same tissues and cross-sectionally in an expanded cohort of 143 HCV-infected individuals. In a longitudinal study, serum BCHE activity were already decreased at study inception in 19 fibrosis progressors compared to 20 fibrosis non-progressors (p<0.05). Non-progressors also had decreased BCHE activity over time compared to initial values, but these evolved a median (range) 8.6 (7.8–11.4) years after the study period inception(p<0.05). Laser captured portal tracts were enriched for immune related genes when compared to hepatocytes but pre-cirrhotic livers lost this enrichment.
Conclusion
Overall, we found that chronic HCV is associated with hepatocyte BCHE loss years before hepatic synthetic function is impaired. These results indicate that BCHE may be involved in the pathogenesis of HCV-related fibrosis among injection drug users.
doi:10.1002/hep.25655
PMCID: PMC3388175  PMID: 22331678
butyrylcholinesterase; Hepacivirus; chronic HCV infection; laser capture microdissection; portal tract
24.  Highly active anti-hepatitis C therapy: seven lessons from HIV 
Antiviral therapy  2012;17(6 0 0):1183-1188.
Summary
The hepatitis C virus (HCV) direct antiviral treatment era is underway. Although there are some important differences, it is likely that the experience with HCV will be similar in many respects to what already occurred with HIV. This paper considers seven important lessons learned with HIV and the degree to which they should be anticipated with HCV.
doi:10.3851/IMP2429
PMCID: PMC3715614  PMID: 23186629
25.  Screening for HCV Infection in Jails 
doi:10.1001/jama.2012.374
PMCID: PMC3701941  PMID: 22453565

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