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Paul S Horn

Publications and source records attributed to Paul S Horn.

17 recordsLinked to original sources
PubMed2006

HCV kinetics, quasispecies, and clearance in treated HCV-infected and HCV/HIV-1-coinfected patients with hemophilia.

Hepatitis C virus (HCV) treatment response rates remain low in HCV/HIV-1-coinfected individuals compared with those with HCV alone. Persons with inherited coagulation disorders have high rates of HCV and HIV-1 infection, but HCV treatment trials in this patient population are scarce. We hypothesized that differences by infection status in HCV viral kinetics would be associated with differences in HCV quasispecies complexity over time and with treatment response disparities. Coinfected and monoinfected patients were enrolled in a treatment trial for pegylated-interferon alpha-2a (peg-IFN) + ribavirin. Patients were treated for 48 weeks and followed for an additional 24. Quantitative HCV RNA was tested at multiple times during and after treatment. Viral kinetic parameters associated with response were estimated with a mathematical model. Quasispecies emergence was determined via heteroduplex complexity assay. Twenty-two patients were HCV RNA-positive at baseline, with no significant demographic or virological differences by infection status. Five of eleven (45%) of monoinfected and 3 of 11 (27%) of coinfected patients achieved sustained viral response (SVR). Peg-IFN efficacy (epsilon) of 90% or greater was associated with probability of end-of-treatment response (ETR) (P = .001) and SVR (P = .06). Patients with SVR had lower baseline quasispecies complexity than those without SVR (P = .07). Those with epsilon of 90% or greater also had lower baseline complexity (P = .07). Coinfection status mediated changes in complexity over time (P = .04). In conclusion, low pretreatment quasispecies complexity may predict peg-IFN response; early peg-IFN response is critical for sustained HCV clearance and is altered in coinfection. Further studies are warranted.

AIDS-Related Opportunistic Infections↗
PubMed2006

Coenzyme Q10 absorption and tolerance in children with Down syndrome: a dose-ranging trial.

Controlled studies of coenzyme Q(10) dosing and tolerance have been reported in adults, but not in pediatric patients. This study compares low- and high-dose coenzyme Q(10) (LiQ-NOL syrup) absorption and tolerance in children with Down syndrome. After a 1-month low-dose (1.0 mg/kg/day) run-in period, all participants received high-dose coenzyme Q(10) (10.0 mg/kg/day) for two additional months (in randomized sequence as one daily dose or split into two daily doses). Chemistry profiles and complete blood counts were determined just before and at the study completion. Plasma coenzyme Q(10) concentrations were determined initially and at each study visit. Parents reported adverse events and study drug evaluations using standardized forms. Most of the 16 children who completed this study tolerated high-dose coenzyme Q(10) well. Uncooperative behavior resulted in premature withdrawal of two participants, and may have been treatment-related. Pre- and posttreatment laboratory test changes were considered to be clinically nonsignificant. Study results indicate that high-dose coenzyme Q(10) (10 mg/kg/day) is well-absorbed and well-tolerated by most children with Down syndrome, and appears to provide plasma concentrations which are comparable to previous adult studies administering much higher coenzyme Q(10) dosages.

Absorption↗
PubMed2006

Elevated cerebrospinal fluid substance p concentrations in posttraumatic stress disorder and major depression.

OBJECTIVE: The authors tested the hypothesis that concentrations of the pain-transmitting neuropeptide substance P are elevated in the CSF of patients with major depression or posttraumatic stress disorder (PTSD), which have overlapping symptoms. The authors also sought to determine if CNS substance P concentrations change on provocation of symptoms in PTSD patients. METHOD: The authors measured CSF substance P concentrations in medication-free patients with either major depression or PTSD and in healthy comparison subjects. Next, using a within-subject, crossover design, the authors sampled CSF for 6 hours through an indwelling subarachnoid catheter in PTSD patients before, during, and after exposure to a 60-minute traumatic or neutral videotape stimulus. RESULTS: Both depressed and PTSD patients had significantly elevated basal CSF substance P concentrations. In the challenge study, marked increases in CSF substance P concentrations were found only after precipitation of PTSD symptoms. CSF substance P concentrations increased by 169% and 90.6% of baseline levels at 10 and 70 minutes, respectively, after the start of the traumatic videotape but changed by only 1.1% and -8.1% of baseline levels 10 and 70 minutes after the start of the neutral videotape. CONCLUSIONS: These results suggest that elevated CNS substance P concentrations are involved in both major depression and PTSD. The marked increase in CSF substance P concentrations during and after the symptom-provoking stimulus, but not after the neutral stimulus, implicates CNS release of substance P in the mechanism of acute PTSD symptoms. These data also reveal that CNS substance P responds acutely to psychological stress in humans.

Acute Disease↗
PubMed2005

Ubiquinol: a potential biomarker for tissue energy requirements and oxidative stress.

BACKGROUND: Coenzyme Q (CoQ) has been suggested as a biomarker for tissue redox status. The aims are (1) to compare ubiquinol-9, ubiquinol-10, ubiquinone-9, ubiquinone-10, total CoQ content and CoQ redox ratio in quadriceps muscle, heart, brain and liver tissues of mdx mice with wild-type controls; and (2) to determine if ubiquinol content and CoQ redox ratio changes are associated with pathological findings in mdx mouse. METHODS: CoQ contents were determined in homogenized quadriceps muscle, heart, liver and brain of age-matched mdx and wild-type control mice by HPLC-EC. Light and electron microscopy studies were conducted using standard pathology methods. RESULTS: Ubiquinol-9 and ubiquinol-10 concentrations are significantly increased in quadriceps and heart muscle of mdx mouse. Increased redox ratios of coenzyme Q(9) and coenzyme Q(10) are also evident in quadriceps, heart and liver tissues in mdx mouse, but not brain. Pathological examination shows marked myofiber regeneration and evidence of mitochondrial proliferation for mdx muscle. CONCLUSIONS: Evidence that changes in ubiquinol content and CoQ redox ratio are related to pathological features in mdx skeletal and heart myofibers suggests that tissue ubiquinol content and CoQ redox ratio may be useful biomarkers for evaluating muscle disorders associated with mitochondrial proliferation and defects in oxidative phosphorylation.

Animals↗
PubMed2005

Muscle coenzyme Q: a potential test for mitochondrial activity and redox status.

The aim of this study is to determine whether coenzyme Q (CoQ) muscle concentrations and redox state are associated with pathologic changes in muscle biopsy specimens. Skeletal muscle biopsies were collected (January 2002-February 2004) and underwent pathologic evaluation. Quadriceps specimens (n = 47) were stratified accordingly: Group 1, controls without evidence of pathologic abnormalities; Group 2, type I myofiber predominance; Group 3, type II myofiber atrophy; Group 4, lower motor unit disease; and Group 5, muscular dystrophy. Ubiquinol-10, ubiquinone-10, total coenzyme Q10 (CoQ10), coenzyme Q9 (CoQ9), total CoQ (CoQ9+CoQ10) concentrations were analyzed in biopsy muscle by high-performance liquid chromatography. Ubiquinone-10, total CoQ10, and total CoQ concentrations were significantly decreased in Group 5. Significant positive correlations (r congruent with 0.40) were found between muscle ubiquinone-10, total CoQ10, and total CoQ concentrations vs the percentage of myofibers having subsarcolemmal mitochondrial aggregates. CoQ redox ratio and the fraction CoQ9/total CoQ were negatively correlated with subsarcolemmal mitochondrial aggregates. A significant correlation (r = 0.328) also occurred between ubiquinol-10 concentration and citrate synthase activity. This study suggests that total CoQ concentration provides a new method for estimating mitochondrial activity in biopsy muscle; and that the muscle CoQ test is feasible and potentially useful for diagnosing CoQ deficiency states.

Adolescent↗
PubMed2005

Viral kinetics in hepatitis C or hepatitis C/human immunodeficiency virus-infected patients.

BACKGROUND AND AIMS: Kinetic modeling of hepatitis C virus (HCV) response to interferon (IFN)-based therapy provides insights into factors associated with treatment outcomes. HCV/human immunodeficiency virus (HIV)-co-infected patients show lower response rates vs. HCV-monoinfected patients. Reasons for this remain unclear. This study evaluated kinetic parameters and treatment responses in co-infected vs monoinfected patients. METHODS: Co-infected patients were randomized within a US multicenter trial (ACTG 5071) to receive pegylated-interferon (PEG-IFN) alfa-2a + ribavirin vs. IFN alfa-2a + ribavirin. Monoinfected controls were matched prospectively for treatment, genotype, age, sex, race, and histology. Quantitative HCV-RNA testing was performed at hours 0, 6, 12, 24, 48, and 72; days 7, 10, 14, 28, and 56; and weeks 12, 24, 48, and 72. RESULTS: Twelve HCV/HIV-co-infected and 15 HCV-monoinfected patients underwent viral kinetic sampling. Among HIV-positive patients the mean CD4(+) count was 325 cells/mm(3). Seventy-five percent of patients were genotype 1. The HCV-RNA level was undetectable at 72 weeks in 25% and 40% of co-infected and monoinfected patients, respectively. Phase 1/2 declines, free virus clearance rate, and infected hepatocyte death rate were not affected by co-infection status but differed by treatment. Efficiency (epsilon) > or = 90% at 60 hours was associated with viral clearance ( P = .02). Modeling with pooled parameters suggests baseline viral load is a key factor in time to response in this cohort. Predicted clearance time increased by 28% in co-infected patients. CONCLUSIONS: Co-infection status did not affect key kinetic parameters. Among kinetic parameters, efficiency was associated significantly with viral clearance. Co-infected patients may require longer treatment duration than monoinfected patients given their generally higher baseline viral loads.

Adult↗
PubMed2005

Higher levels of basal serial CSF cortisol in combat veterans with posttraumatic stress disorder.

OBJECTIVE: Results of basal peripheral cortisol measures in posttraumatic stress disorder (PTSD) have been variable. The authors' goal was to measure CSF cortisol concentrations, which more accurately reflect brain glucocorticoid exposure, in subjects with or without PTSD. METHOD: CSF was withdrawn from a subarachnoid catheter and plasma from a venous catheter, both indwelling, over a 6-hour interval to determine hourly plasma ACTH and cortisol concentrations and hourly CSF cortisol levels in eight well-characterized combat veterans with PTSD and eight matched healthy volunteers. RESULTS: Mean CSF cortisol concentrations were significantly higher in the subjects with PTSD (3.18 ng/ml, SD=0.33) than in the normal volunteers (2.33 ng/ml, SD=0.50), largely due to higher CSF cortisol concentration nadirs. No group differences were observed in either plasma ACTH or peripheral (plasma or urinary free) cortisol. CSF corticotropin-releasing hormone and CSF cortisol concentrations were positively and significantly correlated. CONCLUSIONS: Despite normal peripheral cortisol indexes in the veterans with PTSD, their CNS exposure to cortisol was greater than that of normal comparison subjects.

Adrenocorticotropic Hormone↗
PubMed2004

Complexity and diversity of hepatitis C virus RNA in african americans and whites: analysis of the envelope-coding domain.

African Americans infected with hepatitis C virus (HCV) are less responsive than whites to interferon-based therapy. HCV quasi species have been implicated. Quasi-species complexity and diversity were evaluated in matched African American and white individuals. Complexity and diversity in the first hypervariable region were similar in the 2 groups. Both the frequency of nonsynonymous amino acid substitutions and the mean ratio of nonsynonymous mutations to synonymous mutations were greater in clones derived from white patients. Racial differences in amino acid usage at otherwise conserved positions were observed. Differences in amino acid representation at key positions are suggestive of immunologic and functional selection along racial lines.

Adult↗
PubMed2004

Serum bilirubin levels in the U.S. population: gender effect and inverse correlation with colorectal cancer.

Bilirubin, the primary end product of heme catabolism, is a key marker of liver and hematological disorders, and important cytoprotective properties have been ascribed to this bile pigment. The Third National Health and Nutrition Examination Survey, a comprehensive assessment of health and nutrition in the United States, was analyzed to determine the demographics and correlates of serum bilirubin levels in the general population. Men and women aged 17 and older were included in the weighted analysis, representing a total of 176,748,462 subjects. The mean serum total bilirubin in the adult population is 0.62 +/- 0.003 mg/dL (SEM), with a 97.5% cut-off of 1.4 mg/dL. Serum bilirubin levels are significantly higher in men (0.72 +/- 0.004) than in women (0.52 +/- 0.003 mg/dL) and are lower in non-Hispanic blacks (0.55 +/- 0.005 mg/dL) compared with non-Hispanic whites (0.63 +/- 0.004 mg/dL) and Mexican Americans (0.61 +/- 0.005 mg/dL). Bilirubin concentrations are unrelated to body weight but are reduced in active smokers. Individuals with a history of nondermatological malignancy exhibit significantly lower serum bilirubin concentrations compared with those who do not have a history of nondermatological cancer. In particular, each 1-mg/dL increase in serum bilirubin is associated with a markedly decreased prevalence of colorectal cancer (OR = 0.257; 95% CI 0.254-0.260). In conclusion, serum bilirubin levels vary significantly with gender, race, and smoking status. The observed inverse correlation between serum bilirubin concentrations and a history of nondermatological malignancy, particularly colorectal cancer, warrants further investigation of a potentially important chemopreventive function of bilirubin.

Adolescent↗
PubMed2004

Coenzyme Q10 changes are associated with metabolic syndrome.

BACKGROUND: The purpose of this study was to determine whether coenzyme Q10 (CoQ) concentrations and redox status are associated with components of the metabolic syndrome. METHODS: This is a cross-sectional survey of 223 adults (28-78 years), who were drawn from the ongoing Princeton Follow-up Study in greater Cincinnati. Individuals were assessed for measures of fatness, blood pressure, glucose, lipid profiles, C-reactive protein (CRP), reduced CoQ (ubiquinol), oxidized CoQ (ubiquinone), total CoQ and CoQ redox ratio (ubiquinol/ubiquinone). RESULTS: After adjusting for age, sex and race, we found that total CoQ, ubiquinol and CRP levels are significantly increased in metabolic syndrome. Comparison of minimal risk and high-risk metabolic syndrome groups indicates an increased CoQ redox ratio in the high risk group (p<0.05). Step-wise logistic regression analysis, using age, sex, race, (ln)CRP, total cholesterol, LDL, ubiquinol, ubiquinone and total CoQ as predictors, shows that only age (p=0.001), total CoQ adjusted for plasma lipids (p<0.0001) and (ln)CRP (p<0.005) were significant predictors of metabolic syndrome. CONCLUSIONS: The presence of metabolic syndrome components are associated with increased plasma total CoQ and ubiquinol concentrations after adjusting for age, sex and race. An increase in CoQ redox ratio may indicate a gender-specific adaptive response to oxidative stress in females, but not males.

Adult↗
PubMed2004

Age-related changes in plasma coenzyme Q10 concentrations and redox state in apparently healthy children and adults.

BACKGROUND: Coenzyme Q10 (CoQ) is an endogenous enzyme cofactor, which may provide protective benefits as an antioxidant. Because age-related CoQ changes and deficiency states have been described, there is a need to establish normal ranges in healthy children. The objectives of this study are to determine if age-related differences in reduced CoQ (ubiquinol), oxidized CoQ (ubiquinone), and CoQ redox state exist in childhood, and to establish reference intervals for these analytes in healthy children. METHODS: Apparently healthy children (n=68) were selected from individuals with no history of current acute illness, medically diagnosed disease, or current medication treatment. Self-reported healthy adults (n=106) were selected from the ongoing Princeton Follow-up Study in greater Cincinnati. Participants were assessed for lipid profiles, ubiquinol concentration, ubiquinone concentration, total CoQ concentration, and CoQ redox ratio. RESULTS: Mean total CoQ and ubiquinol concentrations are similar in younger children (0.2-7.6 years) and adults (29-78 years); however, lipid-adjusted total CoQ concentrations are significantly increased in younger children. Also CoQ redox ratio is significantly increased in younger and older children compared with adults. CONCLUSIONS: Elevated CoQ and redox ratios in children may be an indication of oxidative stress effects, which are associated with early development of coronary heart disease.

Adolescent↗
PubMed2003

Reference intervals: an update.

Reference intervals serve as the basis of laboratory testing and aid the physician in differentiating between the healthy and diseased patient. Standard methods for determining the reference interval are to define and obtain a healthy population of at least 120 individuals and use nonparametric estimates of the 95% reference interval. This method is less accurate if the group size is significantly less and does not allow for exclusion of outliers. In order to overcome these limitations many authors in the current literature report reference intervals after arbitrary truncation of the data or use inappropriate parametric calculations. We argue that the use of outlier removal and robust estimators, with or without transformation to normality, address the shortcomings of the standard method and eliminate the need for employing less valid methods.To test these methods of analysis well-defined test groups are required. In a few studies physician-determined health status is provided for each subject along with commonly measured analytes. The NHANES and Fernald studies provide such groups. With such data it is possible to show the range of effects on the reference interval width by including a known non-healthy subgroup. With the NHANES data the effect ranged from negligible to a 30% increase in reference interval width. We found that use of outlier detection with the robust estimator yielded reference intervals that were closer to those of the true healthy group.Another issue is one of demographics. That is, whether or not one should derive separate reference intervals for different demographic groups, e.g., males and females. The standard mathematical test for deriving separate reference intervals is due to Harris and Boyd. Using the NHANES data we examined 33 analytes for each of three ethnic groups (separated by genders). We used the Harris and Boyd procedure and observed that it was necessary to derive separate reference intervals for approximately 30% of the comparisons. The most notable analytes were glucose and gamma GT.The methods used by most laboratories have similar precision, identical units, are linearly related (often on a 1:1 basis) and correlate well with each other. As a result the only difference is the method bias. By using the reference interval width, this bias is eliminated. We argue that the log ratio of the reference interval widths is a good estimate of the variability between groups.

Clinical Laboratory Techniques↗
PubMed2003

Plasma coenzyme Q10 reference intervals, but not redox status, are affected by gender and race in self-reported healthy adults.

BACKGROUND: Abnormal concentrations of coenzyme Q(10) have been reported in many patient groups, including certain cardiovascular, neurological, hematological, neoplastic, renal, and metabolic diseases. However, controls in these studies are often limited in number, poorly screened, and inadequately evaluated statistically. The purpose of this study is to determine the reference intervals of plasma concentrations of ubiquinone-10, ubiquinol-10, and total coenzyme Q(10) for self-reported healthy adults. METHODS: Adults (n=148), who were participants in the Princeton Prevalence Follow-up Study, were identified as healthy by questionnaire. Lipid profiles, ubiquinone-10, ubiquinol-10, and total coenzyme Q(10) concentrations were measured in plasma. The method used to determine the reference intervals is a procedure incorporating outlier detection followed by robust point estimates of the appropriate quantiles. RESULTS: Significant differences between males and females were present for ubiquinol-10 and total coenzyme Q(10). Blacks had significantly higher Q(10) measures than whites in all cases except for the ubiquinol-10/total Q(10) fraction. CONCLUSIONS: The fraction of ubiquinol-10/total coenzyme Q(10) is a tightly regulated measure in self-reported healthy adults, and is independent of sex and racial differences. Different reference intervals for certain coenzyme Q(10) measures may need to be established based upon sex and racial characteristics.

Adult↗
PubMed2003

Measuring outcome in cocaine clinical trials: a comparison of sweat patches with urine toxicology and participant self-report.

AIMS: To evaluate the advantages of using a sweat patch (PharmCheck) for detecting cocaine abuse in cocaine-dependent patients participating in a clinical trial. The utility of the sweat patch was assessed from the following perspectives: the reliability and validity of quantitative sweat patch results, the possible degradation of cocaine to benzoylecgonine (BE) as a function of the length of time that a patch is worn, the completeness of the dataset yielded by thrice-weekly urine toxicology compared with thrice-weekly and weekly sweat patches, and the relative costs associated with sweat patch versus urine measures. DESIGN: Data were collected during a 10-week out-patient clinical trial in which participants wore two sweat patches, one applied every visit and one applied weekly. Urine samples were collected thrice weekly, as were self-reports of substance use. SETTING: A multi-site clinical trial conducted in Boston, Cincinnati and New York, USA. PARTICIPANTS: Twenty-seven participants with comorbid diagnoses of cocaine dependence and adult attention deficit disorder completed the study. MEASUREMENTS: Sweat patch and urine samples were analyzed by standard methods for cocaine and cocaine metabolites. FINDINGS: Quantitative sweat patch measures had good reliability in that the correlation between the weekly and per-visit patches was 0.96 (P < 0.0001). The concurrent validity, as judged by the correlation between quantitative urine BE levels and either weekly (0.76, P < 0.0001) or per-visit (0.73, P < 0.0001) cocaine sweat patch levels was reasonable. The correlation between the self-report of cocaine use and these same two patches, however, was lower (0.40, P < 0.05 and 0.30, P < 0.05, respectively). The results revealed no significant degradation of cocaine to BE associated with wearing the patch for a longer time. Finally, the per-visit patch provided cocaine use data on 80.5% of all study days (a total of 70), while urine toxicology and the weekly patch provided 77.4% and 76.1%, respectively. CONCLUSIONS: The present findings suggest that the PharmCheck patch might be an attractive alternative to urine toxicology for use as an outcome measure in cocaine clinical trials.

Adult↗
PubMed2002

Comparison of methodologies for quantification of hepatitis C virus (HCV) RNA in patients coinfected with HCV and human immunodeficiency virus.

Quantification of hepatitis C virus (HCV) RNA is important in the assessment of HCV-associated liver disease in patients coinfected with HCV and human immunodeficiency virus (HIV). To investigate whether the standard integrity of competing test methodologies might be compromised by higher HCV titers in coinfected patients, 2 technologies (a polymerase chain reaction-based assay [COBAS Amplicor 2.0 assay; Roche Diagnostics] and a branched-chain DNA assay [Versant 3.0; Bayer]) were evaluated by testing paired serum samples from 68 coinfected patients and 137 HCV-monoinfected patients. Although the correlation was highly significant (r=0.81; P<.001), HCV RNA titers expressed in international units per milliliter could not be standardized; statistically significant differences were observed in all quartiles. Significant variability (P<.0007) was observed in the classification of patients as having a high versus a low virus titer (cutoff, 800,000 IU/mL), which suggests that standardization in international units has low efficacy among coinfected patients. Clinicians should note that test variability precludes direct comparability of HCV RNA titers, particularly in coinfected patients with high titers.

Adult↗
PubMedDate not supplied

Blood pressure and cerebrospinal fluid norepinephrine in combat-related posttraumatic stress disorder.

OBJECTIVE: Central nervous system norepinephrine (NE) is normally involved in blood pressure regulation, but it is pathophysiologically elevated in posttraumatic stress disorder (PTSD). METHODS: We monitored blood pressure while performing serial cerebrospinal fluid (CSF) sampling for 6 hours to determine CSF NE concentrations in men with combat-related PTSD (n = 11) and in healthy men (n = 8). RESULTS: CSF NE concentrations strongly and positively correlated with mean diastolic blood pressure in the healthy men (R = 0.93, p <.002) but not in the patients (R = 0.10, p =.77). Within individuals, mean arterial pressure, systolic blood pressure, diastolic blood pressure and pulse pressure were poorly correlated over time in patients with PTSD but highly correlated over time in the healthy men, indicating that measurement of these hemodynamic parameters are poorly prognostic of subsequent measurements of the same parameter in patients with PTSD. CONCLUSION: These data demonstrate the loss of the normal direct relationship between CSF NE and blood pressure in combat veterans with PTSD. Whether this dysynchrony mechanistically relates to the hemodynamic abnormalities in PTSD or, like some of the psychobehavioral symptoms, can be corrected with anti-noradrenergic pharmacotherapy remains to be determined.

Adult↗