Bone mineral density and bone turnover in non-cirrhotic patients with chronic hepatitis C and sustained virological response to antiviral therapy with peginterferon-alfa and ribavirin.

UNLABELLED: Patients with chronic hepatitis C have low bone mineral density and increased bone resorption related to serum transaminase levels. Elevated serum soluble tumor necrosis factor (sTNFR-55) receptor levels may play a role in the bone mass loss in these patients. Bone mass is improved and bone turnover normalized in patients who respond to antiviral therapy with interferon and ribavirin. INTRODUCTION: Low bone mineral density (BMD) has been described in patients with chronic hepatitis C (HCV). The study objective was to evaluate the effect of antiviral therapy on BMD and bone metabolism in non-cirrhotic HCV patients with sustained virological response. METHODS: We conducted a prospective study in 36 consecutive outpatients from the general community with non-cirrhotic HCV and an early and sustained virological response to peginterferon-alfa and ribavirin therapy. Determinations of BMD (dual X-ray absorptiometry at lumbar spine and femoral neck) and biochemical measurements of bone metabolism and sTNFR-55 were made at baseline, after 24 and 48 weeks of antiviral therapy, and at 48 weeks after the end of treatment. RESULTS: Patients had a significantly reduced BMD, which significantly increased during the follow-up. Serum levels of sTNFR-55 and bone turnover markers were increased at baseline and significantly reduced at all subsequent time points. We found an inverse correlation between BMD and both serum aminotransferase levels and urine deoxypyridinoline (D-pyr) and a positive correlation between serum aminotransferases and both urine D-Pyr and serum sTNFR-55. CONCLUSIONS: Patients with chronic hepatitis C have low bone mass associated with increased bone resorption, and some relationship can be expected between serum aminotransferase levels and the degree of bone mass loss. Bone mass may be improved and bone turnover normalized in patients who respond to antiviral therapy. Elevated serum sTRFR-55 levels may play a role in the bone mass loss of these patients.

Does DcR1 (TNF-related apoptosis-inducing-ligand Receptor 3) have any role in human AMD pathogenesis?

It has been postulated that there is a link between age related degenerative diseases and cancer. The TNF-related apoptosis-inducing ligand (TRAIL) has been shown to selectively kill tumor cells by binding to pro-apoptotic and anti-apoptotic receptors. Our aim was to study the levels of anti-apoptotic receptor (DcR1) in age related macular degeneration (AMD) and controls. AMD patients (115) were classified into two groups: Dry and Wet AMD. Wet AMDs were further classified into occult, predominant classic and minimal classic. 61 healthy individuals were recruited as normal controls. After normalization with total protein, DcR1 levels were analyzed by ELISA. Mann Whitney U-statistic was used for analysis of DcR1 ELISA results. We have observed DcR1 levels in serum sample which were significantly lower in AMD patients as compared to controls (p = 0.001). On the other hand, we did not find difference in DcR1 levels between wet and dry AMD. The present study defines the plausible role of DcR1 in AMD pathology signifying a new therapeutic target for AMD.

Modulation of gut barrier function in patients with obstructive jaundice using probiotic LP299v.

OBJECTIVES: This study aimed to determine the effect of LP229v on intestinal permeability and tumour necrosis factor (TNF) p55 receptor concentrations in patients with obstructive jaundice undergoing biliary drainage. PATIENTS AND METHODS: Patients undergoing biliary drainage were recruited and randomized into three groups to receive Lactobacillus plantarum 299v (LP299v), inactivated LP299v (placebo) or water. These were administered daily at noon until 7 days after biliary drainage. Intestinal permeability was measured using the lactulose/mannitol (L/M) dual sugar absorption test on admission, the day before biliary drainage and on days 1 and 7 after biliary drainage. Blood and urine were collected to determine the L/M ratio and the TNF p55 receptor levels at each time point. RESULTS: A total of 25 patients were recruited; 12 had choledocholithiasis and nine had a periampullary tumour. Open surgical biliary drainage was performed in nine patients, endoscopic retrograde cholangiopancreatography in 12 and percutaneous transhepatic cholangiography in two. Five patients received LP299v, five received placebo and seven, water. The median L/M ratio was 0.035 (0.018-0.065) at baseline. No difference existed between the groups on admission, before drainage and on day 7 after drainage (P=0.59, 0.175 and 0.61, respectively). The L/M ratio was lower in the LP299v group on day 1 after drainage [0.01 (0.01) vs. 0.18 (0.03-0.3) and 0.11 (0.07-0.14); P=0.37]. Although the TNF p55 receptor levels were lower on day 1 after drainage in the LP299v group (15.3 vs. 30.9 vs. 82.7 ng/ml; P=0.43), the concentration at the four time points was similar (P=0.24, 0.96, 0.43 and 0.68). CONCLUSION: Pretreatment with probiotic LP299v improves intestinal permeability after biliary drainage and attenuates the inflammatory response. However, a larger multicentre trial is required to determine the effect on clinical outcome.

Circulating TNF alpha receptor levels identify older adults who fail to regain weight after acute weight loss.

OBJECTIVE: Some healthy older adults have difficulty regaining weight after acute weight loss, and the reason for this failure to regain weight is unknown. The objective of this study was to determine if elevated leptin or pro-inflammatory cytokine levels are associated with failure to regain weight over two years after an acute weight loss intervention. DESIGN: Two year prospective study after an acute weight loss intervention. SETTING: University of Washington Medical Center from 2001-2006. PARTICIPANTS: Nineteen older (≥ 70 years old) men and women. MEASUREMENTS: Body weights, health status questionnaire, body composition data, serum leptin, glucose, insulin, C- reactive protein and pro-inflammatory cytokine levels were measured every six months for two years. RESULTS: Five subjects out of 19 failed to regain weight after two years. The subjects who failed to regain weight after 2 years had higher circulating levels of tumor necrosis factor receptor particle 55 (TNFRp55) at baseline and at 6, 12, 18 and 24 months of follow up compared to subjects who regained weight after 2 years (P = 0.02 ). CONCLUSION: Five out of 19 older subjects had difficulty regaining weight for up to 2 years following an acute weight loss intervention, and their TNFRp55 levels were persistently higher than in subjects who regained weight. Greater TNF α action, as reflected by higher circulating levels of TNFRp55, could be contributing towards inability of some older persons to regain weight after acute weight loss.

Gastric and intestinal barrier impairment in tropical enteropathy and HIV: limited impact of micronutrient supplementation during a randomised controlled trial.

BACKGROUND: Although micronutrient supplementation can reduce morbidity and mortality due to diarrhoea, nutritional influences on intestinal host defence are poorly understood. We tested the hypothesis that micronutrient supplementation can enhance barrier function of the gut. METHODS: We carried out two sub-studies nested within a randomised, double-blind placebo-controlled trial of daily micronutrient supplementation in an urban community in Lusaka, Zambia. In the first sub-study, gastric pH was measured in 203 participants. In the second sub-study, mucosal permeability, lipopolysaccharide (LPS) and anti-LPS antibodies, and serum soluble tumour necrosis factor receptor p55 (sTNFR55) concentrations were measured in 87 participants. Up to three stool samples were also analysed microbiologically for detection of asymptomatic intestinal infection. Gastric histology was subsequently analysed in a third subset (n = 37) to assist in interpretation of the pH data. Informed consent was obtained from all participants after a three-stage information and consent process. RESULTS: Hypochlorhydria (fasting gastric pH > 4.0) was present in 75 (37%) of participants. In multivariate analysis, HIV infection (OR 4.1; 95%CI 2.2-7.8; P < 0.001) was associated with hypochlorhydria, but taking anti-retroviral treatment (OR 0.16; 0.04-0.67; P = 0.01) and allocation to micronutrient supplementation (OR 0.53; 0.28-0.99; P < 0.05) were protective. Hypochlorhydria was associated with increased risk of salmonellosis. Mild (grade 1) gastric atrophy was found in 5 participants, irrespective of Helicobacter pylori or HIV status. Intestinal permeability, LPS concentrations in serum, anti-LPS IgG, and sTNFR55 concentrations did not differ significantly between micronutrient and placebo groups. Anti-LPS IgM was reduced in the micronutrient recipients (P <0.05). CONCLUSIONS: We found evidence of a specific effect of HIV on gastric pH which was readily reversed by anti-retroviral therapy and not mediated by gastric atrophy. Micronutrients had a modest impact on gastric pH and one marker of bacterial translocation. TRIAL REGISTRATION: Current Controlled Trials ISRCTN31173864.

TNF receptor p55 and IL-8(72) and IL-8(77) isoforms: blood and urine levels in breast cancer patients.

In the preliminary study reported here, 37 patients with breast cancer and 10 healthy volunteers were analyzed for soluble TNF-R p55 and two variants of IL-8 consisting of 72 and 77 amino acid residues (IL-8(72) and IL-8(77), respectively) in their blood and urine with novel ELISA test systems. The clinical/prognostic values of determining these inflammatory cytokines at different stages of the cancer process appeared to depend on the treatment course being evaluated. In contrast to expectations, it was noted that there was a stabile tendency for decreased TNF-R p55 and IL-8(72) levels in the plasma and urine of breast cancer patients as compared with levels observed with healthy controls. Moreover, patients that underwent polychemotherapy treatments were notable for significant decreases in IL-8(72) and TNF-R p55 levels in their blood plasma; these findings contrasted with significant increases in these parameters in these patients' urine. Interestingly, the IL-8(77) isoform that now appeared both in the urine and plasma of patients was not detectable before initiation of the polychemotherapy. In spite of all these findings, individual fluctuations among these parameters still do not allow us to establish, at this time, any strong correlations between these values with any particular breast cancer stage or a type of treatment. Nonetheless, while the results here are preliminary, they demonstrate that testing for TNF-R, along with IL-8 isoforms, in the blood plasma and urine could potentially present a valid means for monitoring of the overall immune and disease progress/remission status in breast cancer patients. Ongoing studies with larger patient sample sizes, as well as collecting and analyzing samples at multiple time points--to minimize the potential influence of any inherent variability in cytokine levels in humans--will hopefully allow us to specify what these preliminary results reported here suggest, i.e., the potential utility of this experimental approach for determining disease progression or efficacy of treatment in cancer patients.

Efficacy, pharmacodynamics, and safety of VX-702, a novel p38 MAPK inhibitor, in rheumatoid arthritis: results of two randomized, double-blind, placebo-controlled clinical studies.

OBJECTIVE: To assess the efficacy and safety of VX-702, a p38 MAPK inhibitor, in patients with active, moderate-to-severe rheumatoid arthritis (RA). METHODS: Two 12-week, double-blind, placebo-controlled studies of VX-702 were conducted in patients with active, moderate-to-severe RA. In the VeRA study, 313 patients received placebo or 2 daily doses of VX-702. In Study 304, 117 patients received placebo, daily VX-702, or twice weekly VX-702 in addition to concomitant methotrexate (MTX). Study end points included the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (an ACR20 response), ACR50 and ACR70 responses, changes in the serum levels of biomarkers of inflammation, and safety assessments. RESULTS: The numerically superior ACR20 response rates among patients receiving VX-702 compared with those receiving placebo in both studies did not reach pairwise statistical significance at the highest doses in either study. At week 12 in the VeRA study, ACR20 response rates were 40%, 36%, and 28% among patients receiving 10 mg of VX-702, 5 mg of VX-702, and placebo, respectively. In Study 304, the response rates were 40%, 44%, and 22% for patients receiving 10 mg VX-702 daily plus MTX, 10 mg VX-702 twice weekly plus MTX, and placebo, respectively. Reductions in the levels of C-reactive protein, soluble tumor necrosis factor receptor p55, and serum amyloid A were observed as early as week 1 in both studies, but these levels rapidly returned to baseline values by week 4. The overall frequency of adverse events was similar between the VX-702 and placebo groups. In the VeRA study, serious infections were more frequent in the VX-702 groups compared with the placebo group (2.4% versus 0%) but not in Study 304 (2.6% versus 4.9%). CONCLUSION: The modest clinical efficacy plus the transient suppression of biomarkers of inflammation observed in this study suggest that p38 MAPK inhibition may not provide meaningful, sustained suppression of the chronic inflammation seen in RA.

Early versus late onset of multiple organ failure is associated with differing patterns of plasma cytokine biomarker expression and outcome after severe trauma.

Although multiple organ failure (MOF) remains the leading cause of death after trauma, the pathogenic cellular and molecular mechanisms underlying MOF are poorly understood. In addition to proinflammatory and anti-inflammatory mediator cascades, the temporal onset of MOF has generated recent interest because the organ systems involved into MOF seem to deteriorate in a time-dependent fashion after trauma. We therefore investigated the temporal course of MOF in traumatized human patients and evaluated and compared the distribution patterns of cytokine expression, including interleukin (IL) 6, IL-8, IL-10, and the soluble tumor necrosis factor-[alpha] receptors sTNF-R p55 and sTNF-R p75 in early-onset versus late-onset MOF. In addition, we analyzed the predictive value of cytokine biomarkers of MOF and lethal outcome. In a prospective observational cohort study conducted at three trauma centers, all patients (n = 352) admitted to two level 1 trauma centers in Germany were enrolled in the study based on the following inclusion criteria: severe traumatic brain injury (TBI) with a Glasgow Coma Scale (GCS) score of 8 or lower and/or distinct changes in cranial computed tomography and/or multiple injuries (MT) to the body (at least two regions had Abbreviated Injury Scale score of 3 or higher). The incidence of MOF was evaluated using the modified Goris-MOF score. The temporal onset of MOF was divided into early-onset MOF (EMOF, developing on days 0-3), late-onset MOF (LMOF, developing on days 4-10), combined early-onset and late-onset MOF (CMOF), and patients never showing signs of MOF during the observation period. In addition, the levels of the serum cytokine markers IL-6, IL-8, IL-10, sTNF-R p55, and sTNF-R p75 were analyzed at specific posttraumatic time points using established enzyme-linked immunosorbent assay techniques. A total of 352 patients (274 men and 78 women; TBI, 101; TBI + MT, 125; MT, 126) were enrolled into the study. Patients assigned to the EMOF group showed specific disruption of pulmonary and cardiocirculatory function, whereas LMOF was significantly associated with hepatic failure. The patients without signs of MOF and the EMOF patients had the same risk of lethal outcome (8.2% vs. 7.5%); LMOF and CMOF were found to be associated with a 3- to 4-fold increase in mortality (38.5% vs. 30.6%, respectively). Analysis of cytokine serum biomarkers revealed that patients with LMOF showed a biphasic elevation of IL-6 and significantly higher sTNF-R concentrations than did all other subgroups (P < 0.001). In addition, the initial values (days 0-1) of sTNF-R p55 and sTNF-R p75 expression levels had a good predictive capacity for the development of LMOF (p55, 0.75; p75, 0.72); values greater than 0.65 were accepted to have a predictive capacity. These results demonstrate that mortality differs significantly between the development of EMOF and LMOF after traumatic injury. Our results also suggest that serum cytokine measurements may be important early biochemical markers for predicting the development of delayed MOF.

Elevated inflammatory markers in response to prolonged sleep restriction are associated with increased pain experience in healthy volunteers.

CONTEXT: Sleep disturbances, pain, and inflammation co-occur in various medical conditions, but their interrelationships are poorly understood. OBJECTIVE: We investigated the effects of reduced sleep duration (by approximately 50%) to 4 h/night across 10 days, on peripherally circulating inflammatory mediators. In addition, we tested the prediction that degree of inflammation is quantitatively related to the extent to which pain is increased in response to prolonged sleep restriction. DESIGN: Randomized, 16 day controlled in-laboratory study conducted in GCRC. METHODS: Eighteen volunteers were randomly assigned to either 12 days of sleeping 8 h/night or 4 h/night. Participants rated mood and pain symptoms throughout experimental days. Urine was collected and blood was drawn frequently on the baseline day and after the 10th experimental day for 25 hours. OUTCOME MEASURES: Levels of plasma interleukin (IL)-6, serum C-reactive protein (CRP), plasma soluble tumor necrosis factor receptor p55 (sTNF-R p55), urinary levels of prostaglandin (PG) metabolites D2 and E2, subjective assessment of pain and tiredness-fatigue. RESULTS: IL-6 levels were elevated in the 4-h sleep condition over the 8-h sleep condition (P <0.05). CRP levels showed the same trend as IL-6, but did not differ significantly between groups (P = 0.11). Levels of sTNF-R p55 were unchanged in both groups. PG E2 and 11beta-F2alpha metabolite increased in 4-h sleepers, but did not differ significantly from the 8-h sleepers. Elevated IL-6 levels were strongly associated with increased pain ratings in response to sleep restriction (r = 0.67, P <0.01), and this association could not be explained by elevations in tiredness-fatigue. CONCLUSION: Insufficient sleep quantity may facilitate and/or exacerbate pain through elevations of IL-6. In disorders where sleep disturbances are common, insufficient sleep quantity itself may establish and maintain its co-occurrence with pain and increased inflammation.

Increased levels of soluble TNF-alpha receptors and cellular adhesion molecules in patients undergoing bioincompatible hemodialysis.

BACKGROUND: The study aimed to differentiate the effects of hemodialysis (HD) and chronic renal failure (CRF) on the levels of circulating tumor necrosis factor-alpha (TNF-alpha) and TNF-alpha receptors p55 and p75, soluble vascular cell adhesion molecule-1 (sVCAM-1), intercellular adhesion molecule-1 (sICAM-1), soluble endothelial-leukocyte adhesion molecule-1 (sE-selectin) and sP-selectin in 18 patients on regular HD treatment with cuprophane membrane in relation to 15 non-dialyzed CRF patients and 15 healthy controls. METHODS: The serum concentrations were determined with standard ELISA assays. RESULTS: Blood serum p75 and p55 were approximately tenfold increased in CRF (36.7 +/- 6.2 and 27.1 +/- 5.6 ng/ml) and HD patients (45.6 +/- 18.4 and 28.7 +/- 5.9 ng/ml) before the HD session (HD 0), during (HD 20) the session (45.7 +/- 18.4 and 28.5 +/- 7.3 ng/ml) and after (HD 240) the HD session (52.1 +/- 17.4 and 30.9 +/- 8.2 ng/ml) in comparison to control values (5.6 +/- 1.3 and 2.4 +/- 0.8 ng/ml, respectively) (p < 0.01). The highest increment of p75 at the end of HD session (HD 240) was also significantly higher than at preceding time points (HD 0 and 20) (p < 0.05). However, the remaining study parameters did not change during an HD session. Also, there were no relevant changes in TNF-alpha levels if (HD 0) 22.7 +/- 21.5 ng/ml and (HD 240) 21.1 +/- 18.9 ng/ml were compared. Chronic HD status was related to the increase of sVCAM-1 and sICAM-1 levels. Prior to HD, T0 sVCAM-1 and sICAM-1 concentrations were 2,180.4 +/- 761.8 and 567.3 +/- 218.8 ng/ml, during HD (T20): 2,172.7 +/- 759.2 and 602.3 +/- 379.9 ng/ml, and after HD (T240): 2,401.6 +/- 756.4 and 648.3 +/- 183.5 ng/ml, respectively (p < 0.05 vs. controls and CRF patients). sVCAM-1 and sICAM-1 serum levels (1,262.2 +/- 472.9 and 165.6 +/- 50.4 ng/ml) were similar in CRF patients and healthy controls (854.4 +/- 241.5 and 217.6 +/- 74.2 ng/ml, respectively). Even though serum sE- and sP-selectin in CRF patients did not differ from the control (39.8 +/- 21.3 vs. 42.1 +/- 18.9 ng/ml and 187.9 +/- 66.9 vs. 198.8 +/- 62.2 ng/ml, respectively), their levels were increased in HD patients up to 111.9 +/- 54.6 and 453.2 +/- 231.1 ng/ml in patients prior to HD, 118.7 +/- 66.2 and 350.8 +/- 114.8 ng/ml during the HD session and then 132.3 +/- 61.1 and 368.3 +/- 126.6 ng/ml, respectively, after its completion (p < 0.05 in comparison with CRF patients and controls). CONCLUSIONS: The increased circulating TNF-alpha receptors appear more associated with the uremic milieu than HD-related systemic inflammation, whereas increased soluble cellular adhesion molecules in patients undergoing bioincompatible HD may be related to the enhanced systemic inflammation specifically due to maintenance HD.