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Rectal nitric oxide as biomarker in the treatment of inflammatory bowel disease: responders versus nonresponders.

ABSTRACT: AIM:To explore rectal nitric oxide (NO) as biomarker of treatment response in ulcerative colitis (UC) and Crohn's disease (CD), and examine relationships between rectal NO, mucosal expression of NO synthases (NOS), and pro-inflammatory cytokines. METHODS:Twenty-two patients with UC and 24 with CD were monitored during steroid treatment. Rectal NO levels were measured and clinical activities were assessed on days 1, 3, 7 and 28. Mucosal presence of NOS and pro-inflammatory cytokines were analyzed by immunohistochemistry and RT-PCR. RESULTS:Active UC and CD displayed markedly increased rectal NO levels (10950 +/- 7610 and 5040 +/- 1280 parts per billion (ppb), respectively) as compared with the controls (154 +/- 71 ppb, P < 0.001). Rectal NO correlated weakly with disease activity in both UC and CD (r = 0.34 for UC and r = 0.48 for CD, P < 0.01). In 12 patients, a steroid-refractory course led to colectomy. These patients had only slightly increased NO levels (UC: 620 +/- 270 ppb; CD: 1260 +/- 550 ppb) compared to those with a therapeutic response (UC: 18860 +/- 530 ppb, P < 0.001; CD: 10060 +/- 3200 ppb, P < 0.05). CONCLUSION:Rectal NO level is a useful biomarker of treatment response in IBD as low NO levels predicts a poor clinical response to steroid treatment.

SUBMITTER: Ljung T

PROVIDER: S-EPMC4087870 | biostudies-literature | 2006 Jun

REPOSITORIES: biostudies-literature

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Rectal nitric oxide as biomarker in the treatment of inflammatory bowel disease: responders versus nonresponders.

Ljung Tryggve T Lundberg Sofie S Varsanyi Mark M Johansson Catharina C Schmidt Peter T PT Herulf Max M Lundberg Jon O JO Hellstrom Per M PM

World journal of gastroenterology 20060601 21

<h4>Aim</h4>To explore rectal nitric oxide (NO) as biomarker of treatment response in ulcerative colitis (UC) and Crohn's disease (CD), and examine relationships between rectal NO, mucosal expression of NO synthases (NOS), and pro-inflammatory cytokines.<h4>Methods</h4>Twenty-two patients with UC and 24 with CD were monitored during steroid treatment. Rectal NO levels were measured and clinical activities were assessed on days 1, 3, 7 and 28. Mucosal presence of NOS and pro-inflammatory cytokine ...[more]

PMID: 16733856

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Project description:BackgroundTo compare the cost-effectiveness of treating early responders versus early nonresponders to an atypical antipsychotic (risperidone) and the cost-effectiveness of treating early nonresponders maintained on risperidone versus those switched to olanzapine.MethodsThis post hoc analysis used data from a randomized, double-blind, 12-week schizophrenia study (Study Code: HGMN, n = 628). Participants were initially assigned to risperidone therapy. Early response was defined as a ≥ 20% improvement on the Positive and Negative Syndrome Scale (PANSS) total score from baseline to two weeks. Early responders continued on risperidone, whereas early nonresponders were randomized in a double-blind manner to continue on risperidone or switch to olanzapine for 10 additional weeks. Early responders and early nonresponders maintained on risperidone were compared for health-state utilities (benefits) and total cost over the 12-week study; early nonresponders maintained on risperidone or switched to olanzapine were compared from randomization (10-week period). Utilities were derived from the PANSS and adverse events. Mixed models were used to assess group differences in utilities. Treatment costs were calculated based on health states. Incremental cost-effectiveness ratios were then utilized to compare treatment groups.ResultsEarly responders to risperidone had significantly greater total utility and lower total treatment costs than early nonresponders to risperidone. Compared with early nonresponders who continued on risperidone, those who were switched to olanzapine had significantly higher total utility scores at endpoint and numerically lower total treatment costs, reflecting significantly lower nonmedication treatment costs, even though medication costs were significantly higher compared with generic risperidone.ConclusionTreatment of early responders was more cost-effective than treatment of early nonresponders to atypical antipsychotic therapy. Switching early nonresponders to olanzapine resulted in improved treatment effectiveness, met the criteria for some dominance, and appeared modestly more cost-effective than maintaining treatment with generic risperidone.

Project description:Introduction: Synthetic cannabinoid mixtures have been easily accessible for years, leading to the belief that these products were natural and harmless, which contributed to their popularity. Nevertheless, there are many reports of users ending up in hospital due to severe side effects such as tachycardia, aggression, and psychosis. Controlled studies on the effects of synthetic cannabinoids on human performance are lacking. In the present study, we assessed the safety pharmacology of the synthetic cannabinoid JWH-018 after acute administration. Methods: Seventeen healthy cannabis-experienced participants took part in this placebo-controlled, crossover study. Participants inhaled the vapor of JWH-018 (doses ranged between 2 and 6.2 mg) and were subsequently monitored for 12 h, during which vital signs, cognitive performance, and subjective experience were measured. Subjective high scores showed that there is a large variability in the subjective experience of participants. Therefore, a mixed analysis of variance, with "Responder" (i.e., subjective high score >2) as a between-subjects factor and "Drug" as a within-subjects factor (placebo and JWH-018), was used. Results: Serum concentrations of JWH-018 were significantly higher in the responders. Overall, JWH-018 increased heart rate within the first hour and significantly impaired critical tracking and memory performance. Responders to JWH-018 performed more poorly in tests measuring reaction time and showed increased levels of confusion, amnesia, dissociation, derealization, and depersonalization and increased drug liking after JWH-018. Conclusion: JWH-018 administration produced large variability in drug concentrations and subjective experience. Fluctuations in drug delivery probably contributed to the variation in response. JWH-018's impairing effects on cognition and subjective measures were mainly demonstrated in participants who experienced a subjective intoxication of the drug. Lack of control over drug delivery may increase the risk of overdosing in synthetic cannabinoid users.

Project description:ObjectivesTo investigate how bowel dysfunction after sphincter-preserving rectal cancer treatment, known as low anterior resection syndrome (LARS), is perceived by rectal cancer specialists, in relation to the patient's experience.DesignQuestionnaire study.SettingInternational.Participants58 rectal cancer specialists (45 colorectal surgeons and 13 radiation oncologists).Research procedureThe Low Anterior Resection Syndrome Score (LARS score) is a five-item instrument for evaluation of LARS, which was developed from and validated on 961 patients. The 58 specialists individually completed two LARS score-based exercises. In Exercise 1, they were asked to select, from a list of bowel dysfunction issues, five items that they considered to disturb patients the most. In Exercise 2, they were given a list of scores to assign to the LARS score items, according to the impact on quality of life (QOL).Outcome measuresIn Exercise 1, the frequency of selection of each issue, particularly the five items included in the LARS score, was compared with the frequency of being selected at random. In Exercise 2, the answers were compared with the original patient-derived scores.ResultsFour of the five LARS score issues had the highest frequencies of selection (urgency, clustering, incontinence for liquid stool and frequency of bowel movements), which were also higher than random. However, the remaining LARS score issue (incontinence for flatus) showed a lower frequency than random. Scores assigned by the specialists were significantly different from the patient-derived scores (p<0.01). The specialists grossly overestimated the impact of incontinence for liquid stool and frequent bowel movements on QOL, while they markedly underestimated the impact of clustering and urgency. The results did not differ between surgeons and oncologists.ConclusionsRectal cancer specialists do not have a thorough understanding of which bowel dysfunction symptoms truly matter to the patient, nor how these symptoms affect QOL.

Project description:ObjectiveCanakinumab is a human anti-interleukin-1β (anti-IL-1β) blocking agent that effectively neutralizes IL-1β-mediated signaling for treatment of systemic juvenile idiopathic arthritis (JIA). While many patients have dramatic clinical response to IL-1 blockade, approximately one-third fail to respond, but there are currently no validated clinical or immunologic predictors of response. We undertook this study to characterize distinct gene signatures for treatment response and nonresponse to canakinumab in systemic JIA patients.MethodsWe performed a secondary analysis of whole-blood gene expression microarrays using blood samples obtained from healthy controls and systemic JIA patients at baseline and on day 3 after canakinumab treatment (GEO accession no. GSE80060). Patients were considered strong clinical responders if they met the ACR90 response (exhibited ≥90% improvement in the American College of Rheumatology [ACR] JIA response criteria; nonresponders were those who met ACR30 [exhibiting ≤30% improvement in the ACR JIA response criteria]). A random-effects model with patient identity as the random variable was used for differential expression analysis.ResultsWe identified a distinct gene expression signature in patients with a strong clinical response to canakinumab treatment as compared to nonresponders, mediated by up-regulation of neutrophil- and IL-1-associated genes and characterized by increasing divergence from control transcriptomes with increasing clinical response. We also identified a signature including up-regulated CD163 expression that was associated with canakinumab nonresponse. Intriguingly, canakinumab treatment induced either up- or down-regulation of type I interferon (IFN) genes, independent of clinical response.ConclusionHere, we identify a gene signature in systemic JIA patients prior to receiving treatment that distinguishes strong responders to canakinumab from nonresponders. Further prospective studies are needed to assess the utility of these insights for treatment decisions in systemic JIA and to track the association of up-regulated type I IFN signatures with systemic JIA complications.

Project description:Purpose: To investigate the inter-individual variability in duration of anti-vascular endothelial growth factor (VEGF) treatment effect in neovascular age-related macular degeneration (nvAMD).Design: Prospective observational multi-centered study.Participants: Forty-eight patients with nvAMD treated with anti-VEGF injections were included. Both treatment naive (n=25) as well as patients who had previously received treatment with ranibizumab (n=23) more than one month prior to their enrollment were recruited.Methods: Patients received injection with ranibizumab (0.5 mg/0.05 ml) and were followed weekly for 4 weeks with spectral-domain OCT (SD-OCT) assessing the time to maximal reduction of central retinal thickness (CRT) and the presence of intraretinal and subretinal fluid. Other data collected included age, gender, visual acuity, axial length, lens status, and previous injections. The Shapiro-Wilk test was used to examine normal distributions for all variables. Correlations were examined by calculating Spearman's correlation coeficient. Distributions of quantitative variables are described as means (±SD). Qualitative variables are summarized by counts and percentage.Main outcome measures: Time to maximal reduction of CRT and intra- and subretinal fluid after ranibizumab injection.Results: A total of 48 eyes of 48 patients (age 74.8±8.3 years, 62.5% female, 52% treatment naive, 35.4% pseudophakic) were assessed. Two-thirds (64.6%) reached maximal CRT reduction earlier than the standard 4-week interval: 6.3% at 1 week postinjection, 22.9% at 2 weeks postinjection, and 35.4% at 3 weeks postinjection. Only 35.4% of patients had maximal CRT reduction at 4 weeks. Twenty percent of treatment-naive and 34.8% of non-naive patients had a week-4 CRT that was >35 ?m thicker than the earlier occuring lowest CRT value (nadir). The time to maximal CRT reduction was not related to axial length, age, lens status, or history of injections.Conclusions: Optimal dosing interval for maximal CRT reduction may be less than 4 weeks for a significant proportion of patients. Most patients will be classified as complete responders if intervals less than 4 weeks are used to assess anti-VEGF treatment response. Disease load rather than eye size appears to be the driver of anti-VEGF treatment duration and therefore, dosing interval needs to be optimized in the cohort of short-term responders.

Project description:BackgroundCellular senescence can be a functional barrier to carcinogenesis. We hypothesized that inflammation modulates carcinogenesis through senescence and DNA damage response (DDR). We examined the association between senescence and DDR with macrophage levels in inflammatory bowel disease (IBD). In vitro experiments tested the ability of macrophages to induce senescence in primary cells. Inflammation modulating microRNAs were identified in senescence colon tissue for further investigation.Methodology/principal findingsQuantitative immunohistochemistry identified protein expression by colon cell type. Increased cellular senescence (HP1?; P = 0.01) or DDR (?H2A.X; P = 0.031, phospho-Chk2, P = 0.014) was associated with high macrophage infiltration in UC. Co-culture with macrophages (ANA-1) induced senescence in >80% of primary cells (fibroblasts MRC5, WI38), illustrating that macrophages induce senescence. Interestingly, macrophage-induced senescence was partly dependent on nitric oxide synthase, and clinically relevant NO• levels alone induced senescence. NO• induced DDR in vitro, as detected by immunofluorescence. In contrast to UC, we noted in Crohn's disease (CD) that senescence (HP1?; P<0.001) and DDR (?H2A.X; P<0.05, phospho-Chk2; P<0.001) were higher, and macrophages were not associated with senescence. We hypothesize that nitric oxide may modulate senescence in CD; epithelial cells of CD had higher levels of NOS2 expression than in UC (P = 0.001). Microarrays and quantitative-PCR identified miR-21 expression associated with macrophage infiltration and NOS2 expression.ConclusionsSenescence was observed in IBD with senescence-associated ?-galactosidase and HP1?. Macrophages were associated with senescence and DDR in UC, and in vitro experiments with primary human cells showed that macrophages induce senescence, partly through NO•, and that NO• can induce DDR associated with senescence. Future experiments will investigate the role of NO• and miR-21 in senescence. This is the first study to implicate macrophages and nitrosative stress in a direct effect on senescence and DDR, which is relevant to many diseases of inflammation, cancer, and aging.

Dataset Information

Rectal nitric oxide as biomarker in the treatment of inflammatory bowel disease: responders versus nonresponders.

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Rectal nitric oxide as biomarker in the treatment of inflammatory bowel disease: responders versus nonresponders.

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