Transcriptomic and cellular decoding of functional brain connectivity changes reveal regional brain vulnerability to pro- and anti-inflammatory therapies.

BACKGROUND: Systemic inflammation induces acute changes in mood, motivation and cognition that closely resemble those observed in depressed individuals. However, the mechanistic pathways linking peripheral inflammation to depression-like psychopathology via intermediate effects on brain function remain incompletely understood. METHODS: We combined data from 30 patients initiating interferon-α treatment for Hepatitis-C and 20 anti-tumour necrosis factor (TNF) therapy for inflammatory arthritis and used resting-state functional magnetic resonance imaging to investigate acute effects of each treatment on regional global brain connectivity (GBC). We leveraged transcriptomic data from the Allen Human Brain Atlas to uncover potential biological and cellular pathways underpinning regional vulnerability to GBC changes induced by each treatment. RESULTS: Interferon-α and anti-TNF therapies both produced differential small-to-medium sized decreases in regional GBC. However, these were observed within distinct brain regions and the regional patterns of GBC changes induced by each treatment did not correlate suggesting independent underlying processes. Further, the spatial distribution of these differential GBC decreases could be captured by multivariate patterns of constitutive regional expression of genes respectively related to: i) neuroinflammation and glial cells; and ii) glutamatergic neurotransmission and neurons. The extent to which each participant expressed patterns of GBC changes aligning with these patterns of transcriptomic vulnerability also correlated with both acute treatment-induced changes in interleukin-6 (IL-6) and, for Interferon-α, longer-term treatment-associated changes in depressive symptoms. CONCLUSIONS: Together, we present two transcriptomic models separately linking regional vulnerability to the acute effects of interferon-α and anti-TNF treatments on brain function to glial neuroinflammation and glutamatergic neurotransmission. These findings generate hypotheses about two potential brain mechanisms through which bidirectional changes in peripheral inflammation may contribute to the development/resolution of psychopathology.

Quantification of hepatic FOXP3+ T-lymphocytes in HIV/hepatitis C coinfection.

Coinfection with HIV adversely impacts every stage of hepatitis C (HCV) infection. Liver damage in HCV infection results from host antiviral responses rather than direct viral pathogenesis. Despite depressed cellular immunity, coinfected patients show accelerated hepatic fibrosis compared with HCV monoinfected patients. This paradox is poorly understood. T-regulatory (Treg) cells (CD4+ and FOXP3+) are hypothesized to limit hepatic damage in HCV. Our hypothesis was that reduced frequency of hepatic Treg in HIV/HCV coinfection compared with HCV monoinfection may explain poorer outcomes. We quantified FOXP3+, CD4+, CD8+ and CD20+ cells in liver biopsies of 35 male subjects matched by age and ISHAK fibrosis score, 12 HIV monoinfected, 11 HCV monoinfected and 12 HIV/HCV coinfected. Cell counts were performed using indirect immunohistochemical staining and light microscopy. HIV/HCV coinfected subjects had fewer hepatic FOXP3+ (P = 0.031) and CD4+ cells (P = 0.001) than HCV monoinfected subjects. Coinfected subjects had more hepatic CD8+ cells compared with HCV monoinfected (P = 0.023), and a lower ratio of FOXP3+ to CD8+ cells (0.08 vs 0.27, P < 0.001). Multivariate analysis showed number of CD4+ cells controlled for differences in number of FOXP3+ cells. Fewer hepatic FOXP3+ and CD4+ cells in HIV/HCV coinfection compared with HCV monoinfection suggests lower Treg activity, driven by an overall loss of CD4+ cells. Higher number of CD8+ cells in HIV/HCV coinfection suggests higher cytotoxic activity. This may explain poorer outcomes in HIV/HCV coinfected patients and suggests a potential mechanism by which highly active antiretroviral therapy may benefit these patients.

Interferon-alpha-Induced Changes in NODDI Predispose to the Development of Fatigue.

Interferon-alpha (IFN-α) is an important mediator of antiviral immune responses. It is also used clinically in the treatment of hepatitis-C infection. Though effective, IFN-α-based therapies can often impair mood, motivation and cognition, which when severe can appear indistinguishable from major depression. In susceptible patients, fatigue and motivational impairment emerge early and have been linked to changes in basal ganglia (striatal) metabolism, neurochemistry and microstructural integrity. Here we use neurite orientation dispersion and density imaging (NODDI) modeling of multi-shell diffusion MRI to investigate whether changes in orientation-dispersion index (ODI) or neurite density index (NDI) can predict the later emergence of IFN-α-induced fatigue. Eighteen patients initiating IFN-α-based treatment for hepatitis-C underwent diffusion MRI and blood sampling at baseline and 4 h after their first IFN-α injection. They were then followed up with regular psychological assessments for 12 weeks of treatment. IFN-α injection stimulated an acute inflammatory cytokine response and evoked acute fatigue that peaked between 4 and 12 weeks of treatment. Within the brain, IFN-α induced an acute increase in NDI in patients that experienced a simultaneous increase in IFN-α-induced fatigue but not in patients that did not. Acute changes in striatal microstructure additionally predicted the continued development of fatigue but not mood symptoms 4 and 8 weeks later into treatment. Our findings highlight the value of NODDI as a potential in vivo biomarker of the central effects of peripheral inflammation. We highlight the exquisite sensitivity of the striatum to IFN-α and further implicate striatal perturbation in IFN-α-induced fatigue.

Effects of NSAIDs on cryoprobe-induced gastric ulcer healing in rats.

BACKGROUND: Failure of ulcer healing may be critically important to the development of serious gastrointestinal complications in patients on long-term NSAIDs. AIM: To determine the effect of indometacin, celecoxib, a cyclooxygenase-2-specific inhibitor, and nabumetone, a pro-drug, on ulcer healing rates in the rat. METHODS: Gastric ulcers were induced using a cryoprobe. An NSAID or a vehicle control was administered to groups of eight rats for 3 or 6 days (2 mg/kg indometacin, 9 mg/kg celecoxib or 40 mg/kg nabumetone). The ulcer area was measured and epithelial proliferation at the ulcer margins was measured histochemically. The effect of the drugs on intestinal prostaglandin levels was also assessed. RESULTS: The mean ulcer sizes in the four groups on day 3 were comparable. On day 6, control animals and those receiving nabumetone showed significant ulcer healing (P < 0.02), while the mean ulcer sizes in the indometacin (P < 0.01) and celecoxib (P < 0.02) groups were significantly larger than those in the control group. Higher doses of nabumetone (160 mg/kg), however, impaired healing. Intestinal prostaglandins were reduced (P < 0.01) only in indometacin-treated animals. The epithelial proliferation index was significantly lower among indometacin- (P=0.02) and celecoxib-treated (P=0.03) animals compared to controls at day 3. CONCLUSIONS: Celecoxib and indometacin both decreased the epithelial proliferative response and delayed healing of cryoprobe-induced gastric ulcers. In contrast, nabumetone impaired ulcer healing only at very high doses.

Epidemiology and differential diagnosis of NSAID-induced injury to the mucosa of the small intestine.

Non-steroidal anti-inflammatory drugs cause small-bowel inflammation in about 60% of patients receiving these drugs long-term. The inflammation is associated with small intestinal bleeding, protein loss, ulcers and occasionally strictures. Treatment options for NSAID enteropathy include metronidazole, sulphasalazine and misoprostol, and some patients may require surgery. The diagnosis of NSAID enteropathy is not always straightforward. It is especially difficult to differentiate it from the ileitis associated with spondylarthropathy and, at times, that of Crohn's disease. An investigational algorithm is suggested for this purpose. In the last decade a number of small-bowel diseases have been identified, where none were thought to exist, because of the increasing use of enteroscopy and new sensitive tests for intestinal inflammation. Optimal treatments of these conditions are still to be studied.

Carcinoma of the oesophagus causing paraparesis by direct extension to the spinal cord.

A 75-year-old man presented with dysphagia and subsequent paraparesis. He was treated by oesophageal dilatation and by the placement of an 8.4 cm Atkinson tube. It was shown that an oesophago-subarachnoid fistula, a rare complication of carcinoma of the oesophagus, had developed. This resulted from direct extension of the tumour to the spinal cord and caused paraparesis unrelated to treatment.

Non-invasive investigation of inflammatory bowel disease.

The assessment of inflammatory activity in intestinal disease in man can be done using a variety of different techniques. These range from the use of non-invasive acute phase inflammatory markers measured in plasma such as C reactive protein (CRP) and the erythrocyte sedimentation rate (ESR) (both of which give an indirect assessment of disease activity) to the direct assessment of disease activity by intestinal biopsy performed during endoscopy in association with endoscopic scoring systems. Both radiology and endoscopy are conventional for the diagnosis of inflammatory bowel disease (IBD). However these techniques have severe limitations when it comes to assessing functional components of the disease such as activity and prognosis. Here we briefly review the value of two emerging intestinal function tests. Intestinal permeability, although ideally suited for diagnostic screening for small bowel Crohn's disease, appears to give reliable predictive data for imminent relapse of small bowel Crohn's disease and it can be used to assess responses to treatment. More significantly it is now clear that single stool assay of neutrophil specific proteins (calprotectin, lactoferrin) give the same quantitative data on intestinal inflammation as the 4 day faecal excretion of 111Indium labelled white cells. Faecal calprotectin is shown to be increased in over 95% of patients with IBD and correlates with clinical disease activity. It reliably differentiates between patients with IBD and irritable bowel syndrome. More importantly, at a given faecal calprotectin concentration in patients with quiescent IBD, the test has a specificity and sensitivity in excess of 85% in predicting clinical relapse of disease. This suggests that relapse of IBD is closely related to the degree of intestinal inflammation and suggests that targeted treatment at an asymptomatic stage of the disease may be indicated.

Spontaneous clearance and treatment of acute hepatitis C infection in HIV-positive men with 48 weeks of interferon-alpha and ribavirin.

Acute hepatitis C infection in the context of HIV is an emerging problem in men who have sex with men (MSM). We conducted a retrospective cohort study of MSM diagnosed with and treated for acute hepatitis C infection over 10 years. Genotype 1 was the commonest type representing 69% of cases; the spontaneous clearance rate was 20%. The overall sustained virological response (SVR) rate on an intention-to-treat basis was 83%; SVR and was 92% for those completing 48 weeks of treatment. The presence of detectable RNA at week 12 had a 100% negative predictive value for SVR. This is the largest single cohort treated with 48 weeks of interferon and ribavirin and the treatment SVR is one of the highest reported. We propose that a 48-week treatment regimen may be superior to shorter (24-week) regimens though we acknowledge the need for a randomized controlled trial.

De novo Cryoglobulinaemic Mononeuritis Multiplex during Treatment of Chronic Hepatitis C Infection: A Viral Effect or Induced by Pegylated Interferon Alpha?

Cryoglobulinaemic mononeuritis multiplex (MNM) is an extrahepatic manifestation of chronic hepatitis C virus (HCV) infection for which interferon-based antiviral therapy is currently the treatment of choice. Rarely MNM can be associated with HCV treatment though generally in the setting of pre-existing cryoglobulinaemia and detectable HCV viraemia. We report an unusual case of de novo MNM occurring late during the course of pegylated interferon and ribavirin therapy for chronic HCV infection, following a prolonged period of viral suppression. The patient had no evidence of cryoglobulinaemia prior to HCV treatment and undetectable HCV RNA levels at the time of presentation with MNM. The case raises the possibility that MNM could develop as an adverse immunomodulatory effect of pegylated interferon therapy.

Fecal calprotectin as an index of intestinal inflammation.

The assessment of inflammatory activity in intestinal disease in man can be done using a variety of different techniques, from measurement of conventional noninvasive acute-phase inflammatory markers in plasma (C-reactive protein and the erythrocyte sedimentation rate) to the direct assessment of disease activity by intestinal biopsy. However, most of these techniques have significant limitations when it comes to assessing functional components of the disease that relate to activity and prognosis. Here we briefly review the value of a novel emerging intestinal function test, fecal calprotectin. Single stool assay of neutrophil-specific proteins (calprotectin, lactoferrin) give the same quantitative data on intestinal inflammation as the 4-day fecal excretion of indium-111-labeled white cells. Elevated levels of fecal calprotectin have been demonstrated in patients with NSAID-induced enteropathy and have been used in the diagnosis of colorectal cancer. Fecal calprotectin is increased in over 95% of patients with inflammatory bowel disease (IBD) and correlates with clinical disease activity. It reliably differentiates between patients with IBD and irritable bowel syndrome (IBS). More importantly, at a given fecal calprotectin concentration in patients with quiescent IBD, the test has a specificity and sensitivity in excess of 85% in predicting clinical relapse of disease. This suggests that relapse of IBD is closely related to the degree of intestinal inflammation and suggests that targeted treatment at an asymptomatic stage of the disease may be indicated. (c) 2001 Prous Science. All rights reserved.

Role of endoscopic endoprostheses in proximal malignant biliary obstruction.

The management of hilar strictures is dependent upon their resectability and may therefore require a multidisciplinary approach. However, resectability rates for such tumors are reported to be in the region of 15%-20%, and, therefore, palliative therapy will be the mainstay of treatment for most patients. With the presenting symptoms being those of obstructive jaundice and the consequences of cholestasis, a significant improvement in morbidity can be obtained by achieving biliary drainage. A number of options are available, including the placement of Teflon or expandable metallic endoprostheses by either the endoscopic or percutaneous route. Some considerable debate exists as to which route of stent placement is best, and in many circumstances the decision will depend on the availability of local services. Some have suggested that success rates with percutaneous stenting are superior to those for endoscopic placement, but the latter technique may be associated with fewer complications. In competent hands, endoscopic placement does achieve a high rate of success and it should be remembered that a combined approach may further improve success rates. The debate over the use of plastic versus metallic stents is centered around the higher rates of stent occlusion/migration for plastic stents seen in some studies, although a stent change is usually possible. An additional advantage of metallic stents is that they may provide drainage of the side branches of the biliary tree through the mesh. However, possible drawbacks may be a greater difficulty in placement of a second stent where a first provides inadequate drainage, and cost issues often have to be taken into consideration. Considerable debate exists over the optimum number of stents required to achieve adequate drainage and minimize the risks of cholangitis. There is good evidence that if overfilling of the biliary tree with contrast is avoided with only the segments to be drained visualized, a single stent may be all that is required, while others argue that placement of more than one stent may improve survival. In the following review we discuss these issues, and conclude by considering success rates and complications following endoprosthesis insertion; we also discuss the prognosis of patients treated in this way.

Small intestinal permeability.

The noninvasive assessment of small intestinal permeability in humans is now within the capability of any routine biochemistry laboratory. There remain however, many pitfalls for the unwary when performing these tests. Importantly, it has now been shown that normal intestinal permeability relates to geographical location rather than race. Recent studies show that it may be possible to simplify the procedure even further. The main recent focus of interest in measuring intestinal permeability relates to patients with AIDS and inflammatory bowel disease, the effects of nonsteroidal anti-inflammatory drugs on the small bowel, and the use of these tests in the pediatric population and critically ill. Some groups have now started to focus their attention on the possible systemic consequences of increased intestinal permeability, whereas others have shown that increased small bowel permeability results in small intestinal inflammation that may in turn be associated with blood and protein loss.

The effects of a preassessment clinic on nonattendance rates for day-case colonoscopy.

BACKGROUND AND STUDY AIMS: Nonattendance for colonoscopy contributes to an increase in the waiting lists for this procedure. Preassessment clinics routinely run for a number of day-patient surgical procedures have been shown to reduce nonattendance rates by enhancing patient understanding. This study aimed to determine prospectively whether preassessing patients booked for colonoscopy would lead to a reduction in the nonattendance rate. PATIENTS AND METHODS: Nonattendance rates for colonoscopy were assessed in consecutive 9-month periods. During the first period all patients were mailed appointments for colonoscopy with dietary and purgative bowel preparation instructions. During the second period, patients who had never previously undergone a colonoscopic examination were invited to attend a preassessment clinic, while patients who had attended for colonoscopy in the past were sent appointments and purgative instructions in the post. RESULTS: 344 colonoscopies were booked in the first 9-month period and 350 in the second, of which 195 were preassessed. Overall, 60 patients did not attend for colonoscopy during the first 9-month period (17.4%), and 40 (11.4%; P<0.05) did not attend during the second period of study. During the second 9 months only six (3.1%) of the 195 preassessed patients did not attend for colonoscopy, in comparison with 34 (22%; P<0.0001) of the 155 patients not preassessed. CONCLUSIONS: By running a limited preassessment clinic for patients due for colonoscopy, we have shown a significant reduction in the nonattendance rate. If all patients were to attend for preassessment, nonattendance rates for colonoscopy might be reduced to that seen in our preassessment group (3.1%).

Acute auto immune haemolytic anaemia secondary to hepatitis A infection.

Auto immune haemolytic anaemia has been described in association with a variety of hepatotropic viruses, in particular cytomegalovirus, Epstein-Barr virus and hepatitis B. There is a well-recognized association between chronic active hepatitis and auto immune haemolytic anaemia. We present the first reported case of acute hepatitis A which resulted in a fall in haemoglobin concentration from 14.6 to 4.5 g/dl due to an acute haemolytic anaemia with an associated rise in bilirubin from 149 to 960 mumol/l.

Comparison of the intestinal toxicity of celecoxib, a selective COX-2 inhibitor, and indomethacin in the experimental rat.

BACKGROUND: It is suggested that the gastrointestinal toxicity of conventional non-steroid anti-inflammatory drugs (NSAIDs) is due to a 'topical' effect in addition to inhibition of the mucosal constitutive cyclo-oxygenase-1 (COX-1) enzyme. COX-2 selective inhibitors have been shown to have excellent gastrointestinal tolerability, but it is not known whether this is due to their selectivity and/or a lack of a 'topical' effect. We assessed the effects of celecoxib (a highly selective COX-2 inhibitor) on key pathophysiologic events in NSAID enteropathy. METHODS: The 'topical' effects of indomethacin and celecoxib were assessed in vitro (coupled mitochondrial respiration) and in vivo (mitochondrial electron microscopy) and the consequences by study of intestinal permeability (51-Cr-labelled ethylenediamine-tetraacetic acid urinary excretion) and inflammation. We also assessed intestinal prostanoid levels (prostaglandin E, PGE) and the propensity of the drugs to induce intestinal ulcers. RESULTS: Indomethacin uncoupled mitochondrial oxidative phosphorylation in vitro and in vivo, caused a significant (P < 0.0001) increase in intestinal permeability, caused mucosal inflammation and a 90% decline in intestinal PGE levels, and was associated with multiple small intestinal ulcers. Celecoxib caused no significant increase in any of these parameters, did not decrease intestinal PGE levels, and caused no intestinal ulcers. CONCLUSIONS: The intestinal tolerability of celecoxib appears to be due to a combination of the absence of a 'topical' damaging effect and selective COX inhibition.

Faecal calprotectin and faecal occult blood tests in the diagnosis of colorectal carcinoma and adenoma.

BACKGROUND AND AIMS: Testing for faecal occult blood has become an accepted technique of non-invasive screening for colorectal neoplasia but lack of sensitivity remains a problem. The aim of this study was to compare the sensitivity and specificity of faecal calprotectin and faecal occult blood in patients with colorectal cancer and colonic polyps. METHODS: Faecal calprotectin and occult blood were assessed in 62 patients with colorectal carcinoma and 233 patients referred for colonoscopy. The range of normality for faecal calprotectin (0.5-10.5 mg/l) was determined from 96 healthy subjects. RESULTS: Median faecal calprotectin concentration in the 62 patients with colorectal carcinoma (101 mg/l, 95% confidence interval (CI) 57-133) differed significantly from normal (2.3 mg/l, 95% CI 1.6-5.0) with 90% of patients having elevated levels (normal <10 mg/l) whereas only 36/62 (58%) had positive faecal occult bloods. There was no significant difference in faecal calprotectin levels when considering location or Dukes' staging of tumour. Percentage positivity of faecal occult bloods was significantly higher for Dukes' stage C and D cancers compared with Dukes' A and B. In the colonoscopy group, 29 patients with adenomatous polyps were detected in whom the median faecal calprotectin was 12 mg/l (95% CI 2.9-32). Sensitivity for detection of adenomatous polyps was 55% using the calprotectin method and 10% using faecal occult blood testing. The overall sensitivity and specificity of calprotectin for colorectal cancer and adenomatous polyps as a combined group was 79% and 72%, respectively, compared with a sensitivity and specificity of faecal occult blood of 43% and 92%. CONCLUSIONS: Faecal calprotectin is a simple and sensitive non-invasive marker of colorectal cancer and adenomatous polyps. It is more sensitive than faecal occult blood tests for detection of colorectal neoplasia at the cost of a somewhat lower specificity.

Surrogate markers of intestinal inflammation are predictive of relapse in patients with inflammatory bowel disease.

BACKGROUND & AIMS: Prediction of relapse of inflammatory bowel disease has important implications for therapeutic strategies. We assessed whether measurement of intestinal permeability and inflammation could predict relapse of inflammatory bowel disease (IBD). METHODS: Forty-three patients with Crohn's disease (CD) and 37 with ulcerative colitis (UC) in clinical remission provided a stool sample to be assayed for calprotectin (a neutrophil-specific marker), and patients with CD additionally underwent a small intestinal permeability test. Relapse was defined using clinical disease activity indices. RESULTS: Twenty-five (58%) patients with CD and 19 (51%) with UC had a relapse over the 12-month period. Median calprotectin levels in the relapse groups (122 mg/L for CD, 123 mg/L for UC; normal <10 mg/L) differed significantly (P<0.0001) from those of the nonrelapse groups (41.5 mg/L for CD, 29.0 mg/L for UC). At 50 mg/L, the sensitivity and specificity of calprotectin for predicting relapse in all patients with IBD were 90% and 83%, respectively. Permeability in the CD patients who relapsed (median, 0.075; normal <0.04) differed significantly (P = 0. 004) from that in the nonrelapse group (median, 0.038). At the level of 0.05, the sensitivity and specificity of permeability in predicting relapse were 84% and 61%, respectively. CONCLUSIONS: Fecal calprotectin predicts clinical relapse of disease activity in patients with CD and UC, whereas small intestinal permeability is a useful predictor of relapse in patients with small intestinal CD.