Roy Sherwood

Prevalence and Mechanism of Nonsteroidal Anti-Inflammatory Drug–Induced Clinical Relapse in Patients With Inflammatory Bowel Disease

BACKGROUND & AIMS It has been variably suggested that nonselective NSAIDs and cyclooxygenase (COX)-2 selective inhibitors aggravate or ameliorate clinical disease activity in patients with inflammatory bowel disease. We assessed the effect of these drugs in patients with inflammatory bowel disease (n = 209) and the possible mechanisms. METHODS First, patients with quiescent Crohns disease and ulcerative colitis received the non-NSAID analgesic acetaminophen (n = 26) and the conventional NSAIDs naproxen (n = 32), diclofenac (n = 29), and indomethacin (n = 22) for 4 weeks. The Harvey-Bradshaw index was used to define relapse. Second, to assess the mechanism of relapse, intestinal inflammation was quantitated (fecal calprotectin) before and during treatment (20 patients/group) with acetaminophen, naproxen (topical effect, COX-1 and -2 inhibitor), nabumetone (COX-1 and -2 inhibitor), nimesulide (selective COX-2 inhibitor), and low-dose aspirin (selective COX-1 inhibition). RESULTS Nonselective NSAIDs were associated with a 17%-28% relapse rate within 9 days of ingestion. No patient had an early relapse on acetaminophen, nimesulide, or aspirin, whereas those on naproxen and nabumetone (20%) experienced relapse. These clinical relapses were associated with escalating intestinal inflammatory activity. CONCLUSIONS NSAID ingestion is associated with frequent and early clinical relapse of quiescent inflammatory bowel disease, and the mechanism appears to be due to dual inhibition of the COX enzymes. Selective COX-2 inhibition with nimesulide and COX-1 inhibition with low-dose aspirin appear to be well-tolerated in the short-term.

Serum S-100 Protein, Relationship to Clinical Outcome in Acute Stroke

The clinical significance of serum S-100 protein, a protein released by damaged brain tissue, was assessed in patients with acute ischaemic or haemorrhagic stroke and matched controls. Serum S-100 protein concentration was significantly elevated in patients with ischaemic stroke [median (SQR): 0·27 (0·09) μg/L, n = 68] and haemorrhagic stroke [0·43 (0·23) μg/L, n = 13] compared to controls [0·11 (0·03) μg/L, n = 51, P<0·0001]. Although patients with haemorrhagic stroke had higher serum S-100 concentrations compared to patients with ischaemic stroke, this was not quite statistically significant. Serum S-100 concentrations were related to infarct size, large (total anterior circulation) infarcts concentrations having the highest [0·40 (0·22) μg/L], and small vessel (‘lacunar’) infarcts concentrations having the lowest [0·20 (0·06) μg/L, P<0·0005] concentrations. S-100 protein concentration was also significantly related to clinical outcome at three months measured using three disability and handicap scales (n = 81): modified Barthel index (r s=–0·285, P = 0·01), modified Rankin score (r s = 0·313, P = 0·004) and Lindley score (r s = 0·262, P = 0·018) with high values associated with poor clinical outcome. Similarly high values of serum S-100 protein were observed in patients who died or were discharged to an institution [median (SQR): 0·63 (0·29) μg/L and 0·37 (0·13) μg/L, respectively] compared to those who were discharged home [0·26 (0·11) μg/L, P = 0·13]. The present study suggests measurement of serum S-100 protein could be a useful prognostic marker of clinical outcome in acute stroke. Whether S-100 concentrations can be altered by therapeutic intervention in acute stroke remains to be elucidated. Indexing terms: acute stroke/serum S-100/Barthel index/Rankin scale.

Endothelial Function and Weight Loss in Obese Humans

Background: Obesity is a major risk factor for the development of endothelial dysfunction. We explored the effect of different degrees of body mass on endothelial function, lipids, systemic inflammation and glucose homeostasis and the effect of surgically-induced weight loss on endothelial function in severely obese humans. Methods: A cross-sectional study of healthy subjects across a wide range of body fatness was performed to characterize the effect of obesity on flow-mediated dilatation (FMD), systemic inflammation, blood pressure and insulin sensitivity. A longitudinal study was performed to assess the effect of bariatric surgery induced weight loss on these parameters. 73 healthy subjects across a wide range of body mass were recruited; of these, 8 underwent bariatric surgery (median BMI 52.2 kg/m2, interquartile range 50.355.9). Endothelial dependent vasodilatation was measured using the brachial artery vasodilatory response to forearm hyperemia assessed using highresolution ultrasonography. Results: Obese subjects were characterised by a complex collection of abnormalities, with hypertension, impaired glucose homeostasis, systemic inflammation and reduced FMD. BMI ≤25 kg/m2 (median FMD 9.7%, interquartile range 6.8-12.2), BMI >30 kg/m2 (median FMD 6.7% 4.8-7.5), P=0.01 comparing FMD in lean and obese subjects. A mean reduction in weight of 23.4 (4.6) kg produced an improvement in FMD from 5.3% (3.87.0) to 10.2% (7.6-13.3), P=0.01. Conclusions: Even moderate obesity leads to endothelial dysfunction. In severely obese subjects, FMD is normalized by weight loss. This improvement in FMD is associated with a decline in inflammatory markers, blood pressure and insulin. The improvement in FMD occurred despite patients remaining significantly obese. These results suggest that an integrated approach to improving endothelial function in obese humans may be necessary.

The Effect of Benign and Malignant Liver Disease on the Tumour Markers CA19-9 and CEA

The serum concentrations of CA19-9 and carcinoembryonic antigen (CEA) were measured in 150 consecutive patients with histologically proven liver disease admitted to a liver unit for transplant assessment. A significant proportion of the cases studied had a CA19-9 above the upper limit of the reference range (35 kU/L): alcoholic liver disease (73%), primary sclerosing cholangitis (61%), primary biliary cirrhosis (60%), chronic hepatitis B (71%), chronic hepatitis C (84%), autoimmune hepatitis (36%) and hepatocellular carcinoma (54%). CEA was only elevated in a small proportion of the patients with benign liver disease and the degree of elevation was small (15-37 μg/L). Significantly raised CEA was observed in two patients (15%) with hepatocellular carcinoma. Statistically significant correlations were observed between the serum CA19-9 concentration and standard parameters of liver dysfunction: positive correlations with aspartate aminotransferase, alkaline phosphatase and bilirubin and negative correlations with albumin and γ-glutamyltransferase. Positive relationships were also observed between CA19-9 and both CEA and creatinine. Both increased production of CA19-9 from biliary epithelial cells and decreased clearance due to cholestasis may be contributing to the elevation of CA19-9 in the bloodstream. Our data indicate that caution is needed in the interpretation of CA19-9 results in the presence of liver dysfunction.

Substance misuse in early pregnancy and relationship to fetal outcome

Abstract To establish the frequency of substance misuse in early pregnancy in an urban UK population, 807 consecutive positive pregnancy test urine samples were screened for a range of drugs, including cotinine as an indicator of maternal smoking habits. A positive test for cannabinoids was found in 117 (14.5%) samples. Smaller numbers of samples were positive for other drugs:- opiates (11), benzodiazepines (4), cocaine (3) and one each for amphetamines and methadone. Polydrug use was detected in nine individuals. Only two samples tested positive for ethanol. The proportion with a urine cotinine level indicative of active smoking was 34.3%. The outcome of the pregnancy was traced for 288 subjects. Cannabis use was associated with a lower gestational age at delivery (P < 0.005), an increased risk of prematurity (P < 0.02) and reduction in birth weight (P < 0.002). Whilst maternal smoking was associated with a reduction in infant birth weight (P < 0.05), this was less pronounced than the effect of other substance misuse. Conclusion This study suggests that one in six women in South London are using drugs in early pregnancy and that cannabinoid use is associated with a poorer pregnancy outcome.

Cardiac troponin T and I and creatine kinase-MB as markers of myocardial injury and predictors of outcome following percutaneous coronary intervention

AIMS This study was performed to determine the most sensitive biochemical marker for the detection of cardiac myocyte damage potentially sustained during percutaneous coronary intervention (PCI) and to assess whether such a marker can be used to identify patients at increased risk of poor subsequent clinical outcome. METHODS AND RESULTS We studied 109 consecutive patients presenting with clinical stable and unstable angina and undergoing PCI at our institution. Blood was sampled for creatine kinase-MB (CK-MB), cardiac Troponin T (cTnT) and I (cTnI) immediately before and at 6, 14 and 24 h post-PCI. Five patients with raised cardiac markers pre-PCI were excluded from further analysis. The occurrence of major adverse cardiac events (MACE) was documented in-hospital, at 30 days and at long-term clinical follow up of up to 20 months. MACE occurred in 26/109 (24%) patients: death=1, QWMI=4, NQWMI=5, repeat PCI=16 (nine target vessel revascularisations and seven de-novo lesions), CABG=5. cTnI had the highest detection rate for myocardial damage, with 58 cTnI-positive patients, 38 cTnT-positive patients and 28 CK-MB-positive patients in the 24 h following PCI (Pearsons Chi square test, P<0.01). The type of interventional strategy per se was not significantly associated with post-procedural cardiac marker concentrations (Kruskal-Wallis ANOVA, P>0.05). There was a significant association between post-procedural cardiac marker concentrations of CK-MB, cTnT and cTnI and the occurrence of procedural angiographic complications (P=0.0003, 0.0002, 0.001, respectively). All three markers, at each sampling time point between 6 and 24 h post-PCI, showed a significant predictive relationship with MACE in-hospital and at long-term follow up (ROC curve AUC analysis, P<0.05). All three markers provided equally predictive information at each of the three post-procedural sampling time points between 6 and 24 h following PCI. All levels of cardiac marker elevation above the clinically discriminant cut-off values were significantly predictive of outcome at long-term follow up. CONCLUSIONS cTnI proved to be the most sensitive marker in detecting myocardial necrosis following PCI. CK-MB, cTnT and cTnI all provided similarly reliable prognostic information, with cTnT and cTnI being marginally superior in predicting MACE at follow up.

Prediction of cognitive dysfunction after resuscitation from out-of-hospital cardiac arrest using serum neuron-specific enolase and protein S-100

Background: More than 50% of patients initially resuscitated from out-of-hospital cardiac arrest die in hospital. Objective: To investigate the prognostic value of serum protein S-100 and neuron-specific enolase (NSE) concentrations for predicting (a) memory impairment at discharge; (b) in-hospital death, after resuscitation from out-of-hospital cardiac arrest. Methods: In a prospective study of 143 consecutive survivors of out-of-hospital cardiac arrest, serum samples were obtained within 12, 24–48 and 72–96 hours after the event. S-100 and NSE concentrations were measured. Pre-discharge cognitive assessment of patients (n = 49) was obtained by the Rivermead Behavioural Memory Test (RBMT). The relationship between biochemical brain marker concentrations and RBMT scores, and between marker concentrations and the risk of in-hospital death was examined. Results: A moderate negative relationship was found between S-100 concentration and memory test score, at all time points. The relationship between NSE and memory test scores was weaker. An S-100 concentration >0.29 μg/l at time B predicted moderate to severe memory impairment with absolute specificity (42.8% sensitivity). S-100 remained an independent predictor of memory function after adjustment for clinical variables and cardiac arrest timing indices. NSE and S-100 concentrations were greater in patients who died than in those who survived, at all time points. Both NSE and S-100 remained predictors of in-hospital death after adjustment for clinical variables and cardiac arrest timing indices. The threshold concentrations yielding 100% specificity for in-hospital death were S-100: 1.20 μg/l (sensitivity 44.8%); NSE 71.0 μg/l (sensitivity 14.0%). Conclusions: Estimation of serum S-100 concentration after out-of-hospital cardiac arrest can be used to identify patients at risk of significant cognitive impairment at discharge. Serum S-100 and NSE concentrations measured 24–48 hours after cardiac arrest provide useful additional information.

Neutrophil gelatinase—Associated lipocalin predicts acute kidney injury in patients undergoing liver transplantation

Postoperative acute kidney injury (AKI) increases morbidity and mortality after liver transplantation (LT). Novel methods of assessing AKI including cystatin C (CyC) and neutrophil gelatinase–associated lipocalin (NGAL) have been identified as potential markers of AKI. We compare the ability of standard renal markers (serum creatinine [sCr], estimated glomerular filtration rate [eGFR] and intensive therapy unit organ failure scores with CyC and NGAL to predict AKI within the first 48 hours after LT. 95 patients (median age 50 [interquartile range = 41‐59], 60% male) underwent LT (25% with acute liver failure). AKI was defined according to the Acute Kidney Injury Network criteria. Severe AKI was classified as ≥stage 2. NGAL (urine [u] and plasma [p]) and CyC concentrations taken immediately after transplantation on admission to the Liver Intensive Care Unit were compared with standard markers of renal function. Predictive ability was assessed using the area under the curve generated by receiver operator characteristic analysis (AUROC) and logistic regression. Day 0 sCr, uNGAL, pNGAL, CyC, and eGFR predicted AKI as did SOFA (Sequential Organ Failure Assessment) and APACHE II (Acute Physiology and Chronic Health Evaluation II) scores. APACHE II and pNGAL were the most powerful predictors of severe AKI (APACHE II AUROC = 0.87 [0.77‐0.97], P < 0.001; pNGAL AUROC = 0.87 [0.77‐0.92], P < 0.001). Using multivariate logistic regression, APACHE II (odds ratio 1.64/point [95% confidence interval = 1.22‐2.21, P = 0.001] and pNGAL [odds ratio = 1.01/ng/mL [95% confidence interval = 1.00‐1.02], P = 0.002) retained independent significance. A “renal risk score” using APACHE II > 13 and pNGAL > 258 ng/mL was calculated with a score of ≥1 having a 100% sensitivity and 76% specificity for severe AKI. In conclusion, a combination of NGAL and APACHE II predicts AKI with high sensitivity and specificity after LT. Liver Transpl 16:1257‐1266, 2010.

Fecal M2-Pyruvate Kinase (M2-PK): A Novel Marker of Intestinal Inflammation

Background: Surrogate markers of bowel inflammation are increasingly being recognized as important, not only as markers of disease activity in inflammatory bowel disease (IBD) but also to differentiate irritable bowel syndrome (IBS) from IBD. The dimeric M2‐isoform of pyruvate kinase (M2‐PK) has been reported to be elevated in fecal specimens from colorectal cancer (CA) patients, but its role in IBD is unknown. This study investigated the usefulness of fecal M2‐PK in cohorts of patients with IBD, IBS, and CA. Methods: Stool samples were obtained for calprotectin and M2‐PK measurements in patients with previously diagnosed IBD or new patients being investigated for lower gastrointestinal (GI) symptoms in a UK university hospital. Other investigations were performed as directed by the investigating physician and patients with known IBD were assessed for disease activity by a physician global assessment, Harvey–Bradshaw index (HBI), or endoscopic grading. Results: Fecal M2‐PK and calprotectin measurements were obtained for 148 patients: 50 with ulcerative colitis (UC); 31 with Crohns disease (CD), 43 with irritable bowel syndrome/functional bowel disorders (IBS); 7 with colorectal CA, and 17 with miscellaneous conditions (excluded from the analysis). Median M2‐PK values (U/mL) were significantly elevated in UC: 20.0 (95% confidence interval [CI] 5.4–69.0, P < 0.0001), CD: 24.3 (95% CI 6.4–44.0, P < 0.0001), and CA: 7.0 (95% CI 4.3–88.0, P < 0.0006) compared to IBS: 0.1 (95% CI 0.0–3.2). There was a strong linear correlation of M2‐PK with calprotectin levels. A predetermined cutoff level of 3.7 U/mL for a normal M2‐PK test produced a sensitivity, specificity, and positive predictive value (PPV) of 73%, 74%, and 89%, respectively, for organic disease. Furthermore, M2‐PK levels were significantly elevated in active, compared to inactive, disease for CD (30 versus 0.55 U/mL, P < 0.005) and UC (40 versus 1.2 U/mL, P = 0.006), respectively. Conclusions: Fecal M2‐PK is elevated in IBD as well as in CA patients and is a sensitive and relatively specific marker for organic GI pathology, with a PPV of 89%. Furthermore, it appears to be a potentially valuable, noninvasive marker of disease activity in IBD.

Prognostic role of cardiac troponin I after percutaneous coronary intervention in stable coronary disease

Objective: To assess the role of cardiac troponin I (cTnI) in predicting outcome after percutaneous coronary intervention (PCI). Methods and results: cTnI was measured immediately before and at 6, 14, and 24 hours after PCI in 316 consecutive patients with stable symptoms and native coronary artery disease. The study end point was the occurrence of major adverse cardiac events (MACE) at 30 days and at 18 months after PCI: death, Q wave myocardial infarction (MI), or repeat revascularisation in hospital. Postprocedural cTnI increased in 31% of patients. The cumulative MACE rate at 18 months was 25% (17.7% due to repeat PCI procedures). There was a significant association between postprocedural cTnI increase and death, Q wave MI, or both (odds ratio (OR) 3.28, 95% confidence interval (CI) 1.7 to 6.4, p  =  0.01). Post-PCI cTnI increase had a positive predictive value (PPV) for adverse events at 18 months of 0.47 and a negative predictive value (NPV) of 0.96 (OR 18.9, 95% CI 9.7 to 37, p < 0.0001). The presence of both a postprocedural cTnI rise and a procedural angiographic complication gave a PPV for adverse events of 0.69 and an NPV of 0.92 (OR 22.6, 95% CI 2.6 to 68.6, p  =  0.0005). Conclusions: cTnI increased post-procedurally in one third of this stable patient population undergoing elective PCI and was independently and significantly predictive of an increased risk of adverse events at 18 months, predominantly in the form of repeat PCI.