ITPA polymorphisms do not predict additional risk beyond TPMT and NUDT15 for thiopurine-induced cytopenia in inflammatory bowel disease.

INTRODUCTION AND AIM: Thiopurine-related leukopenia is associated with polymorphisms in the thiopurine methyltransferase (TPMT) and nucleoside diphosphate-linked moiety X type motif 15 (NUDT15) genes. However, those polymorphisms explain only a fraction of thiopurine-related leukopenia. Our aim was to study the role of an inosine triphosphate pyrophosphatase (ITPA) polymorphism in patients with inflammatory bowel disease (IBD) and thiopurine-related leukopenia that was unexplained by the TPMT and NUDT15 polymorphisms. MATERIAL AND METHODS: We enrolled consecutive IBD patients on thiopurines (azathioprine or 6-mercaptopurine) from January 2019-March 2020, at a tertiary care center in North India. The presence of the ITPA (C.94C > A) polymorphism was evaluated in all patients, along with its association with thiopurine-related leukopenia. RESULTS: Of the 33 patients (from a total of 119 patients) that developed leukopenia, 8 had the TPMT (n = 1) or NUDT15 (n = 7) polymorphism. Of the remaining 111 patients, their mean age was 36.36 ±â€¯13.54 years and 57 (51.3%) were males. Twenty-five (21.01%) had unexplained leukopenia. The ITPA polymorphism was detected in 4 (16%) patients in the unexplained leukopenia group and 24 (27.9%) patients in the non-leukopenia group (p = 0.228). The odds ratio for predicting leukopenia with the ITPA polymorphism was 0.4921 (95% CI 0.1520-1.5830, p = 0.234). CONCLUSION: The ITPA (C.94C > A) polymorphism was frequently detected in the study population but was not predictive for leukopenia in patients with IBD on thiopurine therapy.

Role of Positron Emission Tomography in Assessing Disease Activity in Ulcerative Colitis: Comparison with Biomarkers.

BACKGROUND: Disease activity in ulcerative colitis (UC) is best assessed clinically by Mayo score. 18-Fluorodeoxyglucose positron emission tomography-computerized tomography (FDG PET-CT) is a noninvasive imaging technique to assess extent, disease activity and response to treatment of UC, especially in high risk population or patients unwilling for endoscopy. AIMS: We conducted a prospective observational study with the aim of assessing and correlating UC disease activity by clinical criteria, endoscopy, histology, serum and fecal biomarkers, and FDG PET-CT. METHODS: Sixty eligible patients of UC were enrolled into three groups (26 remission, 24 moderate and 10 severe activity) as per Mayo score and FDG PET-CT was performed within 72 h of colonoscopy. ESR, CRP, and fecal calprotectin (FC) levels were determined for all patients. RESULTS: Of 60 enrolled patients, 10% patients had proctitis, 43.3% left-sided colitis, and 46.7% extensive colitis. ESR, CRP, FC levels, and rectal PET activity were significantly higher in groups with moderate and severe disease activity. Rectal PET activity showed a significant correlation with the Mayo score (k = 0.465, p < 0.001), endoscopic subscore (k = 0.526, p < 0.001), histological score (k = 0.496, p < 0.001), and FC (k = 0.279, p = 0.031). Extent evaluation by FDG PET-CT and colonoscopy showed a significant correlation (k = 0.582, p < 0.001). Besides, FDG PET-CT identified sacroiliitis in one patient and adenocarcinoma in one patient. CONCLUSION: FDG PET-CT is a reliable noninvasive tool for detection of disease activity, extent in UC with good correlation with Mayo score, histology and fecal biomarkers and accurate predictor of disease remission.

Zollinger-Ellison syndrome: an unusual case of chronic diarrhoea in a child.

Most cases of Zollinger-Ellison syndrome (ZES) are described in adults. It is a rare disorder in childhood. Most cases present with abdominal pain due to peptic ulceration and chronic diarrhoea not responding to general measures. The symptom complex is initially confused with other more common diseases, which lead to a delay in diagnosis. We present a rare case of a-12-year boy who initially presented with abdominal pain, diarrhoea, vomiting and progressive weight loss for over a two-year period before he was finally diagnosed as a case of ZES with the primary tumour in the pancreatic head and with multiple metastasis in both the liver and lymph nodes.

Role of oxidative stress & antioxidant defence in ulcerative colitis patients from north India.

BACKGROUND & OBJECTIVES: Oxidative stress contributes to severity of ulcerative colitis (UC) but the status of erythrocyte antioxidant defence remains unknown. The present study was aimed to study the role of oxidative stress and antioxidant levels in erythrocytes of UC patients from north India. METHODS: A total of 81 adult UC patients and 85 age and sex matched apparently healthy controls were included in this study. Levels of lipid peroxidation (LPO), reduced glutathione (GSH), catalase and superoxide dismutase (SOD) were measured in erythrocytes. RESULTS: Mean age of UC patients was 43.5 yr (range 18-64 yr) while in the control group this was 45.3 yr (range 20-64 yr). LPO, catalase and SOD levels in UC patients were significantly increased (P< 0.05) compared to healthy controls, while GSH levels in UC patients were significantly decreased (P< 0.05) compared to healthy controls Ulcerative colitis activity score (UCAI) was 157.4±27.6 in UC patients. INTERPRETATION & CONCLUSIONS: Increased levels of LPO, SOD, catalase and a decreased level of GSH represent that oxidative stress plays a significant role in pathophysiology of UC. Further, the levels of LPO, GSH, catalase and SOD remained same during different UCAI.

Small intestinal bacterial overgrowth and orocecal transit time in patients of inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) consists of Ulcerative colitis (UC) and Crohn's disease (CD). These two conditions share many common features-diarrhea, bloody stools, weight loss, abdominal pain, fever and fatigue. Small intestinal bacterial overgrowth (SIBO) is frequent in patients with CD but it has not been studied in UC Indian patients. AIM: The study was planned to measure orocecal transit time (OCTT) and SIBO in UC and CD patients. METHODS: One hundred thirty-seven patients of IBD (95 UC and 42 CD) and 115 healthy controls were enrolled. OCTT and SIBO were measured by lactulose and glucose hydrogen breath test respectively. Concentration of hydrogen and methane were measured by SC microlyser from Quintron, USA. RESULTS: Mean±standard deviation (SD) of OCTT in patients of IBD was significantly higher as compared to controls. Furthermore, OCTT was significantly higher in CD patients as compared to UC patients. It was also observed that occurrence of SIBO was significantly higher in IBD patients as compared to controls. The occurrence of SIBO in CD (45.2%) was significantly higher as compared to patients in UC (17.8%) group. Percentage of methane positive IBD patients (2.9%) was significantly lower as compared to methane positive controls (24.4%). CONCLUSION: OCTT was significantly delayed in IBD patients as compared to controls and in CD patients as compared to UC patients. OCTT was significantly higher in SIBO positive IBD patients as compared to SIBO negative patients. Thus, we can suggest that delayed OCTT would have been the cause of increased SIBO in these patients.

Effect of biotherapeutics on antitoxin IgG in experimentally induced Clostridium difficile infection.

PURPOSE: Recurrent diarrhoea after successful treatment of primary Clostridium difficile associated disease (CDAD) occurs due to bowel flora alterations and failure to mount an effective antibody response. Apart from antibiotics, risk factors include immunosuppressive and acid-suppressive drug administration. Biotherapeutics such as probiotic and epidermal growth factor (EGF) may offer potential effective therapy for CDAD. MATERIALS AND METHODS: The effect of biotherapeutics in mounting an antibody response against C. difficile toxins was studied in BALB/c mice challenged with C. difficile after pre-treatment with ampicillin, lansoprazole or cyclosporin. Sera from sacrificed animals were estimated for antitoxin IgG by enzyme linked immunosorbent assay. RESULTS: Antitoxin IgG was significantly higher (P<0.05) in C. difficile challenged groups compared to unchallenged controls, but insignificant (P>0.05) in animals in which C. difficile was given after pre-treatment with cyclosporin compared to those without any pre-treatment, or pre-treatment with antibiotic or lansoprazole. In inter-subgroup comparisons also significant anomaly in production of antitoxin IgG was found. The antitoxin IgG levels were raised in animals administered C. difficile after pre-treatment with ampicillin, but lower in animals administered cyclosporin. High levels of antitoxin IgG were also found in the serum samples of animals receiving lansoprazole and C. difficile. CONCLUSIONS: Probiotics showed their beneficial effect by boosting the immune response as seen by production of antitoxin IgG. Oral administration of EGF did not affect the immune response to C. difficile toxins as significant increase was not observed in the serum antitoxin IgG levels in any of the groups investigated.

Evaluation of fecal myeloperoxidase as a biomarker of disease activity and severity in ulcerative colitis.

BACKGROUND: Subclinical inflammation in ulcerative colitis (UC) can predispose to relapses and biomarkers can detect mucosal inflammation. AIMS: To study the role of fecal myeloperoxidase (FMPO) in assessing disease activity and response to therapy in UC. METHODS: Patients with UC attending our hospital from July 2005 to September 2006 were studied. All patients underwent clinical, endoscopic, and histological assessment for disease extent and severity. Estimation of FMPO levels at baseline and on follow-up was carried out. Age-matched healthy controls were studied for FMPO levels. RESULTS: A total of 55 patients of UC (30 males, 25 females, mean age 38.6 ± 12 years) and 54 age-matched controls (mean age 37.6 ± 13.6 years) were studied. Cases had higher median MPO levels than controls (0.42 [IQR 0.84] vs. 0.06 [IQR 0.12]); (p < 0.001). Cases with endoscopically more severe disease (Gr III & IV; n = 18) had higher median FMPO levels compared to those with milder disease (Gr II, n = 37), [0.075 (IQR 1.315) vs. 0.315 (IQR 0.813); p = 0.02]. The median MPO level in 27 patients was 0.58 [IQR 0.89] units/ml at presentation which on follow-up decreased significantly to 0.18 [IQR 0.42] units/ml (p value 0.002). However, there was no significant association between FMPO and endoscopic extent and histological scores of activity and chronicity. CONCLUSIONS: Fecal MPO is an effective biomarker for assessing disease activity and response to therapy in patients with ulcerative colitis.

Acantholytic squamous cell carcinoma of the oral cavity: an uncommon histological variant of squamous cell carcinoma.

Acantholytic squamous cell carcinoma is a rare and aggressive histological variant of squamous cell carcinoma, characterized by tubular and alveolar patterns as a consequence of the acantholysis. We report a case of acantholytic squamous cell carcinoma in a 70-year-old woman, who was admitted to our institution for the progressively enlarging exophytic and ulcerated lesion. We report this interesting lesion due to the rarity of acantholytic variant of squamous cell carcinoma and the literature is briefly reviewed.

Brush border enzymes and absorptive capacity in extrahepatic portal venous obstruction in children.

BACKGROUND AND OBJECTIVE: Portal hypertension may affect intestinal functions, brush border enzymes and absorption parameters. Information about these in extrahepatic portal venous obstruction (EHPVO) in children is limited and poorly reported. We therefore studied the brush border enzymes and absorptive capacity in EHPVO in children. METHODS: The study was conducted on 52 children of EHPVO. The diagnosis of EHPVO was made on the basis of clinical presentation and ultrasound examination. All patients underwent upper gastrointestinal endoscopy. Endoscopic tissue biopsies from duodenum were taken on aluminum foils and kept immediately at -20°C for estimation of brush border enzymes. Tissue biopsies were homogenized in sodium maleate buffer, 0.1 M pH 6.0, by a homogenizer and processed for the enzymes: lactase, maltase, and sucrase. Enzyme levels were compared to normal healthy controls (n = 20). d-Xylose test, stool acid steatocrit for fat excretion in stools and stool alpha-1 antitrypsin were done to know about the absorptive parameters. RESULTS: Enzyme levels of lactase (6.21 ± 5.67 IU/mg) and sucrase (37.07 ± 21.06 IU/mg) in EHPVO group were significantly lower as compared to lactase (23.32 ± 10.48 IU/mg) and sucrase (95.96 ± 46.55 IU/mg) in normal healthy controls. Maltase levels were lower, but difference was not statistically significant in EHPVO group (56.90 ± 28.65 IU/mg) as compared to normal controls (63.28 ± 22.88 IU/mg). There was no significant difference of urinary d-xylose and stool fat in patients with normal or short stature EHPVO patients. CONCLUSION: EHPVO leads to decrease in levels of brush border enzymes in small bowel but their absorption capacity remains normal.

Influence of previously ingested wheat on fasting breath hydrogen in celiac patients.

The excretion of hydrogen in breath commonly persists, despite an overnight fast. Although the elevation of hydrogen concentration above the fasting value after the administration of a test sugar is evidence of malabsorption, the level of the fasting value itself in untreated celiac patients is unknown. Therefore, we studied the fasting breath hydrogen (FBH(2)) concentration in 40 healthy controls, 35 subjects with functional bowel disorders, and 30 patients of untreated celiac disease with and without bread or wheat diet one day before the test. The fasting level of hydrogen concentration in untreated celiac patients (28.7 +/- 19.5 ppm) was significantly higher than those in healthy volunteers (9.5 +/- 3.4 ppm) and subjects with functional bowel disorders (10.6 +/- 4.5 ppm). The percentage of patients with elevated H(2) fasting levels in untreated celiac disease (82.5%) was significantly higher than that in healthy controls (10%) and subjects with functional bowel disorders (17.1%). In 30 celiac patients, studied with and without wheat-free diet one day before the test, the fasting hydrogen levels decreased from 28.7 +/- 19.5 ppm to 10.6 +/- 3.5 ppm, and becoming normal in all patients of celiac disease. Our results show that the patients of untreated celiac disease should be instructed not to eat things made up of wheat one day before hydrogen breath testing so that the normal fasting hydrogen concentration can be obtained and false-negative hydrogen breath test results can be avoided.

Orocecal transit time in patients with celiac disease from North India: a case control study.

AIM: The mechanisms responsible for bowel disturbances in celiac disease are still unknown. Small bowel motor abnormalities may be involved in this pathological condition; however, there is no study addressing small bowel transit in patients of celiac disease from Northern India. METHOD: The mouth-to-cecum transit time was studied in 80 celiac patients and 80 age and sex matched apparently healthy controls. RESULTS: Orocecal transit time in celiac patients was significantly delayed being 180+/-10.6 minutes (Mean+/-SE) as compared to 105+/-12.4 minutes in apparently healthy controls. CONCLUSION: This prolonged orocecal transit time could be due to impaired small bowel function (deranged motility) in patients with celiac disease.

Reassessment of diagnostic value of antral nodularity for Helicobacter pylori infection in children.

AIM: Antral nodularity is considered as specific for Helicobacter pylori-associated gastritis in children as well as in adults. The aim of this study is to reassess the accuracy of using antral nodularity as a marker for H. pylori-infection in children with various gastroduodenal diseases. METHODS: This prospective study included 725 consecutive children in whom upper digestive endoscopy was performed for gastrointestinal symptoms between June 6, 2003 and May 11, 2007 and gastric antral mucosal biopsy was taken. They were divided within three diagnoses groups: Group I, recurrent abdominal pain (N=252); Group II, celiac disease (N=358) and Group III, miscellaneous diagnoses (N=115). One hundred nineteen children were diagnosed as having antral nodularity and were included in the study. H. pylori were recognized in gastric biopsy on hematoxylin and eosin (H&E) sections; a toluidine blue stain was performed in biopsy suspicious for H. pylori. The appropriate statistical method was applied for analysis of data. RESULTS: The prevalence of antral nodularity in children (M:F:65:54) was 16.4% (119/725). The mean age of children with antral nodularity was 9.4 years (SEM, 0.1 years; range, 2-18 years). The prevalence of antral nodularity increased gradually with age. Fifty out of 119 (42%) children with antral nodularity had recurrent abdominal pain, 26/119 (21.9%) had celiac disease and 43/119 (36.1%) had miscellaneous diagnoses. H pylori-infection was identified in 118/725 (16.3%) children. Antral nodularity had a poor accuracy rate to determine H. pylori-infection (sensitivity, 42%; positive predictive value, 42.4%) and was observed in 50 of 118 (42.4%) H. pylori-positive patients and in 69 of 607 (11.4%) H. pylori-negative patients. CONCLUSION: The antral nodularity is a poor predictor for H pylori-infection in children. During endoscopy, gastric biopsies should always be obtained in children to establish the presence of H pylori-infection.

N-myristoyltransferase: a novel target.

Myristoyl-CoA:Protein N-myristoyltranferase (NMT) is a cytosolic monomeric enzyme which catalyses the transfer of a rare fatty acid, myristate from myristoyl-CoA to the N-terminal glycine residue of a variety of eukaryotic and viral proteins. N-myristoyltransferase is a novel target for anticancer, antiviral and antifungal agents. Recent N-myristoyltransferase inhibitors like benzofurans and benzothiazole derivatives show in vivo antifungal activity and are promising selective fungal N-myristoyltransferase inhibitors.

Recent insights on biochemical and molecular basis for developing antihaemostatic agents: A review.

The normal coagulation process is initiated by disruption and exposure of the subendothelial components of blood vessels. Platelets adhere to subendothelium-bound von Willebrand factor via glycoprotein (GP) Ib complex. This initial interaction per se and the release of platelet agonists transduce signals that leads to the rise in intracellular Ca2+ which induces shape change, prostaglandin synthesis, release of granular contents and conformational changes in platelet Gp IIb-IIIa. Gp IIb-IIIa in activated platelets binds fibrinogen and other adhesive proteins and mediates platelet cohesion the primary haemostatic plug. Furthermore, the activated platelets due to aggregation, result in the formation of fibrin (secondary hemostasis). Normally the haemostatic process plays a delicate balance between keeping the blood in the fluid state to maintain flow and rapidly forming an occluding plug following vessel injury. Thrombosis occurs because of alteration in this delicate balance. Arterial thrombosis occurs in the setting of previous vessel wall injury mostly because of atherosclerosis, while venous thrombosis occurs in areas of stasis. The recent advances in understanding of the haemostatic process have led to a better understanding of the mechanism of action of many antithrombotic drugs and identification of new targets for drug development. The molecular target of the ticlopidine has been identified. Large numbers of IIb-IIIa inhibitors have been developed. The mechanism of action of heparin has been defined at the molecular level. As a result, a synthetic pentasaccharide, based on antithrombin-binding domain of heparin, has been developed and tested successfully in clinical trials. New generation direct thrombin inhibitors are being developed. Factor Xa has a critical position at the convergence of intrinsic and extrinsic pathway. The clinical tolerability and the efficacy of low molecular weight heparins has established that inhibition of further thrombin generation, by blocking factor Xa alone can be an effective way of preventing thrombus growth without inactivating thrombin. A large number of specific factor Xa inhibitors are under development. Some of these are in preliminary clinical trials and appear to be promising. Future clinical trials will determine whether these new drugs will provide better risk-benefit ratio in treatment of thrombotic disorders. Similarly role of thrombolytics has been clearly established in many diseases including coronary artery disease.

Omental cyst in children presenting as pseudoascites: report of two cases and review of the literature.

An omental cyst is a rare intra-abdominal lesion. Absence of characteristic clinical findings make the diagnosis difficult. These cases are reported because of its rarity. The brief review of the features of omental cyst is included in order to increase awareness of this entity.

Coeliac disease in Indian children: assessment of clinical, nutritional and pathologic characteristics.

Coeliac disease is an important cause of chronic diarrhoea, failure to thrive, and anaemia in children. Little information on the disease is available in India. This study was undertaken to determine the prevalence, clinical, anthropometric and histological profiles of coeliac disease in patients attending a tertiary referral centre in India. Coeliac disease was diagnosed in 42 (16.6%) of 246 children with chronic diarrhoea, failure to thrive, and anaemia. The mean ages at onset of symptoms and at diagnosis were 2.4 (range 0.5-10) years and 8.3 (range 3-14) years respectively, and a mean period of delay in diagnosis was 5.9 (range 1-13.5) years. Of the 42 cases, history of failure to thrive was observed in 38 (90%), chronic diarrhoea in 37 (88%), and anaemia in 6 cases. Short stature, under-nutrition, anaemia, oedema of feet, rickets, clubbing of fingers, features of vitamin A deficiency, and B-vitamin deficiency were found in 42, 26, 38, 9, 8, 6, 3, and 2 cases respectively. Onset of symptoms, such as, chronic diarrhoea and failure to thrive, was earlier in children with subtotal villous atrophy than in those with partial villous atrophy (mean +/- SD; 2.00 +/- 1.46 years vs 3.30 +/- 2.72 years; p < 0.05). Results of the study suggest that coeliac disease is not uncommon in Indian children. Coeliac disease should be considered in the differential diagnosis, particularly in children without any symptoms of diarrhoea.

Cervical thymic cyst: report of a case and review of the literature.

Congenital thymic cysts are uncommon and often misdiagnosed as either branchial cleft or cystic hygromas. This paper presents the case of a male child, who presented with a soft, fluctuating mass in the left side of his neck. Surgical excision revealed an ectopic thymic cyst. The histopathologic features of thymic cysts are diagnostic. Ectopic thymic tissue may be an infrequent finding, but it should be included in the differential diagnosis of neck masses, especially in children.