Polymorphisms in apoptosis genes predict response to infliximab therapy in luminal and fistulizing Crohn's disease

BACKGROUND: Infliximab treatment is effective in 70-80% of patients with refractory luminal and fistulizing Crohn's disease. The effect of infliximab is ascribed to induction of apoptosis. AIM: To study whether polymorphisms in apoptosis genes predict the response to infliximab and whether they interact with clinical predictors. METHODS: Cohort of 287 consecutive patients treated with infliximab for refractory luminal (n = 204) or fistulizing (n = 83) Crohn's disease was genotyped for 21 polymorphisms in apoptosis genes. Short-term clinical response was assessed at week 4 (luminal Crohn's disease) or 10 (fistulizing Crohn's disease) after the first infliximab infusion. RESULTS: The response rate was 69% in luminal and 80% in fistulizing Crohn's disease. In luminal Crohn's disease, two genetic predictors were identified: (i) patients with the Fas ligand -843 CC/CT genotype (n = 135) responded in 75%, with the TT genotype (n = 21) in 38% only (P = 0.002; OR = 0.11; 95% CI: 0.08-0.56). (ii) Patients with the caspase-9 93 TT (n = 9) genotype all responded, in contrast with 67% (n = 147) with the CC and CT genotype (P = 0.04; OR = 1.50; 95% CI: 1.34-1.68). Concomitant azathioprine/mercaptopurine therapy overcame the effect of unfavourable genotypes. In the fistulizing Crohn's disease cohort, the same Fas ligand -843 CC/CT genotype was the only predictor of response (P = 0.002; OR = 1.66; 95% CI: 1.21-2.29), interacting with caspase-9 93 polymorphism but not with azathioprine/mercaptopurine. CONCLUSION: We observed that polymorphisms in FasL/Fas system and caspase-9 influence the response to infliximab in luminal and fistulizing Crohn's disease. The strongest association was seen between the Fas ligand -843 TT genotype and non-response. Concomitant mercaptopurine/azathioprine therapy, however, was able to overcome the effect of unfavourable genotypes in luminal disease.     

What is the optimal medical treatment for stable cardiac surgical patients who go into atrial fibrillation after their operation?

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was which medical strategy is the optimal treatment for stable patients going into atrial fibrillation post cardiac surgery. Altogether 281 papers were found from medline and 83 from the Cochrane Central Register of Controlled Trials using the reported search, of which 12 presented the best evidence to answer the clinical question. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results, and study weaknesses of these papers are tabulated. We conclude that there is very little evidence to support any one strategy over another.     

cDNA cloning of a human homologue of the Caenorhabditis elegans cell fate-determining gene mab-21: expression, chromosomal localization and analysis of a highly polymorphic (CAG)n trinucleotide repeat

The two most consistent features of the diseases caused by trinucleotide repeat expansion-neuropsychiatric symptoms and the phenomenon of genetic anticipation-may be present in forms of dementia, hereditary ataxia, Parkinsonism, bipolar affective disorder, schizophrenia and autism. To identify candidate genes for these disorders, we have screened human brain cDNA libraries for the presence of gene fragments containing polymorphic trinucleotide repeats. Here we report the cDNA cloning of CAGR1, originally detected in a retinal cDNA library. The 2743 bp cDNA contains a 1077 bp open reading frame encoding 359 amino acids. This amino acid sequence is homologous (56% amino acid identify and 81% amino acid conservation) to the Caenorhabditis elegans cell fate-determining protein mab-21. CAGR1 is expressed in several human tissues, most prominently in the cerebellum, as a message of approximately 3.0 kb. The gene was mapped to 13q13, just telomeric to D13S220. A 5'-untranslated CAG trinucleotide repeat is highly polymorphic, with repeat length ranging from six to 31 triplets and a heterozygosity of 87-88% in 684 chromosomes from several human populations. One allele from an individual with an atypical movement disorder and bipolar affective disorder type II contains 46 triplets, 15 triplets longer than any other allele detected. Though insufficient data are available to link the long repeat to this clinical phenotype, an expansion mutation of the CAGR1 repeat can be considered a candidate for the etiology of disorders with anticipation or developmental abnormalities, and particularly any such disorders linked to chromosome 13.      

Deletion of the short arm of chromosome 1 (del 1p) is a strong predictor of poor outcome in myeloma patients undergoing an autotransplant.

Several chromosomal abnormalities detected by conventional cytogenetic analysis have an adverse impact on the outcome in myeloma patients. A wide spectrum of abnormalities involving chromosomes 1, 13, 14, and 17 has been described. We analyzed the outcome of 83 patients with clonal cytogenetic abnormalities, who underwent high-dose therapy and autologous stem cell transplantation for multiple myeloma at our institution. Clonal abnormalities were detected at diagnosis by conventional cytogenetic analysis in 83 patients. Patients underwent a single autologous transplant between April 2000 and May 2005. Preparative regimen was high-dose melphalan alone (73), or a combination of topotecan, melphalan, and cyclophosphamide (TMC=10). The most commonly observed chromosomal abnormalities were deletion of chromosome 13 (32%), hyperdiploidy (21%), deletion of chromosome 1p (18%), and t (11; 14) in 7% patients. Median follow-up among surviving patients was 25.5 months. Median interval from diagnosis to autotransplant was 7.7 months (range: 2.5-52). Median progression-free survival (PFS) for the entire group was 19 months and the median overall survival (OS) was 52 months. On univariate analysis, both PFS and OS were significantly shorter in patients with deletion 1p (P=.001 and <.0001, respectively). Thirty-two patients whose cytogenetic abnormalities returned to normal prior to autotransplant had longer PFS and OS than patients with persistent abnormalities (P=.02 and .08, respectively). Deletion 1p is associated with a significantly shorter remission and survival in patients undergoing high-dose therapy and a single autologous transplant for myeloma.     

Factors Associated with Premalignant Epithelial Changes in Chronic Calculous Cholecystitis: A Case–Control Study

Introduction

Gallstones are known to be associated with premalignant changes in the gallbladder epithelium that range from atypical hyperplasia, metaplasia, dysplasia to carcinoma. Recognition of factors associated with these changes in patients with gallstones can potentially be helpful in identifying patients to whom prophylactic cholecystectomy can be offered to reduce the chances of developing carcinoma.

Objective

To identify factors associated with premalignant epithelial changes including atypical hyperplasia, metaplasia, and dysplasia in gallbladder mucosa in patients with chronic calculus cholecystitis.

Materials and methods

This was retrospective case–control study conducted over a period of 10 years from 2004 to 2014. Cases were patients with reported histopathological premalignant epithelial changes along with chronic calculus cholecystitis, and controls were patients without premalignant epithelial changes but chronic calculus cholecystitis. Controls were twice the number of the cases.

Results

Over study period, 92 patients were reported to have premalignant epithelial changes on gall bladder histopathology for whom 184 controls were selected. Of cases, 61 (66%) patients had atypical hyperplasia, while metaplasia and dysplasia were present in 26 (28%) and 5 (5%) cases, respectively. Mean age was 47.5 ± 14.5 years, and 74% of the study population were female. Wall thickness of more than 3 mm (OR = 4.14, p value < 0.001) turned out to be statistically significant independent variables associated with premalignant lesions in gallbladder mucosa.

Conclusion

Odds of premalignant epithelial change in gall bladder mucosa in patients with gall bladder wall thickness of more than 3 mm is four times the odds of patients with wall thickness less than 3 mm, and the effect is statistically significant. Prophylactic cholecystectomy should be considered for this group of patients.

     

Selective stimulation of insulin secretion by CCK-4 analogues having N-terminal modifications

Summary Synthetic analogues of CCK-4 in which Trp¹ was replaced by D-Pro (peptide I), Thz (peptide II) and ΔPro (peptide III) have been studied for their insulin and glucagon releasing activities from the islets of Langerhansin vitro. Peptide I has been found to be the most potent insulin releaser among the three analogues and its activity is comparable to that of CCK-4. Unlike CCK-4, its three analogues (peptides I–III) do not stimulate the release of glucagon with basal concentration of glucose in the medium. However, with increasing glucose concentration, all the three analogues potentiate the glucose stimulus for insulin release. C.D.R.I. Communication n ^o 4735.