Picotamide inhibition of excess in vitro thromboxane B2 release by colorectal mucosa in inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease is associated with increased mucosal release of eicosanoids. Among these, thromboxane A2 has been proposed as a possible inflammatory mediator; its suppression may be a useful therapeutic option. METHODS: Using a tissue incubation technique, we compared release of immunoreactive thromboxane B2 by colonic biopsies from patients with ulcerative colitis, Crohn's disease and controls, and assessed the inhibitory effect of picotamide, a thromboxane synthesis inhibitor-receptor antagonist, which has been widely used in Italy for management of ischaemic heart and cerebrovascular disease. RESULTS: Increased amounts of thromboxane B2 were released from biopsies from patients with active ulcerative colitis (median 238 pg/20 min/mg wet weight (interquartile range 147- 325), n = 12) and active Crohn's disease (252 (174-450), 6) compared with those from patients with quiescent ulcerative colitis (95 (61- 140), 12) or Crohn's disease (105 (57-201), 13), or controls (136 (64- 206), 8). Incubation with picotamide at concentrations between 100 microM and 1 mM reduced thromboxane B2 release (IC50 890 microM). CONCLUSION: Since increased thromboxane A2 production may have pathogenetic importance, thromboxane synthesis inhibitor-receptor antagonists such as picotamide merit therapeutic trial in the management of inflammatory bowel disease.     

DNA flow-cytometric analysis in colorectal cancer: A comparison of metastasizing and non-metastasizing tumours

The most common cause of death in patients with colorectal cancer is metastatic liver disease. In order to identify patients at a high risk of developing hepatic secondaries from colorectal cancers, DNA content was measured in metastasizing colorectal primaries (Group I, n= 32) as well as in their subsequently resected liver secondaries and in sections of non-metastasizing colorectal cancers (Group II, n= 25). A modified interpretation system involving both a DNA index and percentage of cycling cells (those in S and G2 + M phases) was developed. DNA content was measured in paraffin-embedded sections by flow cytometry using internal controls (human peripheral blood mononuclear cells) and non-malignant tissue controls (19 patients with diverticular disease). In Group I there were significantly more tumours with both abnormal ploidy (aneuploid or abnormal tetraploid peak) and > 15% cycling cells compared with Group II (Chi-squared; P= 0.034). The combination of abnormal ploidy and > 15% cycling cells was superior to Dukes’ classification for identifying metastasizing tumours (Logistic Regression; P= 0.047). However, it was not possible to discriminate between the two groups using either DNA ploidy or the percentage of cycling cells alone. The metastasizing colorectal cancers exhibited similar DNA ploidy characteristics and had a similar percentage of cycling cells compared with their liver metastases. These results suggest that tumour DNA ploidy plus the percentage of cycling cells may predict the development of liver metastases and thus survival in patients with colorectal cancer.     

Individual differences in differentiation among alcohol expectancy domains

Prior research indicates that alcohol-related outcome expectancies represent important etiological factors in the understanding of alcohol use/abuse. Although current multidimensional measures assess several substantively different domains of alcohol-related outcome expectancies, there is growing evidence that they may not possess adequate levels of discriminant validity. Therefore, the present study sought to examine whether reliable between-person differences exist in the ability to differentiate among alcohol expectancy domains. The focus of the study was on three sets of intrapersonal characteristics: cognitive resources, cognitive constraints, and alcohol-related experience. Data were collected via household interviews with a random sample of 1125 adults. Multiple regression analysis revealed that higher levels of cognitive resources were associated with increasing levels of differentiation among alcohol expectancy domains. Results are discussed in terms of implications for the development of new or revised multidimensional alcohol expectancy questionnaires. Directions for future research are also discussed.     

Gastric and duodenal mucosal blood flow in patients receiving non-steroidal anti-inflammatory drugs—influence of age, smoking, ulceration and Helicobacter pylori

Using laser Doppler flowmetry, we measured gastric and duodenal mucosal blood flow in 70 patients who had taken non-steroidal anti-inflammatory drugs (NSAIDs) for longer than 4 weeks, and studied the correlation with demographic factors, ulceration, and Helicobacter pylori. Blood flow was also measured in 17 other subjects not taking any drugs. Measurements were taken from healthy-looking mucosa in the gastric antrum and the first part of the duodenum. Both gastric and duodenal blood flow values were significantly lower in patients taking NSAID than in those who did not. In the NSAID group, the median duodenal mucosal blood flow was 150 perfusion units in smokers (n = 29) compared with 175 in non-smokers (P= 0.024), 123 units in patients with duodenal ulcers (n = 12) compared with 160 in those without duodenal ulcers (P= 0.020), 135 units in patients with H. pylori (n= 30) compared with 168 in patients without H. pylori (P= 0.033), and 118 in smokers infected with H. pylori compared with 175 units in non-smokers not infected with H. pylori (F= 13.4, P = 0.0005). There was no correlation with age. Gastric blood flow was not significantly influenced by any of the above variables. These results suggest that chronic NSAID intake is associated with reduced blood flow in both the stomach and duodenum. However, amongst NSAID patients, duodenal, but not gastric, mucosal blood flow is reduced in smokers, and in those with duodenal ulcers and H. pylori. Multivariate analysis showed that only the simultaneous presence of smoking and H. pylori had an independent suppressive effect, and when combined, lower blood flow values are observed which might suggest a synergistic relationship between these two factors.     

Effects of Glycerol on Lung and Liver Tumor Development

Mice of several strains(A/J, SWR, MaMyJ, BALB/cByJ, 129J, andC57BL/6J) were treated with the carcinogens 3-methylcholanthrene,urethane, and 4-nitroquinoline 1 -oxide and then given 1 or5% glycerol in the drinking water for up to 4 months. Effectsof glycerol on lung tumor multiplicity and incidence were evaluated.The effects of glycerol were variable, and in the majority ofexperiments glycerol failed to enhance tumor development inmouse lung. Analysis of cell kinetics did not show a proliferativeresponse of alveolar or bronchiolar cells to glycerol. In rats,glycerol did not enhance the appearance of putative preneoplasticliver foci, and in C3H mice it did not increase the incidenceof spontaneously occurring liver tumors. It is concluded thatglycerol does not increase number or incidence of lung tumorsin the mouse strains used, whether the animals are pretreatedwith a carcinogen or not. Glycerol does not affect liver tumordevelopment.     

Identification of two mutations in a compound heterozygous child with dihydrolipoamide dehydrogenase deficiency

An infant girl with elevated blood lactate, pyruvate, and plasma branched-chain amino acids was diagnosed with dihydrolipoamide dehydrogenase (E3; dihydrolipoamide: NAD+ oxidoreductase, EC 1.8.1.4) deficiency. Activities of the pyruvate dehydrogenase complex and E3 from patient were 26 and 2% of controls in blood lymphocytes, and 11 and 14% in cultured skin fibroblasts, respectively. Western blot analysis demonstrated that the amount of E3 protein in fibroblasts from the patient and her father was about half of controls, while Northern blot analysis showed normal amounts of E3 RNA. DNA sequencing of cloned full-length E3 cDNAs from the patient revealed two mutations in separate alleles. One is a single base insertion of an extra adenine in the last codon of the leader peptide sequence (TAC-->TAAC) leading to a nonsense mutation which results in the premature termination of the precursor E3 polypeptide (Y35X). The other is a missense mutation due to substitution of guanine for adenine, causing an Arg-->Gly substitution at amino acid 460 of the mature protein (R460G) which triggers the loss of E3 activity probably by structural change in the E3 dimer. DNA sequencing of E3 cDNAs from the parents demonstrated that the nonsense mutation was inherited from the father and the missense mutation was inherited from the mother.      

Bacterial meningitis in infants: sonographic findings

A retrospective study was performed on 78 patients (newborn to 2 years old) with clinically proved bacterial meningitis. Sonograms were obtained during the acute illness and medical records were reviewed. The spectrum of sonographic features of meningitis included normal scans (30 patients), ventriculomegaly (11 patients), echogenic sulci (31 patients), extra-axial fluid collections (26 patients), abnormal parenchymal echogenicity (9 patients), evidence of ventriculitis (5 patients), and brain abscess (1 patient). In 46 patients, correlation between the sonographic findings and neurologic outcome on clinical follow-up (6 months to 4 years) was made. Findings of abnormal parenchymal echogenicity and/or moderate-to-marked ventriculomegaly were associated with significant neurologic sequelae; however, echogenic sulci and small extra-axial fluid collections did not appear to have any prognostic significance. Twenty-nine of the 78 patients had sonography without clinical indication of complications of meningitis, and in no patient was a significant abnormality found. Our study suggests that sonography is indicated only when there is clinical suspicion of complications.     

GENETIC ANALYSIS OF TAP2 IN SYSTEMIC LUPUS ERYTHEMATOSUS PATIENTS FROM TWO ETHNIC GROUPS

The aim of this study was to determine whether the TAP2 (Transporterassociated with Antigen Processing 2) locus is involved in susceptibilityto systemic lupus erythematosus (SLE). We adopted the interethnicapproach to overcome problems in the analysis resulting fromlinkage disequilibrium. The TAP2 gene polymorphisms of the codonscorresponding to amino acid positions 379, 565 and 665 wereinvestigated by amplification refractory mutation system polymerasechain reaction (ARMS-PCR) in 186 patients (151 white Europeans,35 Afrocaribbeans) and 183 controls (79 white Europeans, 104Afrocaribbeans). In the European SLE patients, the frequencyof the TAP2 type V-A-TA was marginally lower compared with thecontrol group (31% vs 42%), with negative linkage disequilibriumbetween this TAP2 type and DR3 probably accounting for the difference.For the European SLE patients, we confirmed a significant associationof DR3 with disease status [odds ratio = 4.16, 95% confidenceinterval (CI), 2.08–8.39] and in the patients with DR3there was a significantly high frequency of the TAP2 type V-A-T-.In the Afrocaribbean SLE patients, any associations of diseasestatus with TAP2 phenotype were the inverse of those in theEuropean patients. Thus, in these patients the frequency ofV-A-TA was higher than in controls (46% vs 26%, OR = 2.4, 95%CI 1.01–5.74), while the frequency of V-A-T- was lower(26% vs 40%, not significant). Despite possible sampling error,the lack of a difference in TAP2 status between cases and controlswithin ethnic groups and, if anything, an inverse associationacross ethnic groups, makes it unlikely that the TAP2 polymorphismstudied here is of primary relevance to SLE susceptibility. KEY WORDS: MHC, TAP2, SLE, Interethnic