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.     

Neurologic outcome after heart transplantation in Chagas' disease

Objective - To evaluate the neurologic morbidity after orthotopic heart transplantation (OHT), we examined consecutive Chagas' (Ch) and non-Chagas' (NCh) patients, before and after surgery. Material and methods - We undertook neurological and neuropsychological evaluations in Ch and NCh patients with end-stage cardiac failure, from September 1993 to September 1995. Results - Of 10 Ch patients (mean age=33.6 years; 7 male; mean follow-up=10.8 months) and 13 NCh patients (mean age=50.9 years; 12 male; mean follow-up=15 months) 3 died (rejection and sepsis) without neurologic symptoms. Neurologic complications occurred in 4 Ch and 5 NCh patients. Two Ch patients had skin and myocardial Chagas' reactivation successfully treated, without CNS involvement. NPS performance and return to work rates were similar in both groups. Conclusions - Although Ch patients are potentially at a higher risk of Trypanosoma cruzi reactivation, in addition to all known neurologic complications of OHT, early neurologic complications detected in this sample were similar in Ch and NCh patients and could not be specifically related to Chagas' disease.     

Reflex increases in heart-rate induced by perfusing the hind leg of the rat with solutions containing lactic acid

The hypothesis that metabolic receptors in skeletal muscle influence heart-rate during exercise was tested by means of a perfused preparation of the rat's hind legs. The isolated leg was connected to the body only by nerve and bone and was perfused with tyrode solution. The humoral changes of exercise were simulated by perfusing with modified tyrode solutions in which concentration of K⁺, osmolality, concentrations of lactic acid, and inorganic phosphate were changed to reflect to those occurring during heavy exercise. Only perfusion with a solution enriched with lactic acid elicited a significant increase in heart-rate. The response disappeared when the nerve supply to the leg was cooled or sectioned. 20–60 s after the start of perfusion with solution of high [lactic acid] heart-rate began to increase reaching a maximum ( ± SE = 20.2 ± 8.2,n = 7) after about 2 min. The effect on heart-rate increased when the venous concentration of lactic acid was increased the range from 3 to 10 mmol/l. In further experiments, we tried to separate the effects of pH and lactate. Heart-rate responses were induced only at low pH and at low pH the extent to which heart-rate changed increased with increases in lactate concentration.     

Relative carriage rates of nuclear dehydrogenating clostridia in two populations of different colorectal cancer risk

Carriage of nuclear dehydrogenating clostridia has been associated with colon cancer and implicated in its aetiology. This study has compared the carriage of these organisms in a British population at high risk for the development of colon cancer with a low risk Nigerian population. Clostridia were found in all of the stools from both populations. Nuclear dehydrogenating clostridia were only found in the stools of the British subjects (32%). These results support the suggestion that the carriage rate of nuclear dehydrogenating clostridia in a population is related to the risk of colon cancer.     

Androgen receptor YAC transgenic mice carrying CAG 45 alleles show trinucleotide repeat instability

X-linked spinal and bulbar muscular atrophy (SBMA) is caused by a CAG repeat expansion in the first exon of the androgen receptor (AR) gene. Disease-associated alleles (37-66 CAGs) change in length when transmitted from parents to offspring, with a significantly greater tendency to shift size when inherited paternally. As transgenic mice carrying human AR cDNAs with 45 and 66 CAG repeats do not display repeat instability, we attempted to model trinucleotide repeat instability by generating transgenic mice with yeast artificial chromosomes (YACs) carrying AR CAG repeat expansions in their genomic context. Studies of independent lines of AR YAC transgenic mice with CAG 45 alleles reveal intergenerational instability at an overall rate of approximately 10%. We also find that the 45 CAG repeat tracts are significantly more unstable with maternal transmission and as the transmitting mother ages. Of all the CAG/CTG repeat transgenic mice produced to date the AR YAC CAG 45 mice are unstable with the smallest trinucleotide repeat mutations, suggesting that the length threshold for repeat instability in the mouse may be lowered by including the appropriate flanking human DNA sequences. By sequence-tagged site content analysis and long range mapping we determined that one unstable transgenic line has integrated an approximately 70 kb segment of the AR locus due to fragmentation of the AR YAC. Identification of the cis - acting elements that permit CAG tract instability and the trans -acting factors that modulate repeat instability in the AR YAC CAG 45 mice may provide insights into the molecular basis of trinucleotide repeat instability in humans.