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.     

Evaluation of the occult blood test in screening for colorectal neoplasms. A prospective study using flexible endoscopy

Survival rates from colorectal cancer will rise only when polyps and cancers are found at an earlier, curable stage. Consequently, the purpose of the present study was to compare the yield of colonic neoplasms from flexible sigmoidoscopy and colonoscopy with that from occult blood testing. Results from 474 flexible sigmoidoscopies and 1,115 colonoscopies were prospectively recorded during a four-year study period. Colorectal polyps were found in 111 (23.4%) patients undergoing flexible sigmoidoscopy and 325 (29.1%) patients undergoing colonoscopy. Among the 436 patients with polyps, the occult blood test was negative in 282 (64.7%). Among the 51 patients with colorectal cancers, the occult blood test was negative in 20 (39.1%). Thus, testing for occult blood missed the majority of polyps and a large percentage of the carcinomas. These data indicate that lower gastrointestinal endoscopy is superior to occult blood testing as a screening test for detecting colorectal polyps or cancers. Furthermore, given the high incidence of neoplasia in this patient population, the authors suggest that colonoscopy become the screening test of choice for colorectal cancer.     

Atherosclerotic cardiovascular disease risk in the HAART-treated HIV-1 population

Atherosclerotic cardiovascular disease (CVD), a leading cause of morbidity and mortality in the general population, is also an increasing cause for concern for HIV-infected patients. A number of risk factors for CVD are also associated with HIV disease and HIV therapy, particularly insulin resistance, metabolic dyslipidemia, and inflammation. For example, atherogenic dyslipidemia, a side effect of HIV therapy, is an established risk for CVD in the non-HIV-infected population. As our understanding of atherosclerotic disease evolves, new markers of CVD risk have been identified, including metabolic syndrome definitions and C-reactive protein, a marker of inflammation. Use of these markers, in association with established risk factor guidelines, may serve as important tools in helping HIV physicians implement drug regimens that allow optimum management of metabolic complications associated with HIV and HAART, and thereby reduce CVD risk. The objective of this article is to review the mechanisms of atherosclerotic CVD and to discuss risk factors and markers that can be applied in the evaluation and treatment of CVD in the HIV-positive population.     

Thymic stromal cell specialization and the T-cell receptor repertoire

Ten years ago, we proposed a model for thymus function in which thymic epithelial cells are primarily responsible for imprinting major histocompatibility complex (MHC)-restricted specificity, and bone marrow-derived macrophages or dendritic cells are responsible for the induction of self-tolerance. Since then, transgenic and knockout models have allowed for a dissection of thymic stromal components in vivo, leading to a new understanding of their specialized functions. We have determined that with regard to class II-restricted CD4 T-cell development, two distinct subsets of thymic epithelium help shape the repertoire: Cortical epithelium appears solely responsible for positive selection, whereas a fucose-bearing subset of medullary epithelium is specialized for negative selection. This absolute separation of positive and negative selection into two distinct spatial and temporal compartments leads to a much simpler view of the process of repertoire selection. Finally, a novel view of the function of the thymic medulla is discussed.     

Modifying delivery technique of fenoterol from a metered dose inhaler

Twenty-eight outpatients with bronchial asthma inhaled one puff of fenoterol hydrobromide (200 mcg) from a metered dose inhaler, either held in three different mouth positions or from three different starting lung volumes. Inhaling bronchodilator with closed mouth was significantly less effective than when the mouth was open, or when the inhaler was four cm from the open mouth. Inspiration of drug beginning from 75% of vital capacity resulted in better bronchodilation than starting at residual volume. Patients are likely to obtain maximum benefit from metered dose inhalers when the mouth is open and the inspiratory volume is small.     

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.      

Distribution of fibronectin and laminin in normal and pathological lymphoid tissue.

Forty six lymph nodes were examined with the indirect immunoperoxidase technique for the distribution of fibronectin and laminin. Fibronectin was present in the framework of the tissue and the basal lamina of blood vessels, giving a clear outline of nodal architecture. Intracellular fibronectin was observed in cases of reactive sinus histiocytosis, when about a third of macrophages exhibited strong positivity. Mast cells were positive. A pronounced increase in extracellular fibronectin was seen in nodular sclerosing Hodgkin's disease, although heavily hyalinised areas exhibited only superficial positivity. Reed-Sternberg and mononuclear Hodgkin's cells were consistently negative for fibronectin. Laminin staining was localised to vascular and marginal sinus basement membranes. No cellular positivity was evident. The distribution of laminin indicated a pronounced increase in vascularity in nodular sclerosing Hodgkin's disease, which was especially prevalent within the dense fibrous trabeculae. In contrast, however, examination of the other Rye subtypes showed a lesser degree of vascularity with numbers of vessels similar to those observed in reactive follicular hyperplasia. Laminin was found to be more efficient than factor VIII related antigen as a vascular marker.