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.     

Cyclic nucleotides and suppression of follicle-stimulating hormone release by inhibin

The relative roles of the cyclic nucleotide messengers cAMP and cGMP in the suppression of follicle-stimulating hormone (FSH) secretion in response to inhibin (IBN) were assessed employing rat gonadotropes in monolayer culture. While exposure of cells to gonadotropin-releasing hormone (GnRH) induced a significant increase in the amounts of both FSH and luteinizing hormone (LH) released into the culture medium, these responses were dampened by the administration of IBN (in porcine follicular fluid). Addition of cGMP to the system failed to restore FSH release, while cAMP restored basal FSH release. Modulation of nucleotide metabolism with theophylline, sodium nitroprusside, and a protein kinase inhibitor failed to overcome the IBN-induced suppression of FSH release. The cellular content of calmodulin increased in response to GnRH, a response antagonized by IBN. Cellular levels of cGMP were also increased by GnRH, but this response was unaltered by IBN. The administered drugs all failed to reverse these effects of IBN. These data indicate that the IBN-induced suppression of FSH release is not dependent upon the cyclic nucleotides cAMP and/or cGMP. However, a role in the maintenance of basal FSH synthesis and release for cAMP is indicated.     

Liver transplantation in infants younger than 1 year of age.

OBJECTIVE: The authors report on experience with liver transplantation for infants younger than 1 year of age. SUMMARY BACKGROUND DATA: Over the last 15 years, orthotopic liver transplant has become the only lifesaving procedure available for infants with end-stage liver disease. Many transplant centers initially required infants to reach a specific weight or age to minimize morbidity and mortality. Size-appropriate infant donors also were uncommon. As a result, many children, in the first few years of life, died of their disease. The availability of reduced-size cadaveric and living-related liver transplants has offered the ability to transplant the young infant with liver failure. METHODS: The authors instituted a program to aggressively transplant infants with liver failure in the first year of life using both cadaveric and living-related liver donors. RESULTS: Between June 1991 and January 1995, 13 infants were transplanted for rapidly progressive liver failure. Infant age ranged from 4 to 11 months (mean, 7.5 months). The cause of liver failure included biliary atresia (11), alpha 1-antitrypsin deficiency (1), and liver failure secondary to echovirus 7 (1). The United Network for Organ Sharing status at the time of transplant ranged from status 4, intensive care unit bound (4 patients); status 3, hospitalized (4 patients); or status 2, failing at home (5 patients). Six patients (46%) received cadaveric whole organ (2) or segmental transplants (4). Seven patients (54%) received left lateral segment living-related transplants from parental donors. After operation, patients received cyclosporine or FK506-based immunosuppression. Three patients (23%) required four retransplants (two cadaveric for primary nonfunction; one living-related for graft thrombosis in the face of fungal infection and bile leak). Postoperative complications included primary nonfunction (15%), rejection (85%), graft vascular thrombosis (15%, two of three revascularized successfully), bacterial and fungal infections (77%), and viral infections (46%). Epstein-Barr virus-associated lymphoproliferative developed in two patients (15%). Intestinal perforation requiring reoperation developed in two patients (15%). Bile leaks requiring reoperation or transhepatic stinting or both developed in three patients (23%). Two patients died in the perioperative period (< 1 month) from a combination of primary nonfunction or graft thrombosis and sepsis. Overall survival was 85%, ranging from 11.0 months to 4.5 years. CONCLUSIONS: Orthotopic liver transplantation in infants younger than 1 year of age poses significant challenges from technical and infectious complications. Despite these barriers, overall patient survival is comparable to that of older children and adults.     

Neanderthal reconstructed

A century and a half of controversy concerning the differences between Neanderthals (or Neandertals) and modern humans has left us with many questions and no sign of abatement. One of these remaining questions concerns the articulated structure of the Neanderthal skeleton and how it compares to that of a modern human. Although this question has been tackled many times by more artistic avenues, never has a complete, fully articulated Neanderthal skeleton been constructed systematically using castings from real Neanderthal bones. In an attempt to provide a more objective understanding of Neanderthal stature and biomechanics, a complete Neanderthal skeleton was reconstructed and articulated. This reconstruction was primarily based on the La Ferrassie 1 specimen, with missing or incomplete elements filled in from other Neanderthal cast collections.     

The vasa vasorum and angioplasty

Interruption of flow in the vasa vasorum may lead to medial necrosis and aneurysm formation. The purpose of this study was to determine whether angioplasty produces significant alterations in the morphology or blood flow of the vasa vasorum of the dilated artery. The morphology of the canine vasa vasorum was studied before and after angioplasty; in a separate experiment vessel wall blood flow (VWBF) in canine carotid arteries was measured after angioplasty to determine whether physiologic regulation of the blood flow was disrupted by arterial dilation. No morphologic changes could be demonstrated in the vasa vasorum of the dilated artery; however, VWBF was increased by 1194 +/- 215% (mean +/- standard error, p less than 0.01) between 90 and 120 minutes after angioplasty. VWBF in the adjacent nondilated arterial segment was also increased (720 +/- 177% between 10-30 minutes, p less than 0.01) but returned toward normal after 60 minutes. Adenosine caused a "paradoxical" decrease in VWBF (p less than 0.05) of the dilated arterial segment while causing increased VWBF (p less than 0.05) in the thoracic aorta. Angioplasty appears to produce persistent hyperemia in the dilated arterial wall. A paradoxical response to adenosine suggests that vasa vasorum in the dilated arterial segment are maximally vasodilated. This may be due to mechanical disruption of vasomotor tone or to release of vasoactive substances.