Hypermethylation of the CDKN2/p16 promoter during neoplastic progression in Barrett's esophagus

Background & Aims: Inactivation of the CDKN2/p16^INK4A tumor-suppressor gene is one of the most frequent genetic alterations in human malignancies. In esophageal adenocarcinomas, mutations of the p16 gene or homozygous deletions of the gene locus 9p21 are rare. This study investigated whether p16 promoter hypermethylation is an alternative mechanism for p16 gene inactivation during neoplastic progression in Barrett's esophagus. Methods: A methylation-specific polymerase chain reaction protocol was applied. A total of 95 specimens from 14 patients with Barrett's esophagus were analyzed longitudinally. The p16 promoter status was compared with histomorphological findings. Results: p16 promoter hypermethylation was detected in 9 of the 10 patients who had displayed dysplasia at some time during surveillance, whereas none of the patients who had not displayed dysplasia during surveillance had p16 promoter hypermethylation. p16 promoter hypermethylation was detected in 3% (2 of 67) of the samples without dysplasia, 60% (3 of 5) of the samples with lesions indefinite for dysplasia, 55.6% (10 of 18) of the specimens with low-grade dysplasia, and 75% (3 of 4) of the specimens with high-grade dysplasia. Conclusions: These data suggest that p16 promoter hypermethylation is a common mechanism of p16 gene inactivation during neoplastic progression in Barrett's esophagus.GASTROENTEROLOGY 1998;115:1381-1386     

Crohn's disease in Olmsted County, Minnesota, 1940–1993: Incidence, prevalence, and survival

Background & Aims: Many centers worldwide have reported an increased incidence of Crohn's disease, but population-based data in North America are sparse. We studied the incidence and prevalence of Crohn's disease in Olmsted County, Minnesota, and examined temporal trends in incidence and survival. Methods: Residents diagnosed with Crohn's disease between 1970 and 1993 were incidence cases, and residents with Crohn's disease who were alive on January 1, 1991, were prevalence cases. Cases from previous studies were reconfirmed. Rates were adjusted using 1990 U.S. Census figures for whites. Incidence trends were evaluated with a Poisson regression model. Survival from diagnosis was compared with that expected for U.S. north-central whites. Results: Between 1940 and 1993, 225 incidence cases were identified, for an adjusted incidence rate of 5.8 per 100,000 person-years. On January 1, 1991, there were 145 residents with Crohn's disease, an adjusted prevalence rate of 133 per 100,000, 46% higher than that seen in 1980. Incidence rates before 1964 were significantly lower than those of 1989–1993. Observed survival was less than expected (P = 0.007). Conclusions: The incidence of Crohn's disease has stabilized since the 1970s at a rate higher than that seen previously. Prevalence has increased by 46% since 1980. Overall survival is slightly decreased.GASTROENTEROLOGY 1998;114:1161-1168     

Nitroglycerin rebound associated with vascular, rather than platelet, hypersensitivity

OBJECTIVES

The purpose of this study was to determine whether acute withdrawal of nitroglycerin (NTG) during hemodynamic tolerance is associated with platelet hypersensitivity.

BACKGROUND

Nitroglycerin is an effective antianginal medication but its use is limited by the development of tolerance and rebound. We have previously demonstrated a sustained inhibition of platelet function during continued use of NTG, but whether cessation of NTG is associated with an increase in platelet function that may contribute to rebound is unknown.

METHODS

Normal porcine aortic media were exposed to flowing arterial blood from pigs (n = 8) treated continuously with NTG patches (Nitrodur 0.8 mg/h) for 48 h. Platelet function, blood pressure and the responses to angiotensin II infusion were evaluated before, during and after NTG treatment.

RESULTS

Mean arterial pressure fell by 15% after 3 h of treatment compared with control, returned to baseline by 48 h and increased significantly 2 h after drug removal. Autologous ⁵¹Cr-labelled platelet deposition on the aortic media was reduced by 30% after 48 h of continuous NTG administration compared with baseline (p = 0.02) and remained decreased 2 h after cessation of NTG therapy. Platelet aggregation to thrombin decreased in parallel to the decrease in platelet deposition. Blood pressure increase after intravenous injection of 10 μg of angiotensin II was blunted during treatment with NTG but increased significantly 2 h after cessation of nitrate therapy when compared with baseline.

CONCLUSIONS

Supersensitivity of the vessel wall to vasoconstrictors such as angiotensin 11, but not platelet hyperactivity, may contribute to the rebound phenomenon after acute nitrate withdrawal.