Evaluation of patients with hereditary hemorrhagic telangiectasia with video capsule endoscopy: a single-center prospective study.

BACKGROUND AND STUDY AIMS: Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant disorder characterized by telangiectasia formation that can lead to small-bowel bleeding. In this study, video capsule endoscopy was used to compare the small-bowel findings observed in patients with HHT with those seen in patients without the condition. PATIENTS AND METHODS: We performed capsule endoscopy studies in 93 consecutive patients who were being evaluated for small-bowel bleeding, 38 patients with known or suspected HHT and 55 patients without HHT. Nine patients were excluded because the capsule failed to reach the cecum. The findings in 32 patients with a final diagnosis of HHT and in 48 patients without HHT were recorded and compared. RESULTS: Capsule endoscopy detected telangiectases evenly distributed throughout the small bowel in 26/32 (81%) patients with HHT, compared with 14/48 (29%) in patients without HHT. When active bleeding was observed in patients with HHT (n = 4), the bleeding was within reach of standard small-bowel push enteroscopy in all cases. The presence of five or more gastrointestinal telangiectases by capsule endoscopy had a sensitivity of 75% and a positive predictive value of 86% for diagnosing HHT. Unexpected findings (small-bowel polyps and mass-like lesions) were seen in both groups of patients (6.2% in patients with HHT and 2.1% in patients without HHT). CONCLUSIONS: Small-bowel telangiectases were seen in the majority of patients with HHT and were evenly distributed throughout the small bowel. Telangiectases were observed in only a minority of patients who did not have HHT. Actively bleeding small-bowel telangiectases were located in the proximal and mid-small bowel in patients with HHT, all within reach of an enteroscope. We propose a cutoff point of at least five gastrointestinal telangiectases to support a diagnosis of HHT.

Antisense inhibition of hMLH1 is not sufficient for loss of DNA mismatch repair function in the HCT116+chromosome 3 cell line.

We have reported that transfer of chromosome 3 (Chr3) containing a single wild-type copy of the hMLH1 gene into HCT116 colon cancer cells, a cell line deficient in DNA mismatch repair (MMR) activity attributable to inactivating hMLH1 mutations, corrects all of the aspects of the MMR repair-deficient phenotype. We inhibited the expression of the wild-type hMLH1 gene using antisense RNA in HCT116+Chr3 cells to determine if this would result in reversion to the MMR-deficient phenotype. Despite profound inhibition of hMLH1 expression, DNA MMR activity and alkylation sensitivity were not impaired in the antisense-transfected HCT116+Chr3 cells. Additionally, arrest of the cell cycle at the G2 phase with alkylation damage occurs in these cells, a phenotype associated with MMR proficiency. These results indicate that even with a reduction in the expression of hMLH1 protein below the limits of detection by Western blotting, DNA MMR activity remained fully functional (by direct DNA MMR activity assay). We would speculate that hMLH1 is expressed in substantially greater abundance than would be minimally necessary for DNA MMR and that minor reductions in the expression of this protein would not be sufficient to permit DNA MMR dysfunction. Alternatively, Chr3 may contain a second hMLH1 homologue that might overlap with the function of hMLH1.

Pattern of rat intestinal brush-border enzyme gene expression changes with epithelial growth state.

Enterocyte growth and differentiation occur simultaneously within the epithelium, but little is known regarding any relationship between these two processes. Four rat models of small intestinal epithelial hypo- and hyperplasia (neonatal ontogeny, fasting/refeeding, hypo-/hyperthyroidism, and bombesin treatment) were used to study the regulation of enterocyte gene expression in relation to epithelial growth state. Mucosal scrapings, as well as crypt and villus cell populations, were subjected to Northern blot analyses using radiolabeled cDNA probes corresponding to lactase, intestinal alkaline phosphatase, villin, ornithine decarboxylase (ODC), and the actin control. In all four models, the hypoplastic (atrophic) condition is characterized by high levels of lactase and low levels of the 3.0-kb intestinal alkaline phosphatase mRNA, whereas under hyperplastic conditions this pattern is reversed. The changes in intestinal alkaline phosphatase and lactase are qualitatively similar along the longitudinal axis of the intestine and are proportional to the degree of hyperplasia, as verified by ODC mRNA levels. Furthermore, the crypt-villus axis of differentiation is maintained regardless of epithelial growth state. In conclusion, the pattern of brush-border enzyme gene expression changes as a function of epithelial growth state, indicating a previously unrecognized degree of plasticity to the state of enterocyte differentiation.

Thyroid hormone responsiveness is developmentally regulated in the rat small intestine: a possible role for the alpha-2 receptor variant.

Thyroid hormone (T3) alters gene expression through binding to a receptor protein located within the nucleus of target cells. Multiple forms of the T3 receptor (TR) have been identified and are encoded by the alpha and beta c-erbA genes. We have previously found that TR beta-1 is the major receptor form expressed in the adult rat small intestine, although there are also moderate levels of c-erbA alpha-2, a nonhormone-binding variant that is thought to inhibit T3 action. In developing rats, we studied the regulation of two small intestinal enterocyte genes previously shown to be T3 responsive, lactase and 3.0-kilobase intestinal alkaline phosphatase (IAP). Animals were treated with six daily ip injections of either saline (control) or 30 micrograms/100 g BW T3 (T3 group) and killed at 10 and 25 days of age. Northern analyses of RNA derived from intestinal tissues showed that the magnitude of the T3-induced changes in lactase and IAP gene expression increased with development. Jejunal 3.0-kilobase IAP messenger RNA (mRNA) levels were unaffected by T3 at 10 days, but increased by 15-fold at 25 days. Similarly, jejunal lactase mRNA levels were unchanged by T3 at 10 days, but decreased by 75% at 25 days. Qualitatively similar results were seen in the duodenum and ileum. Studies of TR expression revealed that TR beta-1 mRNA levels were unchanged during the developmental period, whereas the levels of c-erbA alpha-2 decreased by 90% between 5-25 days after birth. These results indicate that the rat small intestine becomes increasingly T3 responsive during postnatal development. These changes occur in parallel with a decline in c-erbA alpha-2 levels, suggesting that this T3 receptor variant may play a role in this hormonal responsiveness.

Thyroid hormone differentially regulates rat intestinal brush border enzyme gene expression.

Thyroid hormone [triiodothyronine (T3)] has been shown to play a critical role in the growth and maturation of the mammalian small intestine, but its mechanism of action has not been well studied. In the current study, an animal model of hypothyroidism and hyperthyroidism was used to study the effects of T3 on the small intestine. Adult rats were treated with propylthiouracil for a 6-week period and then given injections of either saline (hypothyroid) or 30 micrograms/100 g body wt of T3 (hyperthyroid). Northern blot analyses showed marked differential regulation of brush border enzyme gene expression. Lactase messenger RNA (mRNA) levels decreased approximately 75% along the length of the small intestine, whereas sucrase levels were unchanged. The intestinal alkaline phosphatase mRNA species were upregulated by T3, especially the 3-kilobase band, which increased most dramatically in jejunum. Further experiments showed significant levels of both the alpha-1 and beta-1 T3 receptor mRNAs within the small intestinal mucosa. Histological examination showed that T3 treatment causes marked villus hyperplasia throughout the length of the small intestine. These results provide insight into the mechanism by which T3 exerts its influence on the growth and differentiation of the intestinal epithelium.

Recovery of lymphocyte status after radiotherapy.

A survey of the lymphocyte status is reported for 25 patients given routine radiotherapy for carcinoma of the cervix or carcinoma of the breast and other tumours. After an initial lymphopenia there was a return to the initial value of the lymphocyte count by the end of a 12 month period of observation. The PHA index was also measured in these patients and this also showed a progressive rise during the 12 month period following a minimal change after radiotherapy. There was no significant difference between the lymphocyte status of patients given radiotherapy above or below the diaphragm nor between patients with or without knwon metastases at the end of the 12 month period. An additional sample of eight patients with carcinoma of the breast showed a rise in lymphocyte count after surgery before the usual fall after radiotherapy.