Promising new agents for the treatment of inflammatory bowel disorders.

A groundswell of therapeutic modalities is presently sweeping through the field of inflammatory bowel disease (IBD), revolutionising the treatment and management of these disorders. At the forefront of newer agents are biological therapies, also referred to as 'biologics'. These include infliximab (cA2), CDP 571, rhIL-10, ICAM-1 antisense oligonucleotide (ISIS 2302) and opreleukin (rhIL-11). Among these, infliximab and CDP 571 are perhaps the most promising, particularly in Crohn's disease. Both are anti-TNF alpha monoclonal antibody formulations with proven efficacy at doses of 5 mg/kg for inducing remission in patients with moderate to severe refractory Crohn's disease. Infliximab is beneficial in the treatment of fistulous Crohn's disease as well. Anti-inflammatory cytokines such as rhIL-10 and opreleukin (rhIL-11) in early reports appear efficacious in Crohn's disease but not in ulcerative colitis. Budesonide, a second generation glucocorticoid, in an oral controlled ileal release capsule, is an attractive alternative to prednisone for treating active Crohn's disease of the distal ileum and proximal colon. Also available as an enema, budesonide's efficacy approximates that of prednisolone for inducing remission in active distal ulcerative colitis. Postoperative recurrences of Crohn's disease are a common clinical scenario. Recently, mesalazine, metronidazole and mercaptopurine have been re-evaluated in the postoperative setting. In the largest postoperative prophylaxis trial, mercaptopurine was superior to both placebo and mesalazine in preventing clinical, endoscopic and radiographic relapses. Finally, miscellaneous therapies such as transdermal nicotine, nicotine tartrate enemas and topical lidocaine used in pilot studies for ulcerative colitis have shown promise. Case reports of thalidomide and tacrolimus (FK 506) have reported beneficial effects in treating complicated, refractory Crohn's disease.

Peptic ulcer disease in the military aviator: a management approach.

The recognition of Helicobacter pylori as etiologic for most cases of peptic ulcer disease requires a reevaluation of policies for flying eligibility and waiver status in affected aviators. We present a suggested algorithm for managing military aviators with ulcer disease.

Transforming growth factor alpha distribution in rectal crypts as a biomarker of decreased colon cancer risk in patients consuming cellulose.

Data from rat experimental carcinogenesis studies indicate that supplemental dietary cellulose reduces the incidence of colon cancer. Epidemiology studies also indicate that high dietary fiber reduces the risk of colorectal cancer in humans. Patients diagnosed with sporadic adenomas were entered into a randomized clinical trial to determine if supplemental dietary cellulose would reduce the patients' risk for colon cancer. Immunohistochemical staining for transforming growth factor alpha (TGF-alpha) was done on biopsies of rectal mucosa taken from patients at the time of initial polypectomy and 1 year later. Results were evaluated for utility as a surrogate end point biomarker for reduction in colon cancer risk. There was a significant decrease in the fraction of the rectal crypt cells that stained for TGF-alpha in six of seven of the patients given the cellulose supplements but in only one of six of the patients not given cellulose. Thus, whether evaluated as a group or in individual patients, there was a significant decrease in TGF-alpha in rectal crypts due to cellulose intervention, which correlated with the expected ability of supplemental dietary cellulose to decrease the risk for colon cancer. Long-term testing of the ability of dietary cellulose to reduce adenoma recurrence is under way to validate the use of TGF-alpha as a surrogate end point biomarker.

Transjugular intrahepatic portosystemic shunt improves oxygenation in hepatopulmonary syndrome.

Hepatopulmonary syndrome is a complication of chronic liver disease in which arterial hypoxemia results from abnormalities in pulmonary blood flow. Severe hypoxemia can lead to clinical deterioration and death. Although the etiology is unknown, portal hypertension seems to be an important factor in the development of hepatopulmonary syndrome. No effective pharmacological therapy has been identified, but liver transplantation may be curative. Arterial hypoxemia may complicate transplant surgery, however, and resolution of the syndrome after liver transplantation is performed may be delayed. In addition, it seems that complete reversal of oxygenation abnormalities after liver transplantation is performed is unpredictable. We described a patient with hepatopulmonary syndrome who noted improvement in symptoms of dyspnea after the placement of a transjugular intrahepatic portosystemic shunt. Arterial oxygenation and calculated shunt fraction improved significantly during the follow-up period, and liver transplantation was subsequently performed without difficulty. Portal decompression using transjugular intrahepatic portosystemic shunt may represent a palliative therapy for hepatopulmonary syndrome in patients awaiting liver transplantation.

Felinization of the esophagus.

Transient transverse folds of the esophageal mucosa as seen by barium esophagography and on endoscopic examination have been termed "felinization." This finding has been considered a normal variant or has been associated with reflux esophagitis. No symptoms have been associated with its presence. In 280 unselected patients undergoing upper gastrointestinal endoscopy in our clinic, felinization was identified in 24% by prospective visual examination. It was not correlated with sex, age, symptom complex, or common coexistent endoscopic findings. These transverse esophageal folds, although visually interesting, appear to have no clinical significance. The endoscopist should recognize and differentiate them from fixed or persistent folds that can be associated with mucosal disease.

Evaluation of school children at high risk for fragile X syndrome utilizing buccal cell FMR-1 testing.

We describe a pilot project utilizing saliva to identify the FMR-1 mutation in high-risk special education students from four public school districts in Colorado. The program included presentations to special education teachers regarding fragile X syndrome, parental consent for testing, completion of a behavior checklist by the teachers, identification of special education students at high risk for fragile X syndrome, subsequent brief examination of face and hands, collection of a saliva sample by either Gatorade swish or brushing of the inside of the cheek, and analysis for the FMR-1 mutation by PCR. Equivocal samples were studied by direct DNA testing using Southern blot analysis, and abnormal results were confirmed by a blood analysis for the FMR-1 mutation. Mutant individuals received genetic counseling and medical and educational assessments to optimize treatment and intervention. This pilot project was met with enthusiasm by the schools. Of the first 439 students evaluated, 68% were male with an average age of 7.75 years; 13% were mentally retarded or autistic. Most students referred for the evaluation were learning disabled (51%) and/or had an Attention Deficit Hyperactivity Disorder (ADHD) (35%). The overall prevalence of the FMR-1 mutation was 5 of 439 or 1.1%. This relatively low yield is probably due to the high number of non-retarded but learning disabled students tested. Of the mentally retarded patients tested, 3.5% were positive for the FMR-1 mutation; however, of the non-retarded or learning disabled patients, only 0.79% were FMR-1 positive.(ABSTRACT TRUNCATED AT 250 WORDS)

Molecular predictors of cognitive involvement in female carriers of fragile X syndrome.

OBJECTIVE: Fragile X syndrome is caused by a mutation involving expansion of a CGG trinucleotide repeat segment in the fragile X mental retardation-1 (FMR1) gene on the long arm of the X chromosome. This study was undertaken to determine the relative impact of three molecular characteristics of the FMR1 mutation--number of CGG repeats, methylation status, and X inactivation ratio--on the cognitive involvement of female carriers of fragile X syndrome. DESIGN: Retrospective study with new DNA analysis of known female carriers of fragile X syndrome. SETTING: Molecular studies were conducted in a university-based DNA diagnostic laboratory. Patients were originally ascertained through a regional fragile X clinic in a university-affiliated pediatric hospital. PATIENTS: Forty-eight female carriers of fragile X syndrome were studied, including 22 with a premutation (a small expansion to approximately 50 to 200 CGG repeats), 23 with a full mutation (a full expansion to > 200 CGG repeats), and three with both types of mutations (mosaics). RESULTS: Median IQ score was significantly lower for females with a full mutation than for females with a premutation. No significant relationship was found between IQ score and number of CGG repeats or percentage methylation of the mutant allele within each mutation category. In addition, no significant relationship was found between IQ score and the proportion of normal FMR1 alleles on the active X chromosome in the carrier female group as a whole or in either mutation subgroup. Comparisons of leukocytes and saliva-borne epithelial cells in certain full-mutation carriers revealed striking differences in FMR1 mutation sizes. CONCLUSIONS: Mutation category remains the most important predictor of affectedness in female carriers of fragile X syndrome. Our data do not support use of the proportion of normal FMR1 alleles on the active X chromosome as a predictor of cognitive involvement in female carriers with full mutations. Individual tissue-specific differences exist in the heterogeneous sizes of full mutations and in the presence of premutation/full-mutation mosaicism.