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Background: Patients with gastroesophageal reflux disease may suffer from a variety of symptoms from the upper aerodigestive tract. The objective of this study was to determine the impact of dual-probe 24-hr pH monitoring in the diagnosis of reflux-related otolaryngological disorders.Methods: Twenty-two patients with symptoms such as chronic cough, globus pharyngeus, heartburn,dysphonia and burning sensation of the tongue underwent a complete ear, nose and throat examination, 24-hr dual-probe pH monitoring, and oesophago-gastro-duodenoscopy.Results: pH monitoring revealed gastroesophageal (distal) reflux in all patients and pharyngeal (proximal) reflux in 21 patients. Treatment consisted of a proton pump inhibitor (esomeprazole). Within 4 weeks 68 per cent of patients had no laryngopharyngeal symptoms; within 8 weeks 95 per cent of patients were symptom-free.Conclusions: Patients with atypical reflux symptoms such as hoarseness, globus sensation or throat-clearing responded well to anti-reflux treatment.

Although standard medical therapy in Crohn’s disease is efficient in most patients, a substantial proportion of patients suffering from chronic active disease do not adequately respond to standard therapy. In these patients, alternative regimens have to be considered. Due to the major advances in understanding the pathogenesis of this complex disease involving genetic, environmental, microbial and immunological factors, various new biological therapies targeting key mechanisms have emerged. In this review, a critical appraisal of modern therapeutical concepts will be presented, focusing on antibody and small inhibitory molecule therapies, including inhibition of TNF-α and other pro-inflammatory cytokines, adhesion molecules and T cell activation, as well as hormonal therapies.

There is increasing evidence both from, animal models and clinical investigations that luminal bacteria play a pivotal role in the pathogenesis of Crohn's disease (CD). In almost all murine models for spontaneous colitis, animals stay healthy as long as they are kept under germ free conditions. Antibacterial treatment reduces disease severity in some patients with CD. This aforementioned hypothesis is further supported by the identification of the first susceptibility gene for CD. Single nucleotide polymorphisms in the caspase recruitment domain 15 gene (CARD15, formerly known as NOD2) have been identified recently. The respective CARD15 alleles increase the risk of developing CD. The CARD15 protein is located in the cytoplasm of mononuclear cells where it is involved in the recognition of bacterial components leading to subsequent activation of nuclear factor kB. As rare alleles of the SNPs are not found in all patients with CD and as these alleles are found in healthy persons as well, variations in the CARD15 gene are neither necessary nor sufficient for the genetic predisposition to CD. Further genes are supposed to play a crucial role in the pathogenesis of CD. Disturbed activation of the innate immune system by bacterial antigens seems to be crucial in a subgroup of patients with CD. Genes involved in pathways of the innate immune system represent good candidate genes for the predisposition to CD. Abundant polymorphisms in these genes have been described. The putative role of these polymorphisms in the genetic predisposition to CD is revisited for this multifactorial model disease.

Background. Neuropathy of the enteric nervous system and hyperglycaemia are regarded as the main causes of diabetic gastroparesis. Patients and Methods. In ten patients with Type-1 diabetes mellitus and sensomotoric neuropathy gastric emptying half times were compared with ten healthy controls by employing the 13C-octanoic acid and the 13C-sodiumacetate breath test, resp., following the intake of equally composed and isocaloric liquid and solid meals. Plasma glucose concentrations were controlled by permanent intravenous administration of insulin. Results. In diabetes mellitus gastric emptying half times after the intake of the liquid meal (p < 0.05) but not after ingestion of the solid meal were slightly prolonged. Gastric emptying half times in patients and controls were not different when liquid and solid meals were compared. Conclusions. Acute hyperglycaemia appears to be more important than the neuropathy of the enteric nervous system in the pathophysiology of diabetic gastroparesis. The rate of gastric emptying is obviously not dependent on the phase of a meal, but rather on the composition and the caloric content.

The intercellular adhesion molecule-1 (ICAM-1) is of paramount importance for the initiation and propagation of various inflammatory conditions. An increased frequency of allele R241 of the ICAM-1 gene was previously described in p-ANCA-negative as compared to p-ANCA-positive ulcerative colitis and vice versa in Crohn's disease. One hundred sixteen healthy unrelated controls, 121 patients with ulcerative colitis, and 96 patients with Crohn's disease were genotyped for two polymorphisms of the ICAM-1 gene (R/G241, exon 4; and K/E469, exon 6), employing dot-blot hybridization and stratified according to their p-ANCA status. When compared with the control group the frequency of the allele R241 (P= 0.024) and the heterozygous genotype R/G241, P= 0.032) were significantly increased in ulcerative colitis, whereas the homozygous genotype G/G241 was found less frequently (P= 0.022). The heterozygous genotype K/E469 was observed less frequently (P= 0.001 and 0.037, resp.) than the homozygous genotype E/E469, which was more frequent in Crohn's disease and ulcerative colitis (P= 0.002 and 0.012, respectively). Further significant differences concerning the allele or genotype distribution were not observed. After stratification for the p-ANCA status significant differences concerning the frequencies of both the R241 and the E469 alleles were not detected when p-ANCA-positive inflammatory bowel disease and p-ANCA-negative inflammatory bowel disease were compared. Ulcerative colitis and Crohn's disease are associated with polymorphisms of the ICAM-1 gene, which might therefore represent a functional candidate gene. However, the observed associations are independent of the p-ANCA status.

OBJECTIVE: Ghrelin is a new gastric hormone that has been identified as an endogenous ligand for the growth hormone (GH) secretagogue receptor subtype 1a (GHS-R1a). Ghrelin administration however not only stimulates GH secretion but also induces adiposity in rodents by increasing food intake and decreasing fat utilization. We hypothesized that impaired ghrelin secretion in anorexia nervosa may be involved in the pathogenesis of this eating disorder. To examine this hypothesis and to further investigate the role for ghrelin in regulating energy homeostasis, we analyzed circulating ghrelin levels in patients with anorexia nervosa and examined possible correlations with clinical parameters before and after weight gain. METHODS: Plasma ghrelin levels were measured in overnight fasting plasma samples from 36 female patients with anorexia nervosa (age: 25.0+/-1.2 years, BMI: 15.2+/-0.2 kg/m(2)) before and after weight gain following psychotherapeutic treatment intervention in a psychosomatic institution. Plasma ghrelin levels were also measured in fasting plasma samples from 24 age-matched female controls (31+/-1.4 years, BMI: 22.9+/-0.45 kg/m(2)). For quantification of ghrelin levels a commercially available radioimmunoassay (Phoenix Pharmaceuticals, USA) was used. RESULTS: Fasting plasma ghrelin levels in anorectic patients were significantly higher (1057+/-95 pg/ml) than in normal age-matched female controls (514+/-63 pg/ml n=24, P=0.02). Therapeutic intervention in a psychosomatic institution caused an BMI increase of 14% (P<0.001) leading to a significant decrease in circulating ghrelin levels of 25%, (P=0.001). A significant negative correlation between Deltaghrelin and DeltaBMI was observed (correlation coefficient: -0.47, P=0.005, n=36). CONCLUSION: We show for the first time that fasting plasma levels of the novel appetite-modulating hormone ghrelin are elevated in anorexia nervosa and return to normal levels after partial weight recovery. These observations suggest the possible existence of ghrelin resistance in cachectic states such as caused by eating disorders. Future studies are necessary to investigate putative mechanisms of ghrelin resistance such as a possible impairment of intracellular ghrelin receptor signaling in pathophysiological states presenting with cachexia.

OBJECTIVE: Ghrelin is a new gastric hormone that has been identified as an endogenous ligand for the growth hormone (GH) secretagogue receptor subtype 1a (GHS-R1a). Ghrelin administration however not only stimulates GH secretion but also induces adiposity in rodents by increasing food intake and decreasing fat utilization. We hypothesized that impaired ghrelin secretion in anorexia nervosa may be involved in the pathogenesis of this eating disorder. To examine this hypothesis and to further investigate the role for ghrelin in regulating energy homeostasis, we analyzed circulating ghrelin levels in patients with anorexia nervosa and examined possible correlations with clinical parameters before and after weight gain. METHODS: Plasma ghrelin levels were measured in overnight fasting plasma samples from 36 female patients with anorexia nervosa (age: 25.0+/-1.2 years, BMI: 15.2+/-0.2 kg/m(2)) before and after weight gain following psychotherapeutic treatment intervention in a psychosomatic institution. Plasma ghrelin levels were also measured in fasting plasma samples from 24 age-matched female controls (31+/-1.4 years, BMI: 22.9+/-0.45 kg/m(2)). For quantification of ghrelin levels a commercially available radioimmunoassay (Phoenix Pharmaceuticals, USA) was used. RESULTS: Fasting plasma ghrelin levels in anorectic patients were significantly higher (1057+/-95 pg/ml) than in normal age-matched female controls (514+/-63 pg/ml n=24, P=0.02). Therapeutic intervention in a psychosomatic institution caused an BMI increase of 14% (P<0.001) leading to a significant decrease in circulating ghrelin levels of 25%, (P=0.001). A significant negative correlation between Deltaghrelin and DeltaBMI was observed (correlation coefficient: -0.47, P=0.005, n=36). CONCLUSION: We show for the first time that fasting plasma levels of the novel appetite-modulating hormone ghrelin are elevated in anorexia nervosa and return to normal levels after partial weight recovery. These observations suggest the possible existence of ghrelin resistance in cachectic states such as caused by eating disorders. Future studies are necessary to investigate putative mechanisms of ghrelin resistance such as a possible impairment of intracellular ghrelin receptor signaling in pathophysiological states presenting with cachexia.

The gene encoding chemokine receptor 5 (CCR5) is colocalized to the microsatellite marker D3S1573, which was linked with inflammatory bowel disease. Genetic heterogeneity in inflammatory bowel disease might be defined by a combination of the p-ANCA status and immunoregulatory genes. One hundred and twenty healthy unrelated controls, 101 patients with Crohn's disease, and 99 patients with ulcerative colitis were genotyped for the Δ32 mutation of the CCR5 gene. The presence of p-ANCA was determined by the use of indirect immunofluorescence. After genotyping, patients were stratified according to p-ANCA status. The frequency of the Δ32 mutation was not significantly different in controls and patients with Crohn's disease or ulcerative colitis (P0.207 or more). Moreover, the frequency of the mutation was not significantly different in patients with inflammatory bowel disease after stratification for the p-ANCA status (P0.482). Regardless of the p-ANCA status, Crohn's disease and ulcerative colitis are not associated with the Δ32 mutation of the CCR5 gene.

Intestinal vasculitis caused by persistent measles virus infection of intestinal endothelial cells was described in Crohn's disease. Furthermore, endothelial cell autoantibodies have been demonstrated in inflammatory bowel disease (IBD). Autoantibodies against intestinal endothelial cells were visualized by indirect immunofluorescence in patients with IBD, in their healthy first-degree relatives, in patients with infectious enterocolitis, and in healthy, unrelated controls. In intestinal tissue specimens of 22 antibody-positive IBD patients a search for the measles virus genome was performed. Endothelial cell autoantibodies were significantly more frequent in patients with IBD, in both groups of first-degree relatives, and in patients with infectious enterocolitis than in the healthy controls (P= 0.0002 or less). The measles virus genome was found in none of the intestinal biopsies. Endothelial cell autoantibodies are not a genetic but rather an epigenetic (infectious) marker of disease susceptibility. The expression of these autoantibodies is unlikely to be triggered by a persistent measles virus infection.

BACKGROUND & AIMS: Crohn's disease and ulcerative colitis show a familial aggregation. In both diseases, anti-goblet cell autoantibodies (GABs) have been described. The aim of this study was to define the role of GABs in the pathogenesis of inflammatory bowel disease. METHODS: The study population comprised 61 patients with ulcerative colitis, 76 patients with Crohn's disease, 101 first-degree relatives of patients with ulcerative colitis, and 105 first-degree relatives of patients with Crohn's disease. Thirty-five patients with infectious enterocolitis and 56 healthy unrelated subjects served as controls. Autoantibodies were detected by indirect immunofluorescence. RESULTS: Thirty-nine percent of patients with ulcerative colitis (24 of 61) and 30% of patients with Crohn's disease (23 of 76) were positive for GABs. GABs were detected in 21% (21 of 101) of first-degree relatives of patients with ulcerative colitis and in 19% (20 of 105) of first-degree relatives of patients with Crohn's disease. In patients with infectious enterocolitis and in healthy controls, GABs were seen in 3% (1 of 35) and 2% (1 of 56), respectively. The differences between control groups and both groups of patients or their first-degree relatives were significant. CONCLUSIONS: The high prevalence in first-degree relatives suggests that GABs may represent a marker characterizing susceptibility to inflammatory bowel disease. (Gastroenterology 1997 Jul;113(1):101-6)

Due to dietary modifications including the intake of cereals, vegetables and the frequent use of soy milk instead of breast milk, children in developing countries with diarrhea frequently suffer from zinc deficiency. Furthermore, diarrhea leads to excess zinc losses. Beside low energy intake zinc deficiency contributes to continued diarrhea, which in turn accounts for half of the deaths from diarrhea in children. Zinc supplementation leads to accelerated regeneration of the mucosa, increased levels of brush-border enzymes, enhanced cellular immunity and higher levels of secretory antibodies. In addition, in stunted children zinc supplementation results in enhanced catch-up growth via higher levels of insulin-like growth factor-1. Growth retardation is closely related to the risk of diarrheal diseases in children. These pathophysiological conclusions are supported by several controlled clinical trials which have provided evidence that zinc supplementation results in significant reduction in the risk of continued diarrhea. However, it remains to be clarified whether these benefits are attributable to pharmacological effects or if they can be related to the correction of an underlying deficiency state.

Crohn's disease and ulcerative colitis show afamilial aggregation. The role of antinuclearautoantibodies, which occur in both diseases, remains tobe defined. In 76 patients with Crohn's disease, 61patients with ulcerative colitis, 105 first-degreerelatives of patients with Crohn's disease, 101first-degree relatives of patients with ulcerativecolitis, and 40 healthy unrelated controls antinuclearautoantibodies were detected by indirect immunofluorescence.Existence of autoantibodies was correlated with clinicalfeatures. Eighteen percent of patients with Crohn'sdisease (14/76), 43% of patients with ulcerative colitis (26/61), 13% of relatives of patientswith Crohn's disease (14/105), 24% of relatives ofulcerative colitis patients (24/101), and 2% of thehealthy controls (1/40) were positive for antinuclear autoantibodies. The difference between controlsand patients and the first-degree relatives of patientswith ulcerative colitis, respectively, was statisticallysignificant (P ≤ 0.0144). In ulcerative colitis, the existence of antinuclear autoantibodies wasnegatively correlated with immunosuppressive therapy orextraintestinal manifestations (P = 0.0004 and 0.0273,respectively). Antinuclear autoantibodies may represent a factor disposing to the developmentof ulcerative colitis.

GASTROENTEROLOGY 2002;122:2091-2092

A 30-year-old man with underlying Wiskott-Aldrich syndrome, which is a rare X-linked congenital immunodeficiency syndrome characterized by recurrent infections, thrombopenia, eczema and hematopoietic malignancies, presented with bloody diarrhea. Endoscopic and histological evaluation was compatible with ulcerative colitis. Congenital immune defects are paralleled by enterocolitis mimicking inflammatory bowel disease in a substantial number of patients. Despite therapy with prednisolone and 5-ASA compounds, the patient described here experienced a relapse of the colitis twice. Subsequently a JC virus infection of the central nervous system was diagnosed, and he died due to progressive multifocal leukencephalopathy.

GASTROENTEROLOGY 1999;117:1253-1254

GASTROENTEROLOGY 1999;117:280