Validation of the Rome III criteria and alarm symptoms for recurrent abdominal pain in children.

OBJECTIVES: Rome criteria were formulated to define functional gastrointestinal disorders (Rome III criteria, 2006) excluding organic diagnoses when alarm symptoms were absent. The aims of the study were to validate the Rome III criteria as to their capacity to differentiate between organic and functional abdominal pain and to assess the role of alarm symptoms in this differentiation. METHODS: During 2 years all of the patients (ages 4-16 years) presenting with recurrent abdominal pain (Apley criteria) and referred to secondary care were included. Clinical diagnoses were based on protocolized evaluation and intervention with 6-month follow-up. Alarm symptoms were registered. Rome III criteria for functional pain syndromes were assigned independently. Descriptive statistical analyses were performed. RESULTS: In 200 patients (87 boys, mean age 8.8 years), organic (17%), functional (40%), combined organic and functional (9%), spontaneous recovery (27%), and other (8%) clinical diagnoses were established. Alarm symptoms were found in 57.5% (organic causes 56%, functional causes 61%). The evaluation for Rome symptom clusters revealed symptoms of irritable bowel syndrome in 27%, functional dyspepsia in 15%, functional abdominal pain in 28%, functional abdominal pain syndrome in 14.5%, and no pain syndrome in 15.5%. Rome diagnoses, based on symptoms and absence of alarm symptoms, predicted functional clinical diagnosis with sensitivity 0.35 (95% confidence interval 0.27-0.43), specificity 0.60 (0.46-0.73), positive predictive value 0.71 (0.61-0.82), and negative predictive value of 0.24 (0.17-0.32). CONCLUSIONS: The Rome III criteria for abdominal pain are not specific enough to rule out organic causes. Alarm symptoms do not differentiate between organic and functional abdominal pain.

Occult constipation: faecal retention as a cause of recurrent abdominal pain in children.

UNLABELLED: Recurrent abdominal pain (RAP) in children is generally believed to be functional. In practice, many children with RAP become pain-free with laxative therapy. The aims of the study were to establish the role of (occult) constipation in RAP and to investigate whether patients diagnosed with (occult) constipation could be identified by history and physical examination. During 2 years, all patients (age 4-16 years, secondary referral) fulfilling Apley criteria of RAP were included. After exclusion of gastrointestinal infections and food intolerance, laxatives were advised when pain persisted. (Occult) constipation was defined as 'abdominal pain disappearing with laxative treatment and not reappearing within a 6 month follow up period'; 'occult constipation' was diagnosed in patients who did not fulfil the Rome criteria of constipation. Two hundred children (87 M; median age 8.8 years) were evaluated. (Occult) constipation was found in 92 patients (46 %). Of these, 18 had considerable relief of pain when treated for a somatic cause but experienced complete relief only after laxative measures; they were considered to have two diagnoses. Using multivariate analysis, a simple model was developed with cystitis in past history, early satiety and flatulence as predictors for (occult) constipation. The risk of (occult) constipation ranged from 18/58 if no predictor was present to 4/4 if all three were present. CONCLUSION: Laxatives played a pivotal role in the recovery of patients with RAP. We developed a simple model to identify patients at risk of having (occult) constipation.

Protozoa as a cause of recurrent abdominal pain in children.

OBJECTIVES: The aim of this study was to investigate whether protozoa can be identified as a cause of recurrent abdominal pain (RAP), and whether protozoan infections can be recognized by a specific clinical presentation. METHODS: For 2 years, all patients (ages 4-16 years) fulfilling the Apley criteria of RAP referred to secondary care were prospectively evaluated for protozoa (Giardia lamblia, Dientamoeba fragilis, Blastocystis hominis) and treated if positive. Re-examination followed at least 10 days after treatment. Disappearance of pain with eradication and a pain-free follow-up of at least 6 months were considered to be indicative of a causal relation with RAP. The predictive value of the characteristics of the pain for protozoan infections was calculated. RESULTS: Of 220 included patients (92 boys, mean age 8.8 years), 215 brought a stool sample; 73 (34%) carried parasites, 10 of whom had 2 parasites, 2 had 3 parasites. Sixty-five patients were treated. Twenty-five (11%) were pain-free after eradication (21 had D fragilis, 8 B hominis, 4 G lamblia), of whom 11 had another infection (2) or constipation (9) as second diagnosis for the pain. Five had recurrence of infection with D fragilis and were again pain-free with eradication. Patients with protozoa as cause of their pain did not show differences with respect to their presentation when compared with patients with an asymptomatic infection and patients without protozoa. CONCLUSIONS: Protozoa were found as the cause of pain in 6% to 11% of children with RAP. These patients did not show a characteristic presentation when compared with patients with other causes of abdominal pain.

The MUC family: an obituary.

Mucins are glycoproteins that are common on the surfaces of many epithelial cells; they are deemed to mediate many interactions between these cells and their milieu. Several of these mucins form the mucus layer that is found in many hollow organs. The biophysical properties of mucins are related to their extensive O-linked glycosylation rather than directly to their polypeptide sequences. Despite the frequent absence of sequence homology, many human genes encoding mucins have been named MUC followed by a number, unjustly suggesting the existence of one large gene family. In this article, it is suggested that the mucin genes be renamed according to their sequence homologies.

Orphan drug development across Europe: bottlenecks and opportunities.

With the assignment of the 500th European Union orphan drug designation in 2007, the Regulation on Orphan Medicinal Products truly begins to show its potential for delivering new medicines to patients with rare diseases. Here, we analysed European orphan drug development at a national level and unveil a strong relationship between orphan drug development and pharmaceutical innovation performance in Europe. Moreover, we identify gaps in transition from science into orphan drug development as important bottlenecks that exist in several European countries. Our findings underline the importance of innovation-based policies to enhance the development of orphan drugs in Europe.

Combined defects in epithelial and immunoregulatory factors exacerbate the pathogenesis of inflammation: mucin 2-interleukin 10-deficient mice.

Expression of the mucin MUC2, the structural component of the colonic mucus layer, is lowered in ulcerative colitis. Furthermore, interleukin (IL)-10 knockout (IL-10-/-) mice develop colitis and have reduced Muc2 levels. Our aim was to obtain insight into the role of Muc2 and IL-10 in epithelial protection. Muc2-IL-10 double-knockout (Muc2/IL-10(DKO)) mice were characterized and compared to Muc2 knockout (Muc2-/-), IL-10-/- and wild-type (WT) mice. Clinical symptoms, intestinal morphology and differences in epithelial-specific protein levels were analyzed. In addition, levels of the pro-inflammatory cytokines in colonic tissue and serum were determined. IL-10-/- mice were indistinguishable from WT mice throughout this experiment and showed no clinical or histological signs of colitis. Muc2/IL-10(DKO) and Muc2-/- mice showed significant growth retardation and clinical signs of colitis at 4 and 5 weeks, respectively. Muc2/IL-10(DKO) mice had a high mortality rate (50% survival/5 weeks) compared to the other types of mice (100% survival). Microscopic analysis of the colon of Muc2/IL-10(DKO) mice showed mucosal thickening, increased proliferation, superficial erosions and a diminished Muc4 expression. Furthermore, pro-inflammatory cytokines were significantly upregulated, both in tissue (mRNA) and systemically in Muc2/IL-10(DKO) mice. In conclusion, Muc2/IL-10(DKO) mice develop colitis, which is more severe in every aspect compared to Muc2-/- and IL-10-/- mice. These data indicate that (i) in case of Muc2 deficiency, the anti-inflammatory cytokine IL-10 can control epithelial damage, though to a limited extent and (ii) the mucus layer is most likely a key factor determining colitis.

20 years of scientific training of Dutch medical students in an American academic division for pediatric gastroenterology and nutrition: impact on career development.

OBJECTIVES: To evaluate the impact on career development of a program for scientific training of Dutch medical students in an American academic division for pediatric gastroenterology and nutrition. MATERIALS AND METHODS: A survey was undertaken of medical students who were trained in the division of pediatric gastroenterology and nutrition at Tufts University and later at Children's Hospital, Harvard Medical School, Boston, MA. Characteristics of the students, the training period, the scientific output, and their career development were evaluated. RESULTS: A questionnaire was sent to 54 students, of which 39 (72%) responded. The mean time of their rotation was 12.2 +/- 12.1 months. Twenty-five students published 33 scientific manuscripts. Fifteen students obtained a doctorate degree and 4 are involved in a doctorate program. Six theses were directly related to the scientific content of the rotation and were performed under the supervision of American mentors. A total of 59% of the students hold a position as medical specialist, which is a substantially higher percentage than the national average of all graduated medical doctors. Thirty-five percent of them practice pediatrics (of whom 38% practice pediatric gastroenterology) and 22% practice gastroenterology. Seventy-eight percent of the medical specialists hold an academic position. CONCLUSIONS: Dutch medical students who are scientifically trained in a US academic division for pediatric gastroenterology and nutrition--where specialists approached all of the students with a special program to involve them in biomedical research--have a great chance to establish a scientific career track and to become a medical specialist.

Predictors of orphan drug approval in the European Union.

OBJECTIVE: To encourage the development of drugs for rare diseases, orphan drug legislation has been introduced in the USA (1983) and in the EU (2000). Recent literature discusses factors that may influence the development of new orphan medicinal products in the EU. This study aims to identify predictors for successful marketing authorisation of potential orphan drugs in the EU. METHODS: A comparison between randomly selected authorised and a matched sample of not-yet-authorised orphan drug designations has been performed. Determinants in the study included characteristics of the indication, of the product and of the sponsor. Data were collected from the public domain only. RESULTS: Orphan drug approval was strongly associated with previous experience of the sponsor in obtaining approval for another orphan drug (OR = 17.3, 95% CI = 5.6-53.1). Furthermore, existing synthetic entities compared to biotechnology products tended to have a higher likelihood of reaching approval status (OR = 3.9, 95% CI = 0.9-16.6). CONCLUSION: This study showed that experience of a company in developing orphan drugs is an important predictor for subsequent authorisation of other orphan drugs. The same applies for existing (synthetic) molecules, for which much knowledge is available. Further research should be directed towards studying the quality of the clinical development program of those designated orphan medicinal products not reaching approval status.

Cyclooxygenase activity is important for efficient replication of mouse hepatitis virus at an early stage of infection.

Cyclooxygenases (COXs) play a significant role in many different viral infections with respect to replication and pathogenesis. Here we investigated the role of COXs in the mouse hepatitis coronavirus (MHV) infection cycle. Blocking COX activity by different inhibitors or by RNA interference affected MHV infection in different cells. The COX inhibitors reduced MHV infection at a post-binding step, but early in the replication cycle. Both viral RNA and viral protein synthesis were affected with subsequent loss of progeny virus production. Thus, COX activity appears to be required for efficient MHV replication, providing a potential target for anti-coronaviral therapy.

The effect of cytostatic drug treatment on intestine-specific transcription factors Cdx2, GATA-4 and HNF-1alpha in mice.

Chemotherapy-induced intestinal damage is a very important dose-limiting side effect for which there is no definitive prophylaxis or treatment. This is in part due to the lack of understanding of its pathophysiology and impact on intestinal differentiation. The objective of this study was to investigate the gene expression of the small intestinal transcription factors HNF-1alpha, Cdx2, GATA-4 in an experimental model of methotrexate (MTX)-induced intestinal damage, and to correlate these alterations with histological damage, epithelial proliferation and differentiation. HNF-1alpha, Cdx2 and GATA-4 are critical transcription factors in epithelial differentiation, and in combination they act as promoting factors of the sucrase-isomaltase (SI) gene, an enterocyte-specific differentiation marker which is distinctly downregulated after MTX treatment. Mice received two doses of MTX i.v. on two consecutive days and were sacrificed 1, 3 and 7 or 9 days after final injection. Segments of the jejunum were taken for morphological, immunohistochemical and quantitative analyses. Intestinal damage was most severe at day 3 and was associated with decreased expression of the transcriptional factors HNF-1alpha, Cdx2 and GATA-4, which correlated well with decreased expression of SI, and seemed inversely correlated with enhanced proliferation of epithelial crypt cells. During severe damage, the epithelium was preferentially concerned with proliferation rather than differentiation, most likely in order to restore the small intestinal barrier function rather than maintaining its absorptive function. Since HNF-1alpha, Cdx2 and GATA-4 are critical for intestine-specific gene expression and therefore crucial in epithelial differentiation, these results may explain, at least in part, why intestinal differentiation is compromised during MTX treatment.

Adequate feeding and the usefulness of the respiratory quotient in critically ill children.

OBJECTIVE: We determined incidences of underfeeding and overfeeding in children who were admitted to a multidisciplinary tertiary pediatric intensive care and evaluated the usefulness of the respiratory quotient (RQ) obtained from indirect calorimetry to assess feeding adequacy. METHODS: Children 18 y and younger who fulfilled the criteria for indirect calorimetry entered our prospective, observational study and were studied until day 14. Actual energy intake was recorded, compared with required energy intake (measured energy expenditure plus 10%), and classified as underfeeding (<90% of required), adequate feeding (90% to 110% of required), or overfeeding (>110% of required). We also evaluated the adequacy of a measured RQ lower than 0.85 to identify underfeeding, and an RQ higher than 1.0 to identify overfeeding. RESULTS: Ninety-eight children underwent 195 calorimetric measurements. Underfeeding, adequate feeding, and overfeeding occurred on 21%, 10%, and 69% of days, respectively. An RQ lower than 0.85 to identify underfeeding showed low sensitivity (63%), high specificity (89%), and high negative predictive value (90%). An RQ higher than 1.0 to indicate overfeeding showed poor sensitivity (21%), but a high specificity (97%) and a high positive predictive value (93%). Food composition, notably high-carbohydrate intake, was responsible for an RQ exceeding 1.0 in the overfed group. CONCLUSION: Children admitted to the intensive care unit receive adequate feeding on only 10% of measurement days during the first 2 wk of admission. The usefulness of RQ to monitor feeding adequacy is limited to identifying (carbohydrate) overfeeding and excluding underfeeding.

Transcriptional activation of the murine Muc5ac mucin gene in epithelial cancer cells by TGF-beta/Smad4 signalling pathway is potentiated by Sp1.

The nucleotide sequence of the pMS1 clone was submitted to the GenBank Nucleotide Sequence Database under accession number AF288076. Changes in the expression of mucin genes in gastrointestinal cancers is thought to contribute to the development of the disease. In our laboratory we have shown previously that MUC5AC is aberrantly expressed in rectosigmoid villous adenomas. However, the regulatory mechanisms underlying that altered profile of expression is unknown. In order to study its regulation at the transcriptional level, we have isolated and characterized 5.5 kb of the 5'-flanking region of the mouse Muc5ac mucin gene. The promoter is flanked by a TATA box and a transcriptional start site is located 22 bp downstream of the TATA box. Analysis of the sequence showed a high density of binding sites for Smad4, an essential factor in the signalling cascade activated by TGF-beta (transforming growth factor-beta), and Sp1, an important factor in the regulation of MUC5AC. This led us to study Muc5ac regulation by TGF-beta. We show that exogenous addition of TGF-beta to the cells induces Muc5ac endogenous expression, promoter activity and Smad4 binding to the promoter. By co-transfection studies we show that Smad4 is essential for Muc5ac promoter activation and that it does not synergize with Smad2 or Smad3. By gel-retardation and co-transfection assays, we identified Sp1 and Sp3 as important regulators of Muc5ac expression and showed that Smad4 and Sp1 act in a co-operative manner to transactivate Muc5ac promoter activity. Altogether these results bring new insights into the molecular mechanisms of TGF-beta-mediated up-regulation of Muc5ac and enhance our understanding as to how Muc5ac is regulated in certain pathologies of the gastrointestinal tract.

Splanchnic bed metabolism of glucose in preterm neonates.

BACKGROUND: Glucose is a major oxidative substrate for intestinal energy generation in neonatal animals; however, few data in preterm infants are available. Early administration of enteral nutrition, including glucose, may be an effective strategy to support intestinal adaptation to extrauterine life in preterm neonates. OBJECTIVE: The purpose of the present study was to quantify the first-pass uptake and oxidation of glucose by the splanchnic tissues (intestine and liver) in human neonates. DESIGN: Eight preterm infants [birth weight ( +/- SD): 1.19 +/- 0.22 kg, gestational age: 29 +/- 1 wk] were studied while they received 2 different enteral intakes (A: 40% enteral, 60% parenteral, total glucose intake = 7.5 +/- 0.5 mg. kg(-1). min(-1), and B: 100% enteral, total glucose intake = 7.8 +/- 0.4 mg. kg(-1). min(-1)). Splanchnic and whole-body glucose kinetics were measured by use of dual-tracer techniques. RESULTS: During both feeding periods, approximately one-third of dietary glucose intake was utilized during the first pass by the splanchnic tissues. More than three-quarters of this utilized glucose was oxidized in both periods (79 +/- 36% with A and 84 +/- 45% with B). Whole-body glucose oxidation was substantial under both circumstances: 72 +/- 5% and 77% +/- 6% of the glucose flux was oxidized during partial (A) and full (B) enteral feeding, respectively. CONCLUSIONS: Approximately one-third of dietary glucose is utilized during the first pass by the splanchnic tissues, irrespective of the dietary intake. Most of the utilized glucose is used for energy generation.

Specific responses in rat small intestinal epithelial mRNA expression and protein levels during chemotherapeutic damage and regeneration.

The rapidly dividing small intestinal epithelium is very sensitive to the cytostatic drug methotrexate. We investigated the regulation of epithelial gene expression in rat jejunum during methotrexate-induced damage and regeneration. Ten differentiation markers were localized on tissue sections and quantified at mRNA and protein levels relative to control levels. We analyzed correlations in temporal expression patterns between markers. mRNA expression of enterocyte and goblet cell markers decreased significantly during damage for a specific period. Of these, sucrase-isomaltase (-62%) and CPS (-82%) were correlated. Correlations were also found between lactase (-76%) and SGLT1 (-77%) and between I-FABP (-52%) and L-FABP (-45%). Decreases in GLUT5 (-53%), MUC2 (-43%), and TFF3 (-54%) mRNAs occurred independently of any of the other markers. In contrast, lysozyme mRNA present in Paneth cells increased (+76%). At the protein level, qualitative and quantitative changes were in agreement with mRNA expression, except for Muc2 (+115%) and TFF3 (+81%), which increased significantly during damage, following independent patterns. During regeneration, expression of each marker returned to control levels. The enhanced expression of cytoprotective molecules (Muc2, TFF3, lysozyme) during damage represents maintenance of goblet cell and Paneth cell functions, most likely to protect the epithelium. Decreased expression of enterocyte-specific markers represents decreased enterocyte function, of which fatty acid transporters were least affected.

Treatment of inflammatory bowel disease in childhood: best available evidence.

The physician treating children with inflammatory bowel disease is confronted with a number of specific problems, one of them being the lack of randomized, controlled drug trials in children. In this review, the role of nutritional therapy is discussed with a focus on primary treatment, especially for children with Crohn's disease. Then, the available medical therapies are highlighted, reviewing the evidence of effectiveness and side effects in children, as compared with what is known in adults. Nutritional therapy has proven to be effective in inducing and maintaining remission in Crohn's disease while promoting linear growth. Conventional treatment consists of aminosalicylates and corticosteroids, whereas the early introduction of immunosuppressives (such as azathioprine or 6-mercaptopurine) is advocated as maintenance treatment. If these drugs are not tolerated or are ineffective, methotrexate may serve as an alternative in Crohn's disease. Cyclosporine is an effective rescue therapy in severe ulcerative colitis, but only will postpone surgery. A novel strategy to treat Crohn's disease is offered by infliximab, a monoclonal antibody to the proinflammatory cytokine tumor necrosis factor (TNF)-alpha. Based on the best-available evidence, suggested usage is provided for separate drugs with respect to dosage and monitoring of side effects in children.

Interleukin 10-deficient mice exhibit defective colonic Muc2 synthesis before and after induction of colitis by commensal bacteria.

Germ-free (GF) interleukin 10-deficient (IL-10) mice develop chronic colitis after colonization by normal enteric bacteria. Muc2 is the major structural component of the protective colonic mucus. Our aim was to determine whether primary or induced aberrations in Muc2 synthesis occur in GF IL-10 mice that develop colitis after bacterial colonization. GF IL-10 and wild-type mice were colonized with commensal bacteria for various intervals up to 6 weeks. Colitis was quantified by histologic score and IL-12 secretion. Muc2 synthesis, total level of Muc2, and Muc2 sulfation were measured quantitatively. GF IL-10 mice showed 10-fold lower Muc2 synthesis and Muc2 levels compared with GF wild-type mice, but Muc2 sulfation was not different. When bacteria were introduced, IL-10 mice developed colitis, whereas wild-type mice remained healthy. Muc2 synthesis was unchanged in wild-type mice, but IL-10 mice showed a peak increase in Muc2 synthesis 1 week after bacterial introduction, returning to baseline levels after 2 weeks. Total Muc2 levels decreased 2-fold in wild-type mice but remained at stable low levels in IL-10 mice. Upon introducing bacteria, Muc2 sulfation increased 2-fold in wild-type mice, whereas in IL-10 mice Muc2 sulfation decreased 10-fold. In conclusion, a primary defect in colonic Muc2 synthesis is present in IL-10 mice, whereas bacterial colonization and colitis in these mice led to reduced Muc2 sulfation. These quantitative and structural aberrations in Muc2 in IL-10 mice likely reduce the ability of their mucosa to cope with nonpathogenic commensal bacteria and may contribute to their susceptibility to develop colitis.

Metaplasia of the duodenum shows a Helicobacter pylori-correlated differentiation into gastric-type protein expression.

The origin of gastric metaplasia of the duodenum (GMD) remains enigmatic. We studied expression of mucins and trefoil peptides in GMD to gain insight into its phenotype and origin. We examined duodenal tissue of 95 patients (0 to 83 years old, 26 with gastric Helicobacter pylori infection) for the presence of GMD. Expression was examined immunohistochemically of secretory mucins (MUC2, MUC5AC, MUC5B, and MUC6), trefoil peptides (TFF1, TFF2, and TFF3), and sucrase-isomaltase (SI). GMD, found in 37 patients, correlated positively to gastric H. pylori infection, age, and villus atrophy. MUC2 and TFF3, expressed in normal goblet cells, were absent from 100% and 87% of GMD, respectively. GMD ubiquitously expressed MUC5AC, whereas MUC5AC expression in adjacent goblet cells was closely correlated with the extent of GMD. TFF1, TFF2, and MUC6 were found in 84%, 92%, and 65% of GMD, respectively. MUC5B was absent from epithelium and GMD. SI, expressed by villus enterocytes, was absent from GMD. Brunner's glands ubiquitously expressed MUC5B, MUC6, and TFF2. GMD was characterized by the expression of gastric-type proteins MUC5AC, MUC6, TFF1, and TFF2 and the absence of intestinal markers MUC2, TFF3, and SI. In terms of the location of metaplastic cells, our results suggest that epithelial cells migrating toward villus tips switch to gastric-type secretory cells. Positive correlation with infection suggests an inductive role H. pylori in the development of GMD.

Barrett's esophagus is characterized by expression of gastric-type mucins (MUC5AC, MUC6) and TFF peptides (TFF1 and TFF2), but the risk of carcinoma development may be indicated by the intestinal-type mucin, MUC2.

Barrett's esophagus (BE) consists of metaplastic epithelium of the esophagus, generally diagnosed by mucin histochemistry. We aimed to determine which mucins were expressed in BE, and to relate their expression to BE pathology. Archival biopsies of 4 patient groups were selected, based on standard histochemistry: BE without inflammation, BE with inflammation, ulcerating BE, and BE with dysplasia. Sections were stained by immunohistochemistry for secretory mucins (MUC2, MUC5AC, MUC5B, and MUC6), the proliferation marker Ki-67, and mucin-associated trefoil factor family (TFF) peptides (TFF1, TFF2, and TFF3). MUC5AC and TFF2 were expressed at similar high levels in each clinical group. Intestinal metaplasia (IM), detected both histochemically and by the intestinal mucin MUC2, was lowest in inflamed BE. The expression of the intestinal-type TFF3 did not differ among the groups. Ulcerating BE was distinguished by very low expression of MUC6 and MUC5B, but very high expression of TFF1. Proliferation was not different among the groups. In the total group of BE patients, H. pylori infection of the stomach correlated with decreased TFF2 expression in the BE epithelium. We conclude that BE is best characterized by the specific expression of the gastric-type markers, MUC5AC, MUC6, TFF1, and TFF2. Ulcerating BE constitutes the most distinguished group with respect to mucin and TFF expression. Of the intestinal markers, MUC2 is very specific for IM in BE, whereas TFF3 is not a marker for IM. The low occurrence of IM in inflamed BE suggests that these patients may have the lowest risk of developing carcinoma.

Role of mucins in inflammatory bowel disease: important lessons from experimental models.

Inflammatory bowel disease (IBD) is characterized by a chronically inflamed mucosa of the gastrointestinal tract, caused by an underlying immune imbalance and triggered by luminal substances, including bacteria. Mucus forms a gel layer covering the gastrointestinal tract, acting as a semi-permeable barrier between the lumen and the epithelium. Mucins, the building blocks of the mucus gel, determine the thickness and properties of mucus. In IBD in humans, alterations in both membrane-bound and secretory mucins have been described involving genetic mutations in mucin genes, changes in mucin mRNA and protein levels, degree of glycosylation, sulphation, and degradation of mucins. As mucins are strategically positioned between the vulnerable mucosa and the bacterial contents of the bowel, changes in mucin structure and/or quantity probably influence their protective functions and therefore constitute possible aetiological factors in the pathogenesis of IBD. This hypothesis, however, is difficult to prove in humans. Animal models for IBD permit detailed analysis of those aspects of mucins necessary for protection against disease. These models revealed pertinent data as for how changes in mucins, in particular in MUC2, imposed by immunological or microbial factors, may contribute to the development and/or perpetuation of chronic IBD, and shed some light on possible strategies to counteract disease.

Advances in diabetes for the millennium: healthcare systems and diabetes mellitus.

Diabetes presents a host of management issues to the practitioner. With the increasing role of managed care systems, the care of diabetic patients has created many issues in the relationship of physicians and third-party reimbursement agencies. We predict a progressive evolution of diabetes care in light of these changes. The diabetic population will continue to grow rapidly. Collaborative care systems will expand. The paper medical record will be replaced by electronic documentation. The technology of diabetes care will progress rapidly in providing office and home care for diabetes patients. The increasing cost of these interventions and the growing diabetic population will challenge the reimbursement system. We will have to seek for more cost-effective approaches in light of these factors.