Assessing disease activity using the pediatric Crohn's disease activity index: Can we use subjective or objective parameters alone?

BACKGROUND: The pediatric Crohn's disease activity index (PCDAI) is used as a standard tool to assess disease activity in clinical trials for pediatric Crohn's disease. AIM: To examine which items on the PCDAI drive assessment of disease activity, and how subgroups of subjective and objective items reflect change in disease state over time. METHODS: Selective raw data from three prospectively collected datasets were combined, including 703 children with full PCDAI data at baseline, at 3-mo (Q1, n = 670), and 1-year (Q4, n = 474). Change in individual PCDAI scores from baseline to Q1 and to Q4 were examined using the non-weighted PCDAI. RESULTS: Abdominal pain, well-being, weight, and stooling had the highest change scores over time. Objective indicators including albumin, abdominal exam, and height velocity followed. Change scores for well-being and abdominal exam did not explain significant variance at Q1 but were significant predictors at Q4 (P < 0.001 and P < 0.05). Subjective and objective subgroups of items predicted less variance (18% and 22%) on total PCDAI scores at Q1 and Q4 compared to the full PCDAI, or a composite scale (both 32%) containing significant predictors. CONCLUSION: Although subjective items on the PCDAI change the most over time, the full PCDAI or a smaller composite of items including a combination of subjective and objective components classifies disease activity better than a subgroup of either subjective or objective items alone. Reliance on subjective or objective items as stand-alone proxies for disease activity measurement could result in misclassification of disease state.

Localization of fission yeast type II myosin, Myo2, to the cytokinetic actin ring is regulated by phosphorylation of a C-terminal coiled-coil domain and requires a functional septation initiation network.

Myo2 truncations fused to green fluorescent protein (GFP) defined a C-terminal domain essential for the localization of Myo2 to the cytokinetic actin ring (CAR). The localization domain contained two predicted phosphorylation sites. Mutation of serine 1518 to alanine (S(1518)A) abolished Myo2 localization, whereas Myo2 with a glutamic acid at this position (S(1518)E) localized to the CAR. GFP-Myo2 formed rings in the septation initiation kinase (SIN) mutant cdc7-24 at 25 degrees C but not at 36 degrees C. GFP-Myo2S(1518)E rings persisted at 36 degrees C in cdc7-24 but not in another SIN kinase mutant, sid2-250. To further examine the relationship between Myo2 and the SIN pathway, the chromosomal copy of myo2(+) was fused to GFP (strain myo2-gc). Myo2 ring formation was abolished in the double mutants myo2-gc cdc7.24 and myo2-gc sid2-250 at the restrictive temperature. In contrast, activation of the SIN pathway in the double mutant myo2-gc cdc16-116 resulted in the formation of Myo2 rings which subsequently collapsed at 36 degrees C. We conclude that the SIN pathway that controls septation in fission yeast also regulates Myo2 ring formation and contraction. Cdc7 and Sid2 are involved in ring formation, in the case of Cdc7 by phosphorylation of a single serine residue in the Myo2 tail. Other kinases and/or phosphatases may control ring contraction.

Myosin V-mediated vacuole distribution and fusion in fission yeast.

The class V myosins are actin-based motors that move a variety of cellular cargoes [1]. In budding yeast, their activity includes the relocation of a portion of the vacuole from the mother cell to the bud [2, 3]. Fission yeast cells contain numerous (approximately 80) small vacuoles. When S. pombe cells are placed in water, vacuoles fuse in response to osmotic stress [4]. Fission yeast possess two type V myosin genes, myo51(+) and myo52(+) [5]. In a myo51Delta strain, vacuoles were distributed throughout the cell, and mean vacuole diameter was identical to that seen in wild-type cells. When myo51Delta and wild-type cells were placed in water, vacuoles enlarged by fusion. In myo52Delta cells, by contrast, vacuoles were smaller and mostly clustered around the nucleus, and fusion in water was largely inhibited. When cells containing GFP-Myo52 were placed in water, Myo52 was seen to redistribute from the cell poles to the surface of the fusing vacuoles. Vacuole fusion in fission yeast was inhibited by the microtubule drug thiabendazole (TBZ) but not by the actin inhibitor latrunculin B. This is the first demonstration of the involvement of a type V myosin, possibly via an interaction with microtubules, in homotypic membrane fusion.

A MAP kinase-dependent actin checkpoint ensures proper spindle orientation in fission yeast.

The accurate segregation of chromosomes at mitosis depends on a correctly assembled bipolar spindle that exerts balanced forces on each sister chromatid. The integrity of mitotic chromosome segregation is ensured by the spindle assembly checkpoint (SAC) that delays mitosis in response to defective spindle organisation or failure of chromosome attachment. Here we describe a distinct mitotic checkpoint in the fission yeast, Schizosaccharomyces pombe, that monitors the integrity of the actin cytoskeleton and delays sister chromatid separation, spindle elongation and cytokinesis until spindle poles have been properly oriented. This mitotic delay is imposed by a stress-activated mitogen-activated protein (MAP) kinase pathway but is independent of the anaphase-promoting complex (APC).

Shedding a little light on light chains.

Myosin II regulatory light chains have an important role in the organization and function of the contractile machinery at cytokinesis. Two recent reports provide new insights into these important proteins.

Two type V myosins with non-overlapping functions in the fission yeast Schizosaccharomyces pombe: Myo52 is concerned with growth polarity and cytokinesis, Myo51 is a component of the cytokinetic actin ring.

The fission yeast genome project has identified five myosin genes: one type I myosin, myo1(+), two type II myosins, myo2(+) and myp2(+), and two type V myosins, myo51(+) and myo52(+). Cells deleted for myo51(+) show normal morphology and growth rates whereas deletion of myo52(+) results in a partial loss of cell polarity, slow growth and cytokinetic defects. Combining both deletions in a single strain is phenotypically non-additive, myo52(delta) being epistatic to myo51(delta). Overproduction of Myo51 gives rise to elongated cells which fail to form functional septa whereas overproduction of Myo52 results in branched cells with aberrant septa that fail to cleave. Myo52 localises to the poles of growing cells but during cell division it relocalises to the cell equator as a bar that is bisected by the cytokinetic septum. Myo51 shows no obvious localisation during interphase but at cytokinesis it is associated with the contractile cytokinetic actin ring (CAR). Both myosins are dependent upon an intact actin cytoskeleton for localisation. Myo52 partially colocalises with the (alpha)-glucan synthase Mok1 at the cell tips and to a lesser extent at the septum. Mok1 is delocalised and upregulated in myo52(delta) and myo52(delta) cell walls are resistant to digestion by the cell wall degrading enzyme zymolyase. Thus myo52(+) appears to be involved in the local delivery or positioning of vesicles containing cell wall precursors at the cell tips and has a role in the maturation or cleavage of the septum. Myo51 has a non-essential role in cytokinesis as a component of the cytokinetic actin ring.

Corticosteroids in the treatment of gastrointestinal disease.

Corticosteroids remain the mainstay of anti-inflammatory and immunosuppressive therapy for many gastrointestinal conditions. We are now starting to understand their mechanism of action and the phenomenon of corticosteroid resistance. Because of the ubiquity of corticosteroid receptors in virtually all cells of the body, side effects of therapy are common and may affect multiple body sites. Newer corticosteroid analogues are being developed to minimize these complications, and concomitant use of other immunomodulatory drugs often facilitates corticosteroid dosage reduction or even withdrawal in chronic inflammatory states.

Allergic gastroenteropathy in preterm infants.

OBJECTIVES: To determine the clinical presentation, histopathologic features, and outcome of biopsy-proven allergic gastroenteropathy (AGE) in preterm infants. We hypothesized that AGE is a more frequent cause of gastrointestinal disease in this population than previously suspected. STUDY DESIGN: The retrospective portion of the study, from 1992 to 1997, included preterm infants <37 weeks' gestation who underwent biopsy because of suspected AGE. The prospective portion, from January to December 1998, included 20 infants undergoing endoscopy and biopsy because of suspected AGE. RESULTS: Twenty-five infants (12 retrospective/13 prospective) with mean gestational age of 29 weeks at birth and mean postnatal age at diagnosis of 78 days were diagnosed with AGE. Three clinical patterns of presentation were noted: group 1, gastroesophageal reflux disease (n = 5); group 2, non-specific feeding intolerance (n = 8); and group 3, lower gastrointestinal bleeding (n = 12). Ten patients had negative biopsy findings (3 retrospective/7 prospective) and had clinical features indistinguishable from those of groups 1 and 2. Patients in group 3 were most likely to have positive biopsy findings (12 of 12). Fifteen patients responded to a casein hydrolysate formula, and 10 patients required an amino acid-based formula. Patients with AGE who had eosinophilic infiltration and villous atrophy took longer to recover than those with eosinophilic infiltration alone (P <.03). Subsequently, most have tolerated formula challenges and are currently tolerating cow's milk. CONCLUSIONS: AGE may be an under-recognized cause of gastrointestinal symptoms in preterm infants. Confirmation with endoscopy and biopsy can be done safely and provides the basis for appropriate dietary management.

Use of infliximab in the treatment of Crohn's disease in children and adolescents.

BACKGROUND: Crohn's disease is often poorly responsive to conventional therapy with corticosteroids and immunomodulators. A novel chimeric antibody to tumor necrosis factor-alpha, infliximab, has shown utility in the treatment of refractory Crohn's disease in adults. PURPOSE: To evaluate the efficacy of open-label administration of infliximab in children and adolescents with active intestinal Crohn's disease. METHODS: Chart review of the experience with 19 subjects (mean age 14.4 years, range 9 to 19 years) receiving 1 to 3 infusions of infliximab (5 mg/kg/dose) over a 12-week period for corticosteroid-resistant disease (n = 7) or corticosteroid dependence (n = 12). Disease activity was monitored by physician global assessment and the Pediatric Crohn's Disease Activity Index. RESULTS: Significant initial improvement (first 4 weeks after infusion) was noted in all subjects, with Pediatric Crohn's Disease Activity Index values decreasing significantly (mean +/- SD, 42.1 +/- 13.7 to 10.0 +/- 5.6, P <.0001). Over the subsequent 8-week period, 8 of 19 treated subjects had worsening of symptoms, although none deteriorated to severe activity. The mean Pediatric Crohn's Disease Activity Index at 12 weeks was 26.8 +/- 16. 4. The mean daily prednisone dosages at baseline, 4 weeks, and 12 weeks were 28 +/- 14 mg, 20 +/- 12 mg, and 8 +/- 12 mg, respectively (P <.01). Adverse effects were noted in 3 patients during infusion (dyspnea, rash) and were self-limited. CONCLUSIONS: Infliximab is associated with short-term clinical improvement in children and adolescents with severe Crohn's disease. The rapid return of disease activity in some patients suggests that additional dosing strategies may be required. Long-term safety necessitates close monitoring.

Cytokinesis in fission yeast: a myosin pas de deux.

Cytokinesis in the fission yeast, Schizosaccharomyces pombe consists of two distinct but overlapping events: the assembly and constriction of a cytokinetic actomyosin ring (CAR) and the formation of a cross wall or septum. These two processes must be spatially and temporally coordinated both with each other and with other cell cycle events, most notably spindle formation and anaphase chromosome segregation. In fission yeast, the CAR contains two unusual type II myosins, Myo2, encoded by the gene myo2(+), and Myp2, encoded by myp2(+). The relationship of these two proteins to each other and their relative contribution to CAR assembly and contraction is largely unknown. Here we review what is known about the role of each myosin in cytokinesis and present some new information concerning their regulation and possible physical interaction.

Dyspepsia in children and adolescents: a prospective study.

BACKGROUND: Dyspepsia is poorly characterized in the pediatric population. The goal of the current study was to describe the clinical constellation and natural history of dyspepsia in children and adolescents seen in a pediatric gastroenterology practice. METHODS: A standardized questionnaire was administered by a pediatric gastroenterologist to all subjects 5 or more years of age (and their parents or guardians) treated in a referral pediatric gastroenterology practice for 1 month or more of abdominal pain or discomfort, nausea, or vomiting. Subjects with dyspepsia and dyspepsia subtypes (ulcer-like, dysmotility-like) were identified by using previously defined adult criteria. Evaluation and treatment were performed at the discretion of the attending pediatric gastroenterologist. RESULTS: During a 1-year period, 257 patients were screened with 127 subjects fulfilling criteria for dyspepsia (59% girls, 85% white; median age, 11.7 years; median duration of symptoms, 8 months). Symptoms were ulcer-like in 26% and dysmotility-like (nausea predominance) in 15% of subjects. In those with dyspepsia, irritable bowel syndrome and gastroesophageal reflux were noted in 24% and 43%, respectively. Esophagogastroduodenoscopy and biopsy were performed in 56 subjects with 21 (38%) having mucosal inflammation (Helicobacter pylori in 5). The remaining 35 subjects (62%) were considered to have functional dyspepsia. Duration of symptoms less than 1 year and vomiting were risk factors for mucosal inflammation. Follow-up at 6 months to 2 years revealed 70% of subjects were either asymptomatic or much improved regardless of the cause of dyspepsia. CONCLUSION: Most children and adolescents with dyspepsia do not have serious disease. In our referral population H. pylori infection was unusual, and no peptic ulceration was found. Most subjects with functional dyspepsia have improvement of symptoms over time.

Functional gastrointestinal disorders.

When clinicians label a child as having a functional disorder, there is often a pejorative connotation that the symptoms are psychological, imagined, or faked. These symptoms range from chronic abdominal pain to recurrent headaches to fatigue. We say the complaints are functional because we are unable to demonstrate any structural or biochemical abnormality causing them. The degree to which we go searching for these abnormalities varies from case to case and often depends on our own clinical experience, insecurities, and demands of the patient's family. Labeling a child as having a functional complaint can put a tremendous burden on the child and family, because if this concept is presented improperly (as implied above), it can suggest that it is their fault there are symptoms and that if they "got their act together" the symptoms would melt away. Functional gastrointestinal disorders are defined as conditions in which a variable combination of chronic or recurrent gastrointestinal symptoms are present in the absence of demonstrable disease. There may indeed be physiologic abnormalities underlying the symptoms, but at the present time we are unable to detect them. We make a diagnosis based on symptoms, not on demonstrable abnormalities in physical examination or laboratory tests. A number of common pediatric diagnoses fall into this category, including infant regurgitation, chronic nonspecific diarrhea, irritable bowel syndrome, non-ulcer dyspepsia, infant dyschezia, and functional constipation. This paper presents a brief review of our current understanding of each diagnosis and gives suggestions for management.

Childhood functional gastrointestinal disorders.

This is the first attempt at defining criteria for functional gastrointestinal disorders (FGIDs) in infancy, childhood, and adolescence. The decision-making process was as for adults and consisted of arriving at consensus, based on clinical experience. This paper is intended to be a quick reference. The classification system selected differs from the one used in the adult population in that it is organized according to main complaints instead of being organ-targeted. Because the child is still developing, some disorders such as toddler's diarrhea (or functional diarrhea) are linked to certain physiologic stages; others may result from behavioral responses to sphincter function acquisition such as fecal retention; others will only be recognizable after the child is cognitively mature enough to report the symptoms (e.g., dyspepsia). Infant regurgitation, rumination, and cyclic vomiting constitute the vomiting disorders. Abdominal pain disorders are classified as: functional dyspepsia, irritable bowel syndrome (IBS), functional abdominal pain, abdominal migraine, and aerophagia. Disorders of defecation include: infant dyschezia, functional constipation, functional fecal retention, and functional non-retentive fecal soiling. Some disorders, such as IBS and dyspepsia and functional abdominal pain, are exact replications of the adult criteria because there are enough data to confirm that they represent specific and similar disorders in pediatrics. Other disorders not included in the pediatric classification, such as functional biliary disorders, do occur in children; however, existing data are insufficient to warrant including them at the present time. For these disorders, it is suggested that, for the time being, clinicians refer to the criteria established for the adult population.