Opportunistic screening for bone disease using abdominal CT scans obtained for other reasons in newly diagnosed IBD patients.

Bone disease is prevalent among patients with inflammatory bowel disease (IBD), though bone density screening remains underutilized. We used CT scans performed for other indications in IBD patients to identify and monitor osteopenia using CT attenuation values at the lumbar spine. Significant rates of bone disease were detected which would have otherwise gone undiagnosed. INTRODUCTION: Osteoporosis affects about 14-42% of patients with IBD. Though screening is recommended in IBD patients with risk factors, it remains underutilized. In patients with newly diagnosed IBD, we used CT scans performed for other indications to identify and monitor progression of osteopenia. METHODS: Using the Ocean State Crohn's and Colitis Area Registry, we identified adult patients with one or more abdominal CT scans. Each patient had two age- and gender-matched controls. Radiologists measured attenuation through trabecular bone in the L1 vertebral body recorded in Hounsfield units (HU). Generalized estimating equations were used to measure how HU varied as a function of gender, type of IBD, and age. RESULTS: One hundred five IBD patients were included, and 72.4% were classified as "normal" bone mineral density (BMD) and 27.6% as potentially osteopenic: 8.6% with ulcerative colitis and 19.0% with Crohn's disease. We found a decrease in bone density over time (p < 0.001) and that BMD decreases more in Crohn's disease than in ulcerative colitis (p < 0.004). Sixty patients had two CT scans, and mean loss of 9.3 HU was noted. There was a non-significant decrease in BMD over time in patients exposed to > 31 days of steroids and BMD was stable with < 30 days of steroid exposure (p < 0.09). CONCLUSION: Using CT scans obtained for other indications, we found low rates of osteopenia and osteoporosis that may otherwise have gone undiagnosed. Refinement of opportunistic screening may have advantages in terms of cost-savings and earlier detection of bone loss.

Fatigue is highly associated with poor health-related quality of life, disability and depression in newly-diagnosed patients with inflammatory bowel disease, independent of disease activity.

BACKGROUND: Fatigue is common in Crohn's disease (CD) and ulcerative colitis (UC). Data on fatigue in newly diagnosed patients are unavailable. AIM: To report prevalence of fatigue in newly diagnosed CD and UC patients and examine its association with health-related quality of life (HRQOL), depression and disability. METHODS: The Ocean State Crohn's and Colitis Area Registry (OSCCAR) is a statewide cohort of newly diagnosed inflammatory bowel disease patients in Rhode Island. Fatigue was assessed using the Functional Assessment of Chronic Illness Therapy-Fatigue Scale. Patients were administered instruments measuring HRQOL, overall disability and work impairment, and depression. RESULTS: Fatigue was prevalent in 26.4% of 220 subjects. Cohen's d effect sizes for fatigue were large: Short-Form 36 Health Survey mental health component (CD 1.5, UC 1.4) and physical health component (CD 1.4, UC 1.4), EuroQol-5D valuation of current health state (CD 1.2, UC 1.0), Inflammatory Bowel Disease Questionnaire (CD 1.9, UC 1.6) and Patient Health Questionnaire depression scale (CD 1.8, UC 1.7). Fatigued patients reported more work impairment (Score difference: CD 29.5%, UC 23.8%) and activity impairment (score difference: CD 32.3%, UC 25.7%) on the Work Productivity and Activity Impairment Questionnaire. Fatigue's association with all scores remained highly significant despite controlling for disease activity. CONCLUSIONS: Fatigue is strongly associated with poor HRQOL, disability and depression similarly in CD and UC even when controlling for disease activity. Fatigue's association with a wide range of patient-reported outcome measures suggests that monitoring fatigue is a simple way to screen for overall disruption in patient life.

Faecal calprotectin, lactoferrin, M2-pyruvate kinase and S100A12 in severe ulcerative colitis: a prospective multicentre comparison of predicting outcomes and monitoring response.

OBJECTIVE: To compare four faecal markers for their ability to predict steroid refractoriness in severe paediatric ulcerative colitis (UC). Construct validity and responsiveness to change were also assessed. METHODS: This was a prospective multicentre cohort study. Stool samples from 101 children (13.3 + or - 3.6 years; Pediatric UC Activity Index (PUCAI) at admission 72 + or - 12 points) were obtained at the third day of intravenous steroid therapy. Repeated samples at discharge were obtained from 24 children. Predictive validity was assessed using diagnostic utility statistics to predict steroid failure (ie, the need for salvage treatment). Concurrent validity was assessed using correlational analysis with the following constructs: PUCAI, Lindgren and Seo scores, physician's global assessment, albumin, erythrocyte sedimentation rate and C-reactive protein (CRP). Responsiveness was assessed using test utility and correlational strategies. RESULTS: Median values (IQR) were very high at baseline for all four markers (calprotectin 4215 microg/g (2297-8808); lactoferrin 212 microg/g (114-328); M2-pyruvate kinase (M2-PK) 363 U/g (119-3104); and S100A12 469 microg/g (193-1112)). M2-PK was numerically superior to the other three markers and CRP in predicting response to corticosteroid treatment (area under the receiver operating characteristic (ROC) curve 0.75 (95% CI 0.64 to 0.85; p<0.001) vs <0.65 for the others). However, it did not add to the predictive ability of the PUCAI (area under the ROC 0.81 (95% CI 0.73 to 0.89)). M2-PK also had the highest construct validity but with a modest mean correlation with all constructs (r=0.3; p<0.05). None of the markers was responsive to change (Spearman's rho correlation with change in the PUCAI <0.1; p>0.05, area under the ROC curve <0.65; p>0.05). CONCLUSIONS: The four markers were greatly elevated in severe paediatric UC. Only M2-PK had good construct and predictive validity, and none was responsive to change. The PUCAI, a simple clinical index, performed better than the faecal markers in predicting outcome following a course of intravenous corticosteroids in severe UC.

Pediatric gastroenterology at the Mount Sinai hospital.

The history of pediatric gastroenterology at Mount Sinai begins in 1960. Early publications by Drs. Korelitz and Gribetz on the management of inflammatory bowel disease in children served as the preface to forty years of progress in this important area. The history of pediatric gastroenterology includes important work by many individuals, including Horace Hodes, Lotte Strauss and Frederick Kopel. Early observations on the nature of inflammatory bowel disease (IBD), and its course, preceded work on nutritional therapies for IBD, mechanisms of gene-nutrient interactions, regulation of gene transcription, and molecular processes involved in bile transport in the liver and small intestine. Over the last twenty years, the division has grown in size and reputation. Today there are fourteen full-time faculty - 9 M.D.'s and 5 Ph.D.'s - who work in three funded research laboratories. There are also five advanced practice nurses (including three nurse practitioners), two social workers and two nutritionists, as well as several administrators and assistants. In addition to being recognized as a premier center for the treatment of children with general pediatric gastroenterological problems, especially inflammatory bowel disease, the division is also known as one of the nation's largest pediatric liver and liver transplant centers, and it is rapidly becoming one of the largest pediatric short gut syndrome and small bowel transplant centers.

Restorative proctocolectomy in children with ulcerative colitis utilizing rectal mucosectomy with or without diverting ileostomy.

BACKGROUND: Controversies continue concerning the best way to perform restorative proctectomy (RP) for ulcerative colitis (UC). Can rectal mucosectomy and hand-sewn ileoanal anastomosis (IAA) withstand the challenge posed by extrarectal dissection with a double-stapled technique and no mucosectomy? Is a diverting ileostomy mandatory after RP? METHODS: The authors describe 30 consecutive children with UC who underwent RP with rectal mucosectomy and hand-sewn IAA. The authors assess the results and compare the first 14 patients (group 1) treated with temporary diverting ileostomies with the next 16 consecutive patients (group 2) without diverting ileostomies. RESULTS: The average age (13.8 years in group 1 v 10.4 in group 2), duration of illness before resection (3.2 years in group 1 v 1.5 in group 2), and gender breakdown (10 of 14 were girls in group 1, 10 of 16 were girls in group 2) were similar between the two groups. Outcome was not significantly different between the two groups. Average bowel movements per 24-hour period was 5.5 in group 1 and 4.2 in Group 2. Occasional nighttime staining occurred in two patients in group 1 and five in group 2. No one suffered daytime staining in group 1, and one patient had occasional daytime staining in group 2. Average quality of life (on a scale of 0 to 5) as assessed by the patients or parents was 4.4 in group 1 and 4.9 in group 2. There were 10 total complications in group 1. One child required a permanent stoma for ileoanal separation. Two patients required reoperations for complications caused by the diverting ileostomy. The single instance of peritonitis was in group 1 caused by anastomotic leak after ileostomy closure. There were five total complications in group 2, of which, two required temporary stomas for ileoanal separations. CONCLUSIONS: RP with rectal mucosectomy and hand-sewn IAA in children with UC provides good functional results. Peritonitis did not occur in the absence of diversion. Eliminating routine diverting ileostomy avoids the considerable complications and morbidity from the stoma and its closure.

Living related liver transplantation for acute liver failure in children.

The mortality rate among children with acute liver failure (ALF) on the waiting list for liver transplantation is high. We present our experience with living related donor liver transplantation (LRD-LT) in children who required urgent transplantation for ALF. Between December 1995 and July 1997, 6 children underwent LRD-LT for ALF. Cause of liver failure, recipient and donor demographics, clinical and laboratory data, surgical details, complications, and 6-month and 2-year graft and patient survival were recorded. Five boys and 1 girl received left lateral segment grafts from their parents. The mean age was 4 +/- 2.8 years (range, 1 to 9 years). ALF was caused by Wilson's disease in 1 patient and sickle cell intrahepatic cholestasis syndrome in 1 patient; in 4 patients, the cause was unknown. All patients had mental status changes; 2 were on life support. Mean pretransplantation liver function test values were: alanine aminotransferase, 972 +/- 565 U/L (normal, 1 to 53 U/L), total bilirubin, 31.3 +/- 12.4 mg/dL (normal, 0.1 to 1.2 mg/dL), prothrombin time, 34.3 +/- 12.4 seconds (normal, 10.8 to 13.3 seconds), international normalized ratio, 8.46 +/- 5.4 (normal < 2), and fibrinogen, 109 +/- 23.9 mg/dL (normal, 175 to 400 mg/dL). The donors were 5 mothers and 1 father. The mean donor age was 32.5 +/- 7.6 years (range, 19 to 40 years). No donor required blood transfusion, and no donor had any early or late postoperative complications. The donors' mean hospital length of stay was 5 days. In five cases, grafts were blood group-compatible; 1 child received a blood group-incompatible graft. All grafts functioned immediately. No patient had hepatic artery or portal vein thrombosis or biliary complications. The child who received a mismatched graft died of infection of the brain caused by Aspergillus spp at 22 days posttransplantation with a functioning graft. The child with ALF caused by sickle cell intrahepatic cholestasis syndrome developed outflow obstruction 3 months posttransplantation and required retransplantation; he eventually died of vascular complications related to his primary disease. Four children are alive at a mean follow-up of 27 months (range, 14 to 36 months). LRD-LT for children with ALF facilitates timely transplantation without drawing on cadaveric donor resources. The established safety record of LRD-LT made this option appealing to both physicians and parental donors.

Transcriptional repression of the cystic fibrosis transmembrane conductance regulator gene, mediated by CCAAT displacement protein/cut homolog, is associated with histone deacetylation.

Human cystic fibrosis transmembrane conductance regulator gene (CFTR) transcription is tightly regulated by nucleotide sequences upstream of the initiator sequences. Our studies of human CFTR transcription focus on identifying transcription factors bound to an inverted CCAAT consensus or "Y-box element." The human homeodomain CCAAT displacement protein/cut homolog (CDP/cut) can bind to the Y-box element through a cut repeat and homeobox. Analysis of stably transfected cell lines with wild-type and mutant human CFTR-directed reporter genes demonstrates that human histone acetyltransferase GCN5 and transcription factor ATF-1 can potentiate CFTR transcription through the Y-box element. We have found 1) that human CDP/cut acts as a repressor of CFTR transcription through the Y-box element by competing for the sites of transactivators hGCN5 and ATF-1; 2) that the ability of CDP/cut to repress activities of hGCN5 and ATF-1 activity is contingent on the amount of CDP/cut expression; 3) that histone acetylation may have a role in the regulation of gene transcription by altering the accessibility of the CFTR Y-box for sequence-specific transcription factors; 4) that trichostatin A, an inhibitor of histone deacetylase activity, activates transcription of CFTR through the Y-box element; 5) that the inhibition of histone deacetylase activity leads to an alteration of local chromatin structure requiring an intact Y-box sequence in CFTR; 6) that immunocomplexes of CDP/cut possess an associated histone deacetylase activity; 7) that the carboxyl region of CDP/cut, responsible for the transcriptional repressor function, interacts with the histone deacetylase, HDAC1. We propose that CFTR transcription may be regulated through interactions with factors directing the modification of chromatin and requires the conservation of the inverted CCAAT (Y-box) element of the CFTR promoter.

Growth failure as the first expression of malnutrition in children with human immunodeficiency virus infection.

BACKGROUND: To define the onset, pattern, and earliest manifestations of malnutrition related to HIV infection. METHODS: A retrospective cross-sectional analysis of changes in weight and growth in a group of 54 children with perinatally acquired HIV infection was conducted. Eight children had asymptomatic HIV infection, 26 had symptomatic infection, and 20 had symptomatic infection and were referred for nutritional support. RESULTS: We found an early decline in the rate of linear growth with a relative preservation of the weight-for-age. Weight-for-height measurements were preserved until there was advanced HIV-related disease. CONCLUSIONS: This pattern can result in a false impression of adequate nutrition and emphasizes the importance of longitudinal growth data of the child with HIV infection. Evidence of linear growth failure before clinical wasting is apparent is an absolute indication for aggressive nutritional support.

Recurrence of autoimmune hepatitis in children after liver transplantation.

BACKGROUND: Liver transplantation is recognized as the appropriate treatment for end-stage liver disease due to chronic active autoimmune hepatitis. While it was initially thought that the disease did not recur after transplant, it is now generally accepted that adult patients may develop recurrent disease, with studies reporting a recurrence rate of < or = 25%. We have noted a higher incidence of recurrent autoimmune hepatitis in our pediatric patients undergoing liver transplant, with a high incidence of associated morbidity. METHODS: We reviewed the records of six children followed up for autoimmune hepatitis who underwent orthotopic liver transplant for complications of end-stage liver disease. RESULTS: Of the six, five developed recurrent autoimmune hepatitis at a mean time of 11.4 months after transplant. The disease was aggressive, leading to cirrhosis and retransplant in three patients, within 1 year of recurrence. A second recurrence of disease occurred in all three retransplanted patients. One patient has received a third liver transplant, one has died, and one patient is asymptomatic on medical therapy. Autoimmune hepatitis recurred in all four patients receiving tacrolimus. CONCLUSION: We conclude that liver transplant for autoimmune hepatitis is likely to be palliative for most pediatric patients. Potent immunosuppressives such as tacrolimus do not protect against the development of recurrent autoimmune hepatitis.

The role of glutamine, short-chain fatty acids, and nucleotides in intestinal adaptation to gastrointestinal disease.

Important first steps have been taken towards establishing how some nutrients interact with genes and affect intestinal adaptation. These mechanisms may be typical of how other nutrients influence cell function and turnover and help to maintain intestinal integrity. The dietary effects of nucleotides on intestinal cell mucosa act at the gene transcription level. The dietary effects of nucleotides on immune suppression also may act through similar mechanisms. The effects of the other trophic agents may interact at this level or at other levels. Scientific interest in how the various tropic factors work to maintain and repair the gastrointestinal tract is manifested by a growing body of research that demonstrates potential mechanisms for nutrient-gene interaction and how much interactions affect intestinal development and turnover. It seems clear that intestinal gene transcription and the activity of transcription factors are at least sometimes directly related to nutrition. The techniques of molecular biology now permit the exploration and explanation of how dietary factors, such as glutamine, SCFAs, and nucleotides, affect normal and pathologic intestinal mucosal development, function, adaptation, and repair.

Transcription of cystic fibrosis transmembrane conductance regulator requires a CCAAT-like element for both basal and cAMP-mediated regulation.

The cystic fibrosis transmembrane conductance regulator (CFTR) gene in man is controlled by a tightly regulated and weak promoter. The architecture of the CFTR promoter suggests regulatory characteristics that are consistent with the absence of a TATA-like sequence, including the ability to initiate RNA transcription at numerous positions. Detailed investigation of the most proximal region of the human CFTR gene promoter through deletion and mutational analysis reveals that expression is contingent on the conservation of the inverted CCAAT sequence. Basal expression of CFTR transcription and cAMP-mediated transcriptional regulation require the presence of an imperfect and inverted CCAAT element recognized as 5'-AATTGGAAGCAAAT-3', located between 132 and 119 nucleotides upstream of the translational start site. RNA isolated from a transfected pancreatic cell line carrying integrated wild-type and mutant CFTR-directed transgenes was used to map the 5' termini of the transgenic transcripts. Analysis of the transcript termini by ribonuclease protection analysis reflects the direct association of the conserved inverted CCAAT sequence in promoting transcript initiation. Because of the requirement for the inverted CCAAT sequence for promoting transcription of CFTR, the involvement of CCAAT-binding factors is suspected in the regulation of CFTR gene transcription. To test this, we used electrophoretic mobility shift assays to demonstrate that the majority of the binding to the inverted CCAAT element, between -135 and -116, was easily competed for by binding to cognate nucleotide sequences for CCAAT-enhancer binding protein (C/EBP). An antibody specific for the C/EBP-related protein, C/EBP delta, detected C/EBP delta as part of a nuclear protein complex bound to the inverted CCAAT sequence of the CFTR gene. Also, the detection of specific activating transcription factor/cyclic-AMP response element binding protein antigens by antibody supershift analysis of nuclear complexes suggest that species of this family of transcription factors could be involved in the formation of complexes with C/EBP delta within the CFTR gene inverted CCAAT-like element. These studies raise the possibility of interactions between individual members of the C/EBP and activating transcription factor/cyclic-AMP response element binding protein families potentially contribute to the tight transcriptional control rendered by the CFTR gene promoter.

Dietary purine nucleotides and the gastrointestinal tract.

There is a growing body of research that demonstrates a role for dietary nucleotides, the building blocks of RNA and DNA, during intestinal development, turnover, and repair. There is evidence that the effects of purine nucleotides may be mediated through intestinal gene transcription and, more specifically, through the action of transcription factors that, at least sometimes, are directly related to nutrition. Some of the suggested specific roles for dietary nucleotides include the enhancement of the normal host defense system, effects on neonatal lipid metabolism, and influence on iron bioavailability. This review focuses on the potential role of dietary (purine) nucleotides in the maintenance of intestinal integrity and reviews potential mechanisms for these effects.

Energy requirements in Alzheimer's disease patients.

Weight loss in Alzheimer's patients has been observed by many clinicians and reported in the international geriatric literature. It represents a puzzling challenge for clinicians and researchers, and it is an important issue for caregivers and nursing home staff concerned with state and federal requirements for nutrition and weight monitoring. Using indirect calorimetry, we studied the resting energy expenditure of 21 elderly patients; 12 were residing in a community setting, and 9 were institutionalized. Of the 12 community-living patients studied, 5 had early to moderate Alzheimer's disease, and 7 were nondemented control subjects. Of the 9 institutionalized patients, all were severely demented, bedridden, and fed exclusively by gastric tube in a closely monitored clinical environment with daily bedside weighing. Four had Alzheimer's disease, and 5 had multi-infarct dementia (MID). Among the outpatients, the Alzheimer's group showed increased energy requirements (p = 0.028) and a significantly different pattern of fat-free mass compared with control subjects (p = 0.031). These observations on community-residing elderly were consistent with, and extended by our findings on energy requirements of, the demented institutionalized patients. The calorie intake necessary for weight maintenance of the bedridden institutionalized patients was determined during their prolonged institutionalization. The presumed maintenance level of calorie intake was then verified during a 10 wk study. During the 10 wk, we documented no significant change in weight with constant energy intake. Compared with MID patients, Alzheimer's patients tended to weigh less (52.84 vs 56.4 kg; p = 0.20) but actually required more calories (1626 vs 1341 kcal, p < 0.011).(ABSTRACT TRUNCATED AT 250 WORDS)