The Phenotypic Spectrum of New-onset IBD in Canadian Children of South Asian Ethnicity: A Prospective Multi-Centre Comparative Study.

BACKGROUND: Canadian-born children of South Asian [SA] ethnicity develop inflammatory bowel disease [IBD] at similar rates to those among Caucasian children. We evaluated the variation in phenotypic spectrum of IBD in SA and Caucasian children in a national paediatric inception cohort of new-onset IBD. METHODS: Patients aged <17 years, enrolled in a Canadian nationwide inception cohort study, were included. Baseline demographic and IBD phenotypic features were compared between SA and Caucasian children. Longitudinal outcomes through 18 months of follow-up were compared matched by propensity scores. RESULTS: Of 1156 children enrolled over 2014 to 2019, 623 were Caucasian [98% and 88% parents Canadian born] and 114 SA [79% Canadian born, 87% parents SA born]. Fewer SAs have a first-degree relative with IBD, 6% vs 19% in Caucasians, p = 0.002. SAs present at a younger age, median age 11.4 years (interquartile range [IQR] 9.2-14.3) vs 13 years [IQR 10.9-15 years], p = 0.03 and more commonly with a UC/IBD-U [ulcerative colitis/IBD-unclassified] subtype [ratio of UC/IBD-U to CD 1.2:1 vs 1:1.8 for Caucasians, p <0.001]. Additionally, a greater proportion of SA CD patients present with colonic-only disease [colonic-only CD/UC/IBD-U in SAs 67% vs 57% for Caucasians, p = 0.001], and among those with CD, colonic CD in SAs 31% vs 23% in Caucasians, p = 0.20]. Perianal fistulising disease was also numerically more common in SAs (14 [27%] vs 64 [18%], p = 0.06]. Adjusting for differences in phenotypic presentation, anti-tumour necrosis factor [TNF] exposure, and time to initiation was similar, and two-thirds of children, whether anti-TNF exposed or naïve, were in corticosteroid-free clinical remission at 18 months irrespective of ethnicity. CONCLUSIONS: The phenotypic spectrum of new-onset IBD in SA children differs from that of Caucasian children, but treatment and clinical course are similar within phenotypic subgroups.

Development and validation of a generic scale for use in transition programmes to measure self-management skills in adolescents with chronic health conditions: the TRANSITION-Q.

AIM: To develop a generic self-management skills scale for use with adolescents diagnosed with a chronic health condition who are aged 12 to 18 years. BACKGROUND: There is a lack of methodologically sound scales for healthcare teams to use to measure self-management skills in adolescents with chronic conditions transitioning to adult care. METHODS: Adolescents aged 12 to 18 years with a broad range of chronic health conditions, including neurodevelopmental conditions, were recruited from May to August 2013 from nine outpatient clinics at McMaster Children's Hospital (Canada). Thirty-two participated in a cognitive interview, and 337 completed a questionnaire booklet. Interviews were used to develop the TRANSITION-Q. Rasch measurement theory (RMT) analysis was used to identify items that represent the best indicators of self-management skills. Traditional psychometric tests of measurement performance were also conducted. RESULTS: The response rate was 92% (32/32 cognitive; 337/371 field test). RMT analysis resulted in a 14-item scale with three response options. The overall fit of the observed data to that expected by the Rasch model was non-significant, providing support that this new scale measured a unidimensional construct. Other tests supported the scale as scientifically sound, e.g. Person Separation Index = 0.82; good item fit statistics; no differential item function by age or gender; low residual correlations between items; Cronbach's alpha = 0.85; test-retest reliability = 0.90; and tests of construct validity that showed, as hypothesized, fewer skills in younger participants and in participants who required assistance to complete the scale. Finally, participants who agreed they are ready to transfer to adult healthcare reported higher TRANSITION-Q scores than did participants who disagreed. CONCLUSIONS: The TRANSITION-Q is a short, clinically meaningful and psychometrically sound scale. This generic scale can be used in research and in paediatric and adolescent clinics to help evaluate readiness for transition.

Increasing incidence of paediatric inflammatory bowel disease in Ontario, Canada: evidence from health administrative data.

OBJECTIVE: Health administrative databases can be used to track chronic diseases. The aim of this study was to validate a case ascertainment definition of paediatric-onset inflammatory bowel disease (IBD) using administrative data and describe its epidemiology in Ontario, Canada. METHODS: A population-based clinical database of patients with IBD aged <15 years was used to define cases, and patient information was linked to health administrative data to compare the accuracy of various patterns of healthcare use. The most accurate algorithm was validated with chart data of children aged <18 years from 12 medical practices. Administrative data from the period 1991-2008 were used to describe the incidence and prevalence of IBD in Ontario children. Changes in incidence were tested using Poisson regression. RESULTS: Accurate identification of children with IBD required four physician contacts or two hospitalisations (with International Classification of Disease (ICD) codes for IBD) within 3 years if they underwent colonoscopy and seven contacts or three hospitalisations within 3 years in those without colonoscopy (children <12 years old, sensitivity 90.5%, specificity >99.9%; children <15 years old, sensitivity 89.6%, specificity >99.9%; children <18 years old, sensitivity 91.1%, specificity 99.5%). Age- and sex-standardised prevalence per 100 000 population of paediatric IBD has increased from 42.1 (in 1994) to 56.3 (in 2005). Incidence per 100 000 has increased from 9.5 (in 1994) to 11.4 (in 2005). Statistically significant increases in incidence were noted in 0-4 year olds (5.0%/year, p = 0.03) and 5-9 year olds (7.6%/year, p<0.0001), but not in 10-14 or 15-17 year olds. CONCLUSION: Ontario has one of the highest rates of childhood-onset IBD in the world, and there is an accelerated increase in incidence in younger children.

Therapy of severe diabetic ketoacidosis. Zero-mortality under very-low-dose insulin application.

OBJECTIVE: Despite modern concepts in therapy by low-dose insulin application and better care in intensive care units (ICUs), there still is a mortality of 5-10% for severe diabetic ketoacidosis (DKA). The aim of this study was to develop a therapy concept to reduce complications and mortality in DKA. RESEARCH DESIGN AND METHODS: From 1986 to 1997, 114 consecutive patients (mean [range]; age 34 [11-74] years) with type 1 diabetes suffering from severe DKA were treated on ICUs and investigated in a retrospective and prospective study. The following are the criteria for admission onto ICUs: < 7.20 pH level, > 300 mg/dl blood glucose, less than -12 mmol/l base excess, or < 300 mg/dl blood glucose plus severe symptoms (i.e., coma). We treated patients according to the following concepts: very-low-dose insulin application by a basal insulin infusion of 1 U/h (0.5-4.0 U/h i.v.), maximal decrease of blood glucose level by 50 mg. dl-1. h-1, slow-motion reequilibration by fluid substitution of 1,000 ml/h (Ringer-Lactate, NaCl 0.9% or half-electrolyte fluids) in the first 4 h, potassium replacement and heparin (500-1,000 U/h i.v.). RESULTS: When patients were admitted to ICU, we found the following parameters: mean (range); 609.0 (86.0-1,428.0) mg/dl blood glucose level; 7.13 (6.53-7.36) pH level; and -19.7 (-41.2 to -7.0) mmol/l base excess. After 12 h of treatment, we reached the following parameters: mean values; 251 mg/dl blood glucose level, 7.31 pH level, and -9.37 mmol/l base excess level. All patients survived without any lasting deficiencies or fatal complications. CONCLUSIONS: Very-low-dose insulin application and slow-motion reequilibration plus monitored substitution of electrolytes are the basic strategies in the treatment of severe DKA. In our view, small doses of infused insulin are the main reason for the safe results of this therapy program.

Role of the cyclin-dependent kinase inhibitor CDKN2A in familial melanoma.

BACKGROUND: Approximately 8 to 12% of melanoma appears to be inherited in an autosomal dominant form. Although most early stage melanomas can be treated successfully by simple surgical excision, patients with advanced disease are rarely cured even with aggressive chemotherapy and/or immunotherapy. OBJECTIVE: There is now compelling evidence that germline mutations of the CDKN2A gene on chromosome 9p21 predispose to melanoma in a subset of melanoma-prone families. In this article the evidence for the role of CDKN2A in the genesis of familial melanoma is reviewed and the implications of genetic testing in families with this disease are discussed. CONCLUSION: The identification and subsequent surveillance of unaffected individuals who have a genetic predisposition to melanoma may lead to the detection of early (curable) melanomas and to a reduction in mortality.

CDKN2A mutations in multiple primary melanomas.

BACKGROUND: Germ-line mutations in the CDKN2A tumor-suppressor gene (also known as p16, p16INK4a, and MTS1) have been linked to the development of melanoma in some families with inherited melanoma. Whether mutations in CDKN2A confer a predisposition to sporadic (nonfamilial) melanoma is not known. In some patients with sporadic melanoma, one or more additional primary lesions develop, suggesting that some of these patients have an underlying genetic susceptibility to the cancer. We hypothesized that this predisposition might be due to germ-line CDKN2A mutations. METHODS: We used the polymerase chain reaction, single-strand conformation polymorphism analysis, and direct DNA sequencing to identify germ-line mutations in the CDKN2A gene in patients with multiple primary melanomas who did not have family histories of the disease. A quantitative yeast two-hybrid assay was used to evaluate the functional importance of the CDKN2A variants. RESULTS: Of 33 patients with multiple primary melanomas, 5 (15 percent; 95 percent confidence interval, 4 percent to 27 percent) had germ-line CDKN2A mutations. These included a 24-bp insertion at the 5' end of the coding sequence, three missense mutations (Arg24Pro, Met53Ile, and Ser56Ile), and a 2-bp deletion at position 307 to 308 (resulting in a truncated CDKN2A protein). In three families, CDKN2A mutations identical to those in the probands were found in other family members. In two families with mutations, we uncovered previously unknown evidence of family histories of melanoma. CONCLUSIONS: Some patients with multiple primary melanomas but without family histories of the disease have germ-line mutations of the CDKN2A gene. The presence of multiple primary melanomas may signal a genetic susceptibility to melanoma not only in the index patient but also in family members, who may benefit from melanoma-surveillance programs.

A sequencing method for RNA oligonucleotides based on mass spectrometry.

Synthetic oligoribonucleotides up to 22 bases have been sequenced by observing different kinetics in exonuclease-induced phosphodiester bond hydrolysis and detecting the fragments by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS). Common mass spectrometric sequencing methods have disadvantages concerning read length, cost, and specialist instrumentation using RNA as the target molecule because uridine and cytidine have similar masses. Now we are in the position to distinguish U and C by different peak intensities. The method proposed has been verified using specific endonucleases and 13C-labeled nucleotides. This new nongel-based and nonlabeling sequencing strategy offers first RNA sequencing data using the advantages of fast and accurate MALDI-TOF-MS. Preparation steps and measurements are performed in less than 1 h.

Affected members of melanoma-prone families with linkage to 9p21 but lacking mutations in CDKN2A do not harbor mutations in the coding regions of either CDKN2B or p19ARF.

Mutations in the gene encoding the cell cycle inhibitor CDKN2A have been identified in some melanoma kindreds linked to 9p21. However, many such families show no evidence of mutations in the coding regions of CDKN2A. In this study, we examined whether two other potential tumor suppressors, CDKN2B and p19ARF, which also map within the 9p21 region, play a role in the development of familial melanoma. We found no mutations in the coding regions of either gene in melanoma-prone families with evidence of linkage to 9p21. We conclude either that another melanoma susceptibility gene exists within this chromosomal area or that mutations in noncoding regions of CDKN2A, CDKN2B, or p19ARF predispose to melanoma.

Cytotoxic effects of pamidronate on monolayers of human intestinal epithelial (Caco-2) cells and its epithelial transport.

Pamidronate (APD) is a new drug in the treatment of osteolytic bone diseases. Caco-2 cells were used to study the cytotoxic effects of APD on intestinal epithelium and also the transport (mechanism) of APD across the intestinal epithelium. We investigated the cytotoxic effect of APD by combining two spectrophotometric assays [neutral red (NR) uptake and lactate dehydrogenase (LDH) release] with a morphological assay (electron microscopy). The amount of APD transported across the Caco-2 monolayer was measured by HPLC. The permeability of the monolayer was studied by determining the transepithelial electrical resistance (TEER). The results show that after exposing the Caco-2 cells to increasing concentrations of APD [dose range calculated on the basis of relevance to the oral dose administered to patients] the NR uptake decreased while LDH loss increased, which is indicative of a cytotoxic effect of APD. Ultrastructural alterations, including a widening in intercellular spaces and, at higher doses, complete cell death, were observed. The transport percentage of nontoxic doses of APD was low, while the TEER decreased with increasing doses of APD. In conclusion, APD is cytotoxic for Caco-2 cells. As the transport percentage of nontoxic doses of APD is low and APD reduces the TEER, it is hypothesized that APD is transported paracellularly.

Pulmonary infiltrates associated with naproxen.

Pulmonary infiltrates developed in three middle-aged women while receiving naproxen sodium. Weakness, fatigue, cough, low-grade fever, and eosinophilia in blood and/or sputum were common to all. All symptoms and findings resolved within a few days after discontinuing naproxen therapy in two cases and with use of corticosteroids (prednisone) in one case. A hypersensitivity reaction due to naproxen seemed to be the likely cause.

[Hemihypertrophy, nevus sebaceous, multiple bone cysts and cerebroretinal angiomatosis: a complex phakomatosis]. / Hemihypertrophie, Naevus sebaceus, multiple Knochenzysten und zerebroretinale Angiomatose: eine komplexe Phakomatose

Report on a girl, who died at the age of 6 1/2 years having exhibited different dysplasias which are characteristic features of several phakomatoses: congenital cutaneous pigmentations, fibrolipoma of the scalp, hypertrophy of the right leg, multiple cysts of the long bones (fibrous dysplasia), and an aneurysma racemosum of the retina and mid-brain (syndrome of Bonnet-Blanc-Dechaume).