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We obtained Hubble Space Telescope/Wide Field Camera 3 imaging of a sample of ten of the nearest and brightest nuclear clusters (NCs) residing in late-type spiral galaxies, in seven bands that span the near-UV to the near-IR. Structural properties of the clusters were measured by fitting two-dimensional surface brightness profiles to the images using GALFIT. The clusters exhibit a wide range of structural properties, with F814W absolute magnitudes that range from -11.2 to -15.1 mag and F814W effective radii that range from 1.4 to 8.3 pc. For 6 of the 10 clusters in our sample, we find changes in the effective radius with wavelength, suggesting radially varying stellar populations. In four of the objects, the effective radius increases with wavelength, indicating the presence of a younger population that is more concentrated than the bulk of the stars in the cluster. However, we find a general decrease in effective radius with wavelength in two of the objects in our sample, which may indicate extended, circumnuclear star formation. We also find a general trend of increasing roundness of the clusters at longer wavelengths, as well as a correlation between the axis ratios of the NCs and their host galaxies. These observations indicate that blue disks aligned with the host galaxy plane are a common feature of NCs in late-type galaxies, but are difficult to detect in galaxies that are close to face-on. In color-color diagrams spanning the near-UV through the near-IR, most of the clusters lie far from single-burst evolutionary tracks, showing evidence for multi-age populations. Most of the clusters have integrated colors consistent with a mix of an old population (>1 Gyr) and a young population (∼100-300 Myr). The wide wavelength coverage of our data provides a sensitivity to populations with a mix of ages that would not be possible to achieve with imaging in optical bands only. The surface brightness profiles presented in this work will be used for future stellar population modeling and dynamical studies of the clusters.

KA1858+4850 is a narrow-line Seyfert 1 galaxy at redshift 0.078 and is among the brightest active galaxies monitored by the Kepler mission. We have carried out a reverberation mapping campaign designed to measure the broad-line region size and estimate the mass of the black hole in this galaxy. We obtained 74 epochs of spectroscopic data using the Kast Spectrograph at the Lick 3 m telescope from 2012 February to November, and obtained complementary V-band images from five other ground-based telescopes. We measured the Hβ light curve lag with respect to the V-band continuum light curve using both cross-correlation techniques (CCF) and continuum light curve variability modeling with the JAVELIN method and found rest-frame lags of days and τJAVELINdays. The Hβ rms line profile has a width of σline = 770 ± 49 km s-1. Combining these two results and assuming a virial scale factor of f = 5.13, we obtained a virial estimate of for the mass of the central black hole and an Eddington ratio of L/L Edd 0.2. We also obtained consistent but slightly shorter emission-line lags with respect to the Kepler light curve. Thanks to the Kepler mission, the light curve of KA1858+4850 has among the highest cadences and signal-to-noise ratios ever measured for an active galactic nucleus; thus, our black hole mass measurement will serve as a reference point for relations between black hole mass and continuum variability characteristics in active galactic nuclei.

Hundreds of Type 2 quasars have been identified in Sloan Digital Sky Survey (SDSS) data, and there is substantial evidence that they are generally galaxies with highly obscured central engines, in accord with unified models for active galactic nuclei (AGNs). A straightforward expectation of unified models is that highly obscured Type 2 AGNs should show little or no optical variability on timescales of days to years. As a test of this prediction, we have carried out a search for variability in Type 2 quasars in SDSS Stripe 82 using difference-imaging photometry. Starting with the Type 2 AGN catalogs of Zakamska et al. and Reyes et al., we find evidence of significant g-band variability in 17 out of 173 objects for which light curves could be measured from the Stripe 82 data. To determine the nature of this variability, we obtained new Keck spectropolarimetry observations for seven of these variable AGNs. The Keck data show that these objects have low continuum polarizations (p ≲ 1% in most cases) and all seven have broad Hα and/or Mg II emission lines in their total (unpolarized) spectra, indicating that they should actually be classified as Type 1 AGNs. We conclude that the primary reason variability is found in the SDSS-selected Type 2 AGN samples is that these samples contain a small fraction of Type 1 AGNs as contaminants, and it is not necessary to invoke more exotic possible explanations such as a population of "naked" or unobscured Type 2 quasars. Aside from misclassified Type 1 objects, the Type 2 quasars do not generally show detectable optical variability over the duration of the Stripe 82 survey. © 2014. The American Astronomical Society. All rights reserved..

BACKGROUND: The marked increases in the incidence of type 1 diabetes in recent decades strongly suggest the role of environmental influences. These environmental influences remain largely unknown. OBJECTIVE: To investigate atopy and home environment (such as children living at home, sharing a bedroom and house moves) as potential risk factors for type 1 diabetes. SUBJECTS AND METHOD: In Northern Ireland, 175 children with type 1 diabetes and 4859 control children completed a questionnaire on atopy experience, family composition and home environment. Control children from two age groups (6-8 yr old and 13-14 yr old) were identified from randomly selected primary and secondary schools across Northern Ireland. Cases were identified from a population-based type 1 diabetes register. RESULTS: There was little evidence of a difference in the proportion of participants with a history of atopy in the cases compared with controls. There was a significant reduction in the risk of diabetes in children who lived with more siblings {odds ratio (OR) = 0.58 [95% confidence interval (95% CI) 0.39-0.85] in children who lived with three or more siblings compared with one or none} and in children who moved house more often [OR = 0.59 (95% CI 0.40-0.88) in children who moved house twice or more compared with never]. CONCLUSION: The reduced risk of type 1 diabetes in children living with siblings, sharing a bedroom and moving house more often could reflect the protection afforded by exposure to infections in early life and consequently may provide support for the hygiene hypothesis. [ABSTRACT FROM AUTHOR]

Electroneurodiagnostic technologists play a key role in health care. It is time for these allied health professionals to make a commitment and contribution, using scientific methodology, to the body of medical research and publication. Research methods, quantitative, qualitative, and mixed research design will be reviewed. Introduced is an innovative research approach that is applicable to END practice; it is called, action research. [ABSTRACT FROM AUTHOR]

Background: Prior experimentation has shown that loss of the tyrosine kinase (TK) signaling domain of the Ron receptor leads to marked hepatocyte protection in a model of lipopolysaccharide-induced acute liver failure (ALF) in D-galactosamine (GalN)-sensitized mice. The aim of this study was to identify the role of Ron in the regulation of hepatic gene expression., Methods: Microarray analyses were performed on liver RNA isolated sequentially from wild-type (WT) and TK-/- mice during the progression of ALF. Gene array data were validated using Western and immunohistochemistry analyses as well as with ex vivo culture systems., Results: At baseline, 101 genes were differentially expressed between WT and TK-/- livers, which regulate processes involved in hypoxia, proliferation, apoptosis and metabolism. One hour after ALF induction, WT livers exhibited increased cytokine expression compared to TK-/- livers, and after 4 hours, an induction of suppressor of cytokine signaling (SOCS) genes as well as JAK-STAT pathway activation were prominent in TK-/- livers compared to controls., Conclusion: Our studies suggest a novel hepato-protective mechanism in Ron TK-/- mice wherein increased and sustained SOCS production and JAK-STAT activation in the hepatocyte may inhibit the destructive proinflammatory milieu and promote survival factors which blunt hepatic death and the ensuing development of ALF.

Aim: To assess the association of POMC haplotype-tagged single nucleotide polymorphisms (htSNPs) with the development of type 1 diabetes (T1D) in a Caucasian population., Methods: All exons, intron 1, and approximately 6-kb upstream and 3-kb downstream of the POMC gene were bidirectionally resequenced to identify DNA polymorphisms in 30 individuals. Allele frequencies were determined (60 chromosomes) and efficient htSNPs were selected using the htSNP2 programme. Genotyping was performed in 390 cases, 339 controls and 245 T1D parent-offspring trios, using Taqman, Sequenom and direct-sequencing technologies., Results: Thirteen polymorphisms (two novel) with a minor allele frequency greater than 1% were identified. Six POMC htSNPs (rs3754863 G>A, ss161151662 A>G, rs3754860 C>T, rs1009388 G>C, rs3769671 A>C, rs1042571 G>A) were identified. Allele and haplotype frequencies were similar between case and control groups (P>0.60 by permutation test), and assessment of allele transmission distortion from informative parents to affected offspring also failed to find any association. Stratification of these analyses for age-at-onset and HLA-DR risk group (DR3/DR4) revealed no significant associations. A haplotype block of 9.86-kb from rs3754863 to rs1042571 was identified, encompassing the POMC gene. Comparison of haplotype frequencies identified the GGCGAG haplotype as protective against T1D in 12.9% of cases vs. 18.3% of controls: χ(2)=8.18, Pc=0.03 by permutation test., Conclusion: The POMC SNP haplotype GGCGAG may have a protective effect against T1D in the UK population. However, this finding needs to be replicated, and the cellular and molecular processes influenced by this POMC haplotype determined to fully appreciate its impact., (Copyright © 2011. Published by Elsevier Masson SAS.)

Aims: Macrophage migration inhibitory factor (MIF) is a potent pro-inflammatory cytokine whose production is transcriptionally regulated by glucose. Experimental data from both Type 1 diabetes mellitus (T1D) patients and animal models suggests a role for MIF in the development of T1D. The aim of this study was to employ gene resequencing to identify common DNA polymorphisms in the MIF gene and subsequently assess haplotype tagged single nucleotide polymorphisms (htSNPs) using a combination of case-control and family-based association analyses in order to assess the association of MIF htSNPs with the development of T1D in a white population., Methods: All exons, introns and approximately 3 kb upstream and downstream of the MIF gene were screened for DNA polymorphisms in 46 individuals using DNA sequencing. Genotyping of the htSNPs was performed in 432 cases, 407 control subjects and 290 T1D parent-offspring trios, using Taqman, Sequenom, Pyrosequencing and fluorescence-based microsatellite technologies., Results: Twenty-three polymorphisms (two novel) with a minor allele frequency > 10% were identified. Four MIF htSNPs (rs875643 G>A, rs7388067 C>T, rs5844572 -/CATT, rs6003941 T>G) were identified. Allele and haplotype frequencies were similar between case and control groups (P > 0.6 by permutation test) and assessment of allele transmission distortion from informative parents to affected offspring also failed to find an association. Stratification of these analyses for age-at-onset and human leukocyte antigen (HLA)-DR risk group (DR3/DR4) did not reveal any significant associations., Conclusions: It is unlikely that common polymorphisms in the MIF gene strongly influence susceptibility to T1D in the UK population.

Heterozygous activating mutations in the KCNJ11 gene encoding the pore-forming Kir6.2 subunit of the pancreatic beta cell K(ATP) channel are the most common cause of permanent neonatal diabetes (PNDM). Patients with PNDM due to a heterozygous activating mutation in the ABCC8 gene encoding the SUR1 regulatory subunit of the K(ATP) channel have recently been reported. We studied a cohort of 59 patients with permanent diabetes who received a diagnosis before 6 mo of age and who did not have a KCNJ11 mutation. ABCC8 gene mutations were identified in 16 of 59 patients and included 8 patients with heterozygous de novo mutations. A recessive mode of inheritance was observed in eight patients with homozygous, mosaic, or compound heterozygous mutations. Functional studies of selected mutations showed a reduced response to ATP consistent with an activating mutation that results in reduced insulin secretion. A novel mutational mechanism was observed in which a heterozygous activating mutation resulted in PNDM only when a second, loss-of-function mutation was also present.

Aims/hypothesis: We investigated the association between the incidence of type 1 diabetes mellitus and remoteness (a proxy measure for exposure to infections) using recently developed techniques for statistical analysis of small-area data., Subjects, Materials and Methods: New cases in children aged 0 to 14 years in Northern Ireland were prospectively registered from 1989 to 2003. Ecological analysis was conducted using small geographical units (582 electoral wards) and area characteristics including remoteness, deprivation and child population density. Analysis was conducted using Poisson regression models and Bayesian hierarchical models to allow for spatially correlated risks that were potentially caused by unmeasured explanatory variables., Results: In Northern Ireland between 1989 and 2003, there were 1,433 new cases of type 1 diabetes, giving a directly standardised incidence rate of 24.7 per 100,000 person-years. Areas in the most remote fifth of all areas had a significantly (p=0.0006) higher incidence of type 1 diabetes mellitus (incidence rate ratio=1.27 [95% CI 1.07, 1.50]) than those in the most accessible fifth of all areas. There was also a higher incidence rate in areas that were less deprived (p<0.0001) and less densely populated (p=0.002). After adjustment for deprivation and additional adjustment for child population density the association between diabetes and remoteness remained significant (p=0.01 and p=0.03, respectively)., Conclusions/interpretation: In Northern Ireland, there is evidence that remote areas experience higher rates of type 1 diabetes mellitus. This could reflect a reduced or delayed exposure to infections, particularly early in life, in these areas.

Aims: To assess the care received, compared to national guidelines, and to investigate factors associated with glycaemic control in children and adolescents with type 1 diabetes attending clinics in Northern Ireland., Methods: An audit of the care provided to all patients attending 11 paediatric diabetes clinics commenced in 2002. A research nurse interviewed 914 patients completing a questionnaire recording characteristics, social circumstances, and aspects of diabetes management, including the monitoring of complications and access to members of the diabetes team. Glycaemic control was measured by glycosylated haemoglobin (HbA1c), determined at a DCCT aligned central laboratory., Results: The average HbA1c concentration was 8.8% (SD 1.5%), with 20% of patients achieving recommended HbA1c levels of less than 7.5%. In the year prior to the audit, 76% of patients were reviewed by a diabetes specialist nurse and 42% were tested for microalbuminuria. After adjustment for confounding factors, better glycaemic control was identified, particularly in patients who had attended exactly four diabetes clinics in the previous year, were members of the patient association Diabetes UK, and lived with both natural parents., Conclusions: In Northern Ireland only a minority of patients achieved recommended HbA1c levels. Furthermore, children and adolescents with diabetes were reviewed by fewer specialists and were less intensively monitored for microvascular complications than recommended. There was evidence of better control in children who were members of Diabetes UK, suggesting that parental attitude and involvement could lead to benefits.

Interleukin 18 (IL18) is a proinflammatory cytokine whose levels are increased in the subclinical stage of insulin-dependent (type I) diabetes mellitus. Previous case-control studies have reported associations between IL18 -607C>A and -137G>C promoter polymorphisms and type I diabetes. We performed case-control and family-based association studies employing Pyrosequencing to assess if these IL18 polymorphisms are also associated with the development of type I diabetes in the Northern Ireland population. The chi2 analysis of genotype and allele frequencies for the IL18 polymorphisms in cases (n=433) vs controls (n=426) revealed no significant differences (P>0.05). Assessment of allele transmission distortion from informative parents to affected offspring also failed to confirm previously reported associations. Stratification of these analyses for age-at-onset and HLA-DR type did not reveal any significance associations. In conclusion, our data do not support the strong positive associations of IL18 promoter polymorphisms with type I diabetes reported in previous smaller studies.

Objective: Limited joint mobility (LJM), one of the earliest clinically apparent long-term complications of type 1 diabetes, is a risk marker for subsequent microvascular complications. We hypothesize that the prevalence of LJM may have decreased during the past two decades due to improved standards of glycemic control., Research Design and Methods: A single observer performed a survey in 204 consecutive patients with type 1 diabetes (106 men and 98 women, age 27 +/- 1 years, HbA(1c) 8.3 +/- 0.1%, duration of diabetes 14.5 +/- 0.8 years, insulin dose 63 +/- 2 units/day). We used the same examination method and criteria for assessment of LJM as used by us in an earlier study in 1981-1982., Results: The prevalence of LJM has fallen from 43 to 23% between the 1980s and 2002 (P < 0.0001). The relative risk for LJM in 2002 compared with the 1981-1982 cohort was 0.53 (0.40 < RR < 0.72, P < 0.0001). The prevalence of LJM was increased with longer duration of diabetes (<10 years, 13%; 10-20 years, 19%; 20-29 years, 30%; >30 years, 65%; P < 0.001). The relative risk for those with a mean HbA(1c) <7% in 2002 was 0.3 (0.1 < RR < 1.2, P = 0.05) when compared with those with mean HbA(1c) >7%., Conclusions: The present study confirms the hypothesis that the prevalence of LJM is lower than 20 years ago and that improved standards of glycemic control and diabetes care may have contributed to this occurrence. Joint limitation in type 1 diabetes is strongly associated with duration of diabetes. The presence of LJM remains a common and important clinical marker for subsequent microvascular disease and can be a useful clinical tool for identification of patients at increased risk.

Aims: To investigate perinatal risk factors for childhood Type 1 diabetes in a UK population cohort., Methods: Perinatal data have been routinely recorded in Northern Ireland for all births in the period 1971-86 (n = 447 663). Diabetes status at the age of 15 years was ascertained in this cohort by identifying 991 children from 1079 registered with Type 1 diabetes diagnosed from 1971 to 2001 and date of birth in the period 1971-86., Results: Increased Type 1 diabetes risk was associated with higher maternal age, paternal age, birth weight and birth weight for gestational and lower gestational age. After adjustment for maternal age, the association between Type 1 diabetes and paternal age remained significant [relative risk (RR) = 1.52 (1.10, 2.09) comparing father's age 35 years or more to less than 25 years] but not vice versa [RR = 1.11 (0.80, 1.54) comparing mother's age 35 years or more to less than 25 years]. Increased birth order was associated with a significant decrease in the risk of Type 1 diabetes [adjusted RR = 0.75 (0.62, 0.90) comparing birth order three or more with firstborn], but this only became apparent when adjustment was made for maternal age. Furthermore this association with birth order was significant only for diabetes diagnosed under the age of 5 years., Conclusions: Our analysis demonstrates, for the first time in a UK regional cohort setting, that maternal age and paternal age at delivery, birth order, birth weight and gestational age are significantly associated with Type 1 diabetes risk.

The adenomatous polyposis coli (APC) tumor suppressor is a major regulator of the Wnt signaling pathway in normal intestinal epithelium. APC, in conjunction with AXIN and GSK-3beta, forms a complex necessary for the degradation of beta-catenin, thereby preventing beta-catenin/T-cell factor interaction and alteration of growth-controlling genes such as c-MYC and cyclin D1. Inappropriate activation of the Wnt pathway, via Apc/APC mutation, leads to gastrointestinal tumor formation in both the mouse and human. In order to discover novel genes that may contribute to tumor progression in the gastrointestinal tract, we used cDNA microarrays to identify 114 genes with altered levels of expression in Apc(Min) mouse adenomas from the duodenum, jejunum, and colon. Changes in the expression of 24 of these 114 genes were not observed during mouse development at embryonic day 16.5, postnatal day 1, or postnatal day 14 (relative to normal adult intestine). These 24 genes are not previously known Wnt targets. Seven genes were validated by real-time reverse transcription-PCR analysis, whereas four genes were validated by in situ hybridization to mouse adenomas. Real-time reverse transcription-PCR analysis of human colorectal cancer cell lines and adenocarcinomas revealed that altered expression levels were also observed for six of the genes Igfbp5, Lcn2, Ly6d, N4wbp4 (PMEPA1), S100c, and Sox4.

Mutation of the APC tumor suppressor gene is one of the earliest events in the development of most colorectal tumors. The APC gene encodes multiple protein isoforms through a complicated pattern of expression and alternative splicing. The role that each isoform plays in cellular physiology is unknown, although the presence of some of these isoforms in postmitotic cells suggests a role in controlling cell growth or promoting differentiation. Three APC isoforms that differ in their amino-terminal domains were evaluated by gene transfer experiments using a colon cancer cell line that lacks functional APC. All three isoforms alter cellular morphology and affect cell growth by elongating the G1 phase of the cell cycle. The conventional APC and brain-specific APC isoforms suppress the tumorigenic phenotype of cultured cells, while the 0.3 APC isoform does not. In support of these experiments, BrdU incorporation as a marker for S-phase entry occurs at a higher level in transiently transfected cells with 0.3 APC when compared to cells transfected with the other isoforms. All three APC isoforms colocalize with microtubules and dramatically reduce beta-catenin activity to the same extent in transiently transfected cancer cells, suggesting that the different effects of each isoform on tumorigenesis may be nontranscriptional in origin.

Aims: To determine whether routine outpatient monitoring of growth predicts adrenal suppression in prepubertal children treated with high dose inhaled glucocorticoid., Methods: Observational study of 35 prepubertal children (aged 4-10 years) treated with at least 1000 microg/day of inhaled budesonide or equivalent potency glucocorticoid for at least six months. Main outcome measures were: changes in HtSDS over 6 and 12 month periods preceding adrenal function testing, and increment and peak cortisol after stimulation by low dose tetracosactrin test. Adrenal suppression was defined as a peak cortisol < or =500 nmol/l., Results: The areas under the receiver operator characteristic curves for a decrease in HtSDS as a predictor of adrenal insufficiency 6 and 12 months prior to adrenal testing were 0.50 (SE 0.10) and 0.59 (SE 0.10). Prediction values of an HtSDS change of -0.5 for adrenal insufficiency at 12 months prior to testing were: sensitivity 13%, specificity 95%, and positive likelihood ratio of 2.4. Peak cortisol reached correlated poorly with change in HtSDS (rho = 0.23, p = 0.19 at 6 months; rho = 0.33, p = 0.06 at 12 months)., Conclusions: Monitoring growth does not enable prediction of which children treated with high dose inhaled glucocorticoids are at risk of potentially serious adrenal suppression. Both growth and adrenal function should be monitored in patients on high dose inhaled glucocorticoids. Further research is required to determine the optimal frequency of monitoring adrenal function.

HPLC methodology was investigated for the simultaneous determination of cisapride and ranitidine in small volume paediatric plasma samples. Such a simultaneous determination proved difficult due to the small sample volumes, the low concentrations of the drugs and the different log P values of the two compounds. The two drugs and their respective internal standards were separated "on-cartridge" using HLB Solid Phase Extraction cartridges and the samples quantified by individual HPLC methodologies. The technique has been applied successfully to 60 paediatric plasma samples containing both cisapride and ranitidine.

Aims: To examine derived indices of beta cell function, peripheral insulin sensitivity, and the pancreatic response to intravenous glucose loading in children with a previous history of transient neonatal diabetes currently in remission, repeated after a period of two or more years., Methods: The standard intravenous glucose tolerance test (IVGTT) was used to measure the first phase insulin response (FPIR) cumulatively at one and three minutes. In addition, fasting insulin and glucose values were used to estimate insulinogenic indices (beta cell function) and QUICKI (insulin sensitivity)., Patients: Six patients with known previous transient neonatal diabetes currently in remission with no exogenous insulin requirement were tested. Control data from 15 children of a similar age were available for derived fasting indices of beta cell functional capacity and insulin sensitivity., Results: One child had a subnormal insulin secretory response to intravenous glucose that remained abnormal two and four years later. The other children had relatively normal or entirely normal responses over two years. Measures of beta cell function and insulin sensitivity in the fasting state showed comparable results to those obtained from normal controls., Conclusions: Most children with transient neonatal diabetes in remission have no evidence of beta cell dysfunction or insulin resistance in the fasting state, although they might have been expected to show subtle defects given the tendency to relapse in adolescence. Measures of insulin response to intravenous glucose loading are often normal but suggest future recurrence if profoundly abnormal.

Intercellular adhesion molecule-1 (ICAM-1) functions via its ligands, the leucocyte integrins, in adhesion of immune cells to endothelial cells and in T cell activation. The third immunoglobulin-like extracellular domain binds integrin Mac-1 and contains a common non-conservative aminoacid polymorphism, G241R. Phenotypically, ICAM-1 has been associated with type 1 diabetes, a T-cell-mediated autoimmune disease. We assessed two independent datasets, and noted that R241 was associated with lower risk of type 1 diabetes than is G241 (3695 families, relative risk 0.91, p=0.03; 446 families, 0.60, p=0.006). Our data indicate an aetiological role for ICAM-1 in type 1 diabetes, which needs to be confirmed in future genetic and functional experiments.

Objective: To review the published literature and perform a meta-analysis summarizing the evidence in support of an inverse association between type 1 diabetes and the atopic disorders: asthma, eczema, and allergic rhinitis in children., Research Design and Methods: MEDLINE, Web of Science, and PubMed were searched to identify relevant studies. These were assessed on quality criteria, and odds ratios (ORs) and 95% CIs were calculated for each study from the reported prevalences of atopy in children with diabetes and in control children. Meta-analysis was then used to derive a combined OR and test for heterogeneity in findings between studies., Results: Twenty-five studies were identified. Heterogeneity in the findings from different studies was evident but was considerably reduced when the asthma and rhinitis analyses were restricted to those studies judged to be of adequate design. The meta-analysis revealed an inverse association between asthma and type 1 diabetes, but the finding only attained significance when analysis was restricted to the studies of adequate design (OR 0.82, 95% CI 0.68-0.99). In this subset an association of similar magnitude was observed between eczema and type 1 diabetes (0.82, 0.62-1.10) although this failed to attain statistical significance, and heterogeneity between studies was still present. There was little evidence of an association between rhinitis and type 1 diabetes (0.97, 0.82-1.16) in this subset of studies., Conclusions: Our analysis suggests that there is a small but significant reduction in the prevalence of asthma in children with type 1 diabetes, but the findings for the other atopic diseases are less conclusive.

Genes and mechanisms involved in common complex diseases, such as the autoimmune disorders that affect approximately 5% of the population, remain obscure. Here we identify polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4)--which encodes a vital negative regulatory molecule of the immune system--as candidates for primary determinants of risk of the common autoimmune disorders Graves' disease, autoimmune hypothyroidism and type 1 diabetes. In humans, disease susceptibility was mapped to a non-coding 6.1 kb 3' region of CTLA4, the common allelic variation of which was correlated with lower messenger RNA levels of the soluble alternative splice form of CTLA4. In the mouse model of type 1 diabetes, susceptibility was also associated with variation in CTLA-4 gene splicing with reduced production of a splice form encoding a molecule lacking the CD80/CD86 ligand-binding domain. Genetic mapping of variants conferring a small disease risk can identify pathways in complex disorders, as exemplified by our discovery of inherited, quantitative alterations of CTLA4 contributing to autoimmune tissue destruction.

A recent study employing Australian and UK type 1 diabetes families has demonstrated significant transmission bias to affected offspring of a polymorphism (1188A allele; termed allele 1) in the 3' untranslated region (3'UTR) of the interleukin 12B (IL12B) gene which encodes the IL-12p40 subunit of the pro-inflammatory cytokine IL-12. However, results from replication studies in other populations have been controversial. We performed both case-control (n=120 cases; n=330 controls) and family-based (n=307 families) association studies, using the transmission disequilibrium test, to investigate if allele 1 is associated with early-onset type 1 diabetes in Northern Ireland. No association was observed between allele 1 and type 1 diabetes in either case-control (80.8% vs 80.8%; P=0.98) or family-based (49.7% transmissions; P=0.94) studies. Our results do not support earlier reports of an association between allele 1 in the 3'UTR of the IL12B gene and type 1 diabetes.

Clinical evidence of cerebral oedema occurs in approximately 1% of diabetic ketoacidosis episodes. Mortality from this serious complication is falling, but little is known of long term outcome. We describe hypopituitarism and executive dysfunction developing two years after cerebral oedema complicating diabetic ketoacidosis in a 12 year old with type 1 diabetes.

Previous studies have established a critical role of both TFIIB and RNA polymerase II (RNAPII) in start site selection in the yeast Saccharomyces cerevisiae. However, it remains unclear how the TFIIB-RNAPII interaction impacts on this process since such an interaction can potentially influence both preinitiation complex (PIC) stability and conformation. In this study, we further investigate the role of TFIIB in start site selection by characterizing our newly generated TFIIB mutants, two of which exhibit a novel upstream shift of start sites in vivo. We took advantage of an artificial recruitment system in which an RNAPII holoenzyme component is covalently linked to a DNA-binding domain for more direct and stable recruitment. We show that TFIIB mutations can exert their effects on start site selection in such an artificial recruitment system even though it has a relaxed requirement for TFIIB. We further show that these TFIIB mutants have normal affinity for RNAPII and do not alter the promoter melting/scanning step. Finally, we show that overexpressing the genetically isolated TFIIB mutant E62K, which has a reduced affinity for RNAPII, can correct its start site selection defect. We discuss a model in which the TFIIB-RNAPII interaction controls the start site selection process by influencing the conformation of PIC prior to or during PIC assembly, as opposed to PIC stability.

High-dose inhaled corticosteroids, greater than 400 mcg per day of beclomethasone dipropionate or equivalent, can cause adrenal insufficiency, but a hypoglycemic crisis has not been reported with the use of nebulized corticosteroids. We describe a 21-month-old asthmatic boy who had a hypoglycemic seizure during a proven acute adrenal crisis secondary to high-dose nebulized budesonide treatment., (Copyright 2002 Wiley-Liss, Inc.)

All patients identified in the neonatal screening programme for congenital hypothyroidism in Northern Ireland between 1983 and 1993 were reviewed. 131 infants were recalled because of TSH elevation of whom 85 proved to have true permanent congenital hypothyroidism, while 44 had transient TSH elevation and 2 cases died before the diagnosis could be confirmed. TSH elevation at presentation was milder in the transient group and these infants were more likely to be unwell and/or suffering from congenital malformation.

A sensitive HPLC method for the determination of ranitidine in small-volume (0.5 mL) paediatric plasma samples is described. Plasma samples were extracted using a simple, rapid solid phase extraction (SPE) technique developed using disposable copolymer packed SPE cartridges. Chromatographic separation was achieved by reverse-phase HPLC with isocratic elution using a microBondapak C18 column and a phosphate buffer (10 mM, pH 3.75)-acetonitrile (87:13 v/v) mobile phase with UV detection at 313 nm. The HPLC system exhibited linearity in the range 8-800 ng mL(-1). Intraday % CV and % bias values were in the range 1.28-8.09% (% bias -4.33 to -0.87) and interday % CV and % bias values were in the range 0.73-15.28% (% bias -1.80 to + 1.65). The limits of detection and quantitation obtained were 2 ng mL(-1) and 8 ng mL(-1), respectively, and ranitidine extraction recoveries from plasma ranged from 92.30 to 103.88%. In this study, the developed HPLC and SPE methodologies have been successfully applied to the determination of ranitidine concentrations in 68 paediatric plasma samples. The sampled population was drawn from patients already receiving the study drug therapeutically. Patients recruited had received ranitidine by two main routes - oral and intravenous. The plasma concentrations of ranitidine encountered in paediatric samples following oral or intravenous administration of a range of prescribed doses are presented graphically. These profiles are based on analysis of the first 68 plasma samples obtained from the first 35 patients recruited to the study receiving ranitidine by the oral or intravenous route.

The extraction of diclofenac from spiked aqueous and plasma samples by liquid-liquid extraction (LLE) and solid phase extraction (SPE) methods is compared. The SPE methodology utilised a hydrophilic lipophilic balanced (HLB) copolymer as the extraction phase. Using a literature HPLC method, a calibration curve for diclofenac was constructed in the range 1.0-50.0 microg/ml. Diclofenac spiked samples (aqueous and plasma) were extracted by LLE and SPE methodologies. The SPE resulted in higher extraction efficiencies (mean 94.9%) than the LLE (mean 78.9%) with %R.S.D.s similar in both methods (3.2 vs. 2.1%, respectively). The SPE method was suitable for the extraction of diclofenac from small volume paediatric plasma samples.

The general transcription factor TFIIB is a key component in the eukaryotic RNA polymerase II (RNAPII) transcriptional machinery. We have previously shown that a yeast TFIIB mutant (called YR1m4) with four amino acid residues in a species-specific region changed to corresponding human residues affects the expression of genes activated by different activators in vivo. We report here that YR1m4 can interact with several affected activators in vitro. In addition, YR1m4 and other mutants with amino acid alterations within the same region can interact with TATA-binding protein (TBP) and RNAPII normally. However, YR1m4 is defective in supporting activator-independent transcription in assays con-ducted both in vitro and in vivo. We further demonstrate that the interaction between the C-terminal core domain and the N-terminal region is weakened in YR1m4 and other related TFIIB mutants. These results suggest that the intramolecular interaction property of yeast TFIIB plays an important role in transcription regulation in cells.

Background: Associations between genotype and intellectual outcome in patients with phenylketonuria are complicated because intelligence is influenced by many variables, including environmental factors and other genetic determinants. Intellectual changes with age, both on and after relaxation of diet, vary within the patient population. This study aims to determine whether a significant association exists between genotype and change in intelligence after relaxation of diet., Methods: 125 patients with hyperphenylalaninaemia and phenylketonuria whose diet was relaxed after 8 years of age. Verbal, performance, and full scale intelligence quotients at 8, 14, and 18 years were expressed as standard deviation scores (IQ-SDS), and genotype as predicted residual enzyme activity (PRA) of phenylalanine hydroxylase., Results: IQ-SDS at 8, 14, and 18 years were significantly below normal; no association was found between PRA and IQ-SDS. Significant reductions in verbal and full scale IQ-SDS occurred between 8 and 14 years and 8 and 18 years. There was a significant association between PRA and the reduction in verbal, performance, and full scale IQ between these years. Multiple regression analysis of 18 year results, using 8 year results as covariates, supported the association between PRA and IQ-SDS; after adjustment for phenylalanine control, both up to and after the age of 8 years, the full scale IQ-SDS at 14 and 18 years was 0.15 higher for each 10% increase in PRA., Conclusions: Genotype might be useful in predicting the likelihood of intellectual change in patients with hyperphenylalaninaemia and phenylketonuria whose diet is relaxed after the age of 8 years.

McCune-Albright syndrome consists of fibrous dysplasia of bone, café-au-lait skin pigmentation, and endocrine dysfunction (usually precocious puberty). Other endocrine abnormalities occur in a minority of patients, and of these, Cushing's syndrome is the least often recognized. We present 5 children (4 girls) with features of McCune-Albright syndrome who had Cushing's syndrome in the infantile period (<6 months). In 2 children spontaneous resolution occurred, but the remaining 3 required bilateral adrenalectomy. In addition, all 4 girls have experienced precocious puberty, and 3 children demonstrated radiologic evidence of nephrocalcinosis. Understanding of the underlying defect causing McCune-Albright syndrome emphasizes the importance of searching for other endocrine dysfunction in these children.

Aims: To examine active and passive tobacco smoke exposure in children and adolescents attending a diabetic clinic., Methods: Salivary cotinine concentrations were measured by gas chromatography and questionnaire data on the smoking habits of patients, families and friends were analysed as well as recording of glycosylated haemoglobin (HbA1c), body mass index (BMI) and social deprivation score., Results: Salivary cotinine concentrations identified 7% of the patients as active smokers and 72% as passive smokers. The mean cotinine concentration in those with no identifiable source of exposure was 0.10 (95% confidence interval 0.05-0.14) ng/ml, 2.81 (2.24-3.38) ng/ml in the passive smoking group and 1003.69 (55.96-151.41) ng/ml in the active smokers. Cotinine concentrations in passive smokers increased with the number of sources of exposure. The mean cotinine concentration was also higher when the mother was the sole source compared to other sources. There was no statistically significant correlation to smoking exposure and HbA1c BMI and deprivation scores., Conclusion: Tobacco smoke exposure may pose serious health risks to children and adolescents with diabetes and additional public health measures are required to reduce overall exposure.

Wolcott-Rallison syndrome is a rare autosomal recessive condition characterized by diabetes mellitus arising in early infancy and multiple epiphyseal dysplasia. To date, nine cases have been described in the world literature. We report an affected girl who died at the age of 4 years and on whom a full autopsy was performed. In addition to neonatal diabetes mellitus and epiphyseal dysplasia, this child had mental retardation and recurrent episodes of self-limiting hepatic failure. Autopsy revealed severe pancreatic hypoplasia and markedly abnormal pancreatic histology, while histology of the bone was consistent with epiphyseal dysplasia. There was laryngeal stenosis and pulmonary hypoplasia. The heart was enlarged with mitral value dysplasia and stenosis, left atrial dilatation, left ventricular hypertrophy, and endocardial fibroelastosis. Examination of the central nervous system showed arrhinencephaly and cerebellar cortical dysplasia. The liver showed minor histological abnormalities but no features were present to account for the recurrent hepatic failure. In addition to Wolcott-Rallison syndrome this child had a deletion at 15q11-12 in 65% of her cells.

A fatal case attributed to amlodipine intoxication is presented. The deceased was a 15-year-old girl who allegedly ingested 14 10-mg Istin tablets. Amlodipine concentration in peripheral blood was determined (2.7 mg/L) and was compared with published therapeutic and toxic data for amlodipine and some other dihydropyridine calcium channel-blocking agents. Amlodipine concentrations in liver, blood, and stomach contents were also determined.

Recent experiments in yeast (Saccharomyces cerevisiae) cells have identified a species-specific region of yeast transcription factor IIB (TFIIB) located at residues 144-157. According to the human TFIIB structure, this region is part of a solvent-exposed helix in the first repeat of the carboxyl-terminal core domain. In this report, we systematically analyze four positions in this region (Lys-147, Cys-149, Lys-151, and Glu-152) that together have been shown previously to be important for yeast TFIIB's function in vivo. Our experiments suggest that all of these four positions, and in particular positions 151, 149, and 152, are critical for yeast TFIIB's ability to support cell growth. In addition, we describe an intragenic suppressor screening experiment to identify mutations that reverse, or partially reverse, the temperature-sensitive phenotype of a yeast TFIIB derivative bearing amino acid changes at these four positions to human residues. The suppressor mutations reveal changes at positions 115, 117, and 182 that are located outside the species-specific region of yeast TFIIB, suggesting an extended surface available to interact with other proteins. Finally, we demonstrate that the suppressor mutations restore gene activation in vivo, further supporting the idea that one important function of yeast TFIIB in living cells is to mediate gene activation.