Are cities becoming more unhealthy? An analysis of mortality rates in Belfast and Dublin between 1981 and 1991 to illustrate a methodological difficulty with ecological studies.
Explore the source record for details and available documents.
Humans↗
Biomedical subjects
A Kelly
Publications and source records attributed to A Kelly.
Hyperinsulinism/hyperammonemia syndrome in children with regulatory mutations in the inhibitory guanosine triphosphate-binding domain of glutamate dehydrogenase.
The hyperinsulinism/hyperammonemia (HI/HA) syndrome is a form of congenital hyperinsulinism in which affected children have recurrent symptomatic hypoglycemia together with asymptomatic, persistent elevations of plasma ammonium levels. We have shown that the disorder is caused by dominant mutations of the mitochondrial enzyme, glutamate dehydrogenase (GDH), that impair sensitivity to the allosteric inhibitor, GTP. In 65 HI/HA probands screened for GDH mutations, we identified 19 (29%) who had mutations in a new domain, encoded by exons 6 and 7. Six new mutations were found: Ser(217)Cys, Arg(221)Cys, Arg(265)Thr, Tyr(266)Cys, Arg(269)Cys, and Arg(269)HIS: In all five mutations tested, lymphoblast GDH showed reduced sensitivity to allosteric inhibition by GTP (IC(50), 60--250 vs. 20--50 nmol/L in normal subjects), consistent with a gain of enzyme function. Studies of ATP allosteric effects on GDH showed a triphasic response with a decrease in high affinity inhibition of enzyme activity in HI/HA lymphoblasts. All of the residues altered by exons 6 and 7 HI/HA mutations lie in the GTP-binding domain of the enzyme. These data confirm the importance of allosteric regulation of GDH as a control site for amino acid-stimulated insulin secretion and indicate that the GTP-binding site is essential for regulation of GDH activity by both GTP and ATP.
Enzyme Inhibitors↗
Premature adiposity rebound in children treated for acute lymphoblastic leukemia.
The adiposity rebound (AR), when body mass index begins to increase after its nadir in childhood, is a critical period for the regulation of energy balance and adult obesity risk. The aim of the present study was to test whether children treated for acute lymphoblastic leukemia (ALL) experience premature AR. This might, in part, explain their tendency to develop obesity. Timing of AR was assessed by visual inspection of body mass index plots in 68 patients treated for ALL in first remission. This sample comprised all eligible patients treated in Scotland between 1991 and 1998, age 30 months or less at the time of diagnosis. Timing of AR in patients was compared against a cohort of 889 healthy British children studied during the 1990s using the same method. AR occurred significantly earlier in the patients treated for ALL (chi(2) test, P < 0.001). The AR had occurred in 43% (29 of 68) of the patients and 4% (40 of 889) of the comparison group by age 37 months. At 49 months AR had occurred in 81% (55 of 68) of the patients and 21% (190 of 889) of the comparison group. Treatment of ALL is associated with a significantly advanced AR. This might, in part, explain the extremely high prevalence of obesity in long-term survivors. Clinical management should focus on minimizing excess weight gain during therapy to reduce long-term obesity risk.
Adipose Tissue↗
Acute insulin responses to leucine in children with the hyperinsulinism/hyperammonemia syndrome.
Mutations of glutamate dehydrogenase cause the hyperinsulinism/hyperammonemia syndrome by desensitizing glutamate dehydrogenase to allosteric inhibition by GTP. Normal allosteric activation of glutamate dehydrogenase by leucine is thus uninhibited, leading us to propose that children with hyperinsulinism/hyperammonemia syndrome will have exaggerated acute insulin responses to leucine in the postabsorptive state. As hyperglycemia increases beta-cell GTP, we also postulated that high glucose concentrations would extinguish abnormal responsiveness to leucine in hyperinsulinism/hyperammonemia syndrome patients. After an overnight fast, seven hyperinsulinism/hyperammonemia syndrome patients (aged 9 months to 29 yr) had acute insulin responses to leucine performed using an iv bolus of L-leucine (15 mg/kg) administered over 1 min and plasma insulin measurements obtained at -10, -5, 0, 1, 3, and 5 min. The acute insulin response to leucine was defined as the mean increase in insulin from baseline at 1 and 3 min after an iv leucine bolus. The hyperinsulinism/hyperammonemia syndrome group had excessively increased insulin responses to leucine (mean +/- SEM, 73 +/- 21 microIU/ml) compared with the control children and adults (n = 17) who had no response to leucine (1.9 +/- 2.7 microU/ml; P < 0.05). Four hyperinsulinism/hyperammonemia syndrome patients then had acute insulin responses to leucine repeated at hyperglycemia (blood glucose, 150-180 mg/dl). High blood glucose suppressed their abnormal baseline acute insulin responses to leucine of 180, 98, 47, and 28 microU/ml to 73, 0, 6, and 19 microU/ml, respectively. This suppression suggests that protein-induced hypoglycemia in hyperinsulinism/hyperammonemia syndrome patients may be prevented by carbohydrate loading before protein consumption.
Adolescent↗
Effect of glucocorticoid therapy on energy intake in children treated for acute lymphoblastic leukemia.
Despite a widespread belief that glucocorticoid therapy is associated with positive energy balance and excess weight gain there is a dearth of quantitative evidence about its effects and the underlying mechanisms of any effects. The primary aim of the present study was to quantify the effect of dexamethasone and prednisone treatment on energy intake in children treated for childhood acute lymphoblastic leukemia. A secondary aim was to test for differences in excess weight gain between patients treated using the 2 glucocorticoids. We measured energy intake in 26 patients (mean +/- SD age, 6.3 +/- 2.3 yr) during a 5-d period "on" steroids and again in the week before steroid treatment. Changes in body mass index from diagnosis to 1 and 2 yr postdiagnosis were expressed as SD scores. Steroid treatment was associated with a significant increase in energy intake of approximately 20% (mean paired difference, 1.7 MJ/d; SD, 2.8; 95% confidence interval, 0.7-2.8 MJ/d), with no significant difference between the 2 steroids. The mean change in body mass index SD score was +0.38 (SD, 1.10; P < 0.05) to 1 yr and +0.68 (SD, 1.38; P < 0.05) to 2 yr, with no significant difference between the 2 groups of patients. Glucocorticoid treatment in childhood acute lymphoblastic leukemia increases energy intake markedly, and this effect contributes to the excess weight gain and obesity characteristic of patients being treated for acute lymphoblastic leukemia.
Body Mass Index↗
Hormone selectivity in thyroid hormone receptors.
Separate genes encode thyroid hormone receptor subtypes TRalpha (NR1A1) and TRbeta (NR1A2). Products from each of these contribute to hormone action, but the subtypes differ in tissue distribution and physiological response. Compounds that discriminate between these subtypes in vivo may be useful in treating important medical problems such as obesity and hypercholesterolemia. We previously determined the crystal structure of the rat (r) TRalpha ligand-binding domain (LBD). In the present study, we determined the crystal structure of the rTRalpha LBD in a complex with an additional ligand, Triac (3,5, 3'-triiodothyroacetic acid), and two crystal structures of the human (h) TRbeta receptor LBD in a complex with either Triac or a TRbeta-selective compound, GC-1 [3,5-dimethyl-4-(4'-hydroy-3'-isopropylbenzyl)-phenoxy acetic acid]. The rTRalpha and hTRbeta LBDs show close structural similarity. However, the hTRbeta structures extend into the DNA-binding domain and allow definition of a structural "hinge" region of only three amino acids. The two TR subtypes differ in the loop between helices 1 and 3, which could affect both ligand recognition and the effects of ligand in binding coactivators and corepressors. The two subtypes also differ in a single amino acid residue in the hormone-binding pocket, Asn (TRbeta) for Ser (TRalpha). Studies here with TRs in which the subtype-specific residue is exchanged suggest that most of the selectivity in binding derives from this amino acid difference. The flexibility of the polar region in the TRbeta receptor, combined with differential recognition of the chemical group at the 1-carbon position, seems to stabilize the complex with GC-1 and contribute to its beta-selectivity. These results suggest a strategy for development of subtype-specific compounds involving modifications of the ligand at the 1-position.
Acetates↗
Dysregulation of insulin secretion in children with congenital hyperinsulinism due to sulfonylurea receptor mutations.
Mutations in the high-affinity sulfonylurea receptor (SUR)-1 cause one of the severe recessively inherited diffuse forms of congenital hyperinsulinism or, when associated with loss of heterozygosity, focal adenomatosis. We hypothesized that SUR1 mutations would render the beta-cell insensitive to sulfonylureas and to glucose. Stimulated insulin responses were compared among eight patients with diffuse hyperinsulinism (two mutations), six carrier parents, and ten normal adults. In the patients with diffuse hyperinsulinism, the acute insulin response to intravenous tolbutamide was absent and did not overlap with the responses seen in either adult group. There was positive, albeit significantly blunted, acute insulin response to intravenous dextrose in the patients with diffuse hyperinsulinism. Graded infusions of glucose, to raise and then lower plasma glucose concentrations over 4 h, caused similar rises in blood glucose but lower peak insulin levels in the hyperinsulinemic patients. Loss of acute insulin response to tolbutamide can identify children with diffuse SUR1 defects. The greater response to glucose than to tolbutamide indicates that ATP-sensitive potassium (KATP) channel-independent pathways are involved in glucose-mediated insulin release in patients with diffuse SUR1 defects. The diminished glucose responsiveness suggests that SUR1 mutations and lack of KATP channel activity may contribute to the late development of diabetes in patients with hyperinsulinism independently of subtotal pancreatectomy.
ATP-Binding Cassette Transporters↗
What drugs are our frail elderly patients taking? Do drugs they take or fail to take put them at increased risk of interactions and inappropriate medication use?
OBJECTIVE: To determine whether there were discrepancies between what medications frail elderly outpatients took and what physicians thought they took and whether discrepancies put patients at risk of taking inappropriate drugs and of increasing the potential for drug interactions. DESIGN: Case series. SETTING: Day Hospital Program at St Mary's of the Lake Hospital in Kingston, Ont. PARTICIPANTS: One hundred twenty community-living elderly patients attending the Day Hospital Program in 1998. Three patients and two family physicians declined to participate. MAIN OUTCOME MEASURES: Lists of medications being taken by patients compared with lists of medications in physicians' charts. Category according to explicit criteria that each drug fell into and risk of drug interactions as determined by the Clinidata Drug Interaction Program. RESULTS: Of the 120 patients, 115 had at least one discrepancy between their lists of medications and their physicians' lists. Of the 1390 medications on the lists, 521 (37%) were being taken by patients without their doctors' knowledge, 82 (6%) were not being taken by patients when doctors thought they were, and 133 (10%) were on both patients' and their doctors' lists but with dosages or frequency of administration that were different. More potential drug interactions were identified on patients' lists than on physicians' lists. No increase in risk of inappropriate drug use was identified. CONCLUSION: Family physicians are often unaware of all the medications their patients are actually taking. Medications used by patients without physicians' knowledge increase the likelihood of drug interactions. Family physicians should look at and inquire about all medications, including over-the-counter drugs, their patients are actually taking.
Aged↗
Changes in rainfall chemistry and airborne particulates during a period of major local industrial change.
Data from a site in central Scotland were used to quantify the changes in rainfall quality from 1989 to 1998. During this period there have been major changes in industrial activities in the area, particularly the decline in local steel-making and steel-processing activities. Many element concentrations in rainfall decreased over time in parallel with the phased reduction in the activity of local pollutant sources. Trend analyses of the rainfall data identified that the most significant responses have been the lower concentrations of Ca, SO4-S and Mn. There was also a dramatic decline in the capture of airborne particulates by the interception rainfall gauges. Particulates were found to contain mainly hematite, magnetite and quartz, that is similar to what would be expected to be derived from the neighbouring steel industries. The eventual disappearance of these particulates and the responses in rainfall quality match the timescale for the decline and closure of some of the potential sources of pollutants.
Air Pollutants↗
Identification and characterization of a beta proteasome subunit cluster in the Japanese pufferfish (Fugu rubripes).
The low molecular mass polypeptide (LMP2, LMP7, and MECL-1) genes code for beta-type subunits of the proteasome, a multimeric complex that degrades proteins into peptides as part of the MHC class I-mediated Ag-presenting pathway. These gene products are up-regulated in response to infection by IFN-gamma and replace the corresponding constitutively expressed subunits (X, Y, and Z) during the immune response. In humans, the LMP2 and LMP7 genes both reside within the class II region of the MHC (6p21.3), while MECL-1 is located at 16q22.1. In the present study, we have identified all three IFN-gamma-regulated beta-type proteasome subunits in Fugu, which are present as a cluster within the Fugu MHC class I region. We show that in this species, LMP7, LMP2, and MECL-1 are linked. Also within this cluster is an LMP2-like subunit (which seems specific to all teleosts tested to date) and a closely linked LMP7 pseudogene, indicating that within Fugu and potentially other teleosts, there has been an additional regional duplication involving these genes.
Animals↗
Association between SSRIs and upper gastrointestinal bleeding. Coprescription of antiulcer drugs with SSRIs is fairly common.
Explore the source record for details and available documents.
Anti-Ulcer Agents↗
Long-term potentiation in dentate gyrus of the rat is inhibited by the phosphoinositide 3-kinase inhibitor, wortmannin.
The pivotal role of inositol phospholipids in cell signalling has been placed centre-stage again with the recognition that phosphoinositide (PI) 3-kinase is implicated in several cellular processes. Stimulation of PI-3 kinase requires activation of the 85 kD regulatory subunit which relies on tyrosine phosphorylation, one consequence of which is activation of the 110 kD catalytic subunit. In this study, we have investigated the role of PI 3-kinase in the expression of long-term potentiation (LTP) in perforant path-granule cell synapses of the rat. We report that intracerebroventricular injection of wortmannin inhibited expression of LTP, though it did not affect the early change in the synaptic response. Activation of PI 3-kinase was enhanced in tetanized tissue prepared from dentate gyrus, compared with untetanized tissue, but this effect was inhibited in tissue prepared from wortmannin-pretreated rats. LTP was associated with increased glutamate release, as previously described, but this effect was also inhibited in tissue prepared from wortmannin-pretreated rats. The results presented demonstrate that wortmannin also exerted an inhibitory effect on KCl-stimulated glutamate release and calcium influx in hippocampal synaptosomes in vitro. The evidence presented is consistent with the hypothesis that PI 3-kinase activation, possibly by NGF, plays a role in expression of LTP in dentate gyrus.
Androstadienes↗
Protein synthesis in entorhinal cortex and long-term potentiation in dentate gyrus.
Despite the concentration of effort in recent years, the mechanisms underlying the expression of long-term potentiation (LTP) in the hippocampus remain elusive, but amidst the uncertainty and sometimes controversy, one consistent finding is emerging; this is that late-phase LTP requires synthesis of proteins. This hypothesis was first proposed by a number of groups who reported that the more persistent components of LTP were blocked by protein synthesis inhibitors, and was supported by a significant literature which indicated that morphological changes accompanied LTP. Recent evidence indicated that the increase in protein synthesis may be cAMP-dependent and that subsequent activation of the transcription factor, CREB, represented one step in the cascade of events leading to protein synthesis. Whether protein synthesis occurs in presynaptic or postsynaptic neurons, or both, is still a subject of debate. Here we present evidence which suggests that LTP in perforant path-granule cell synapses is accompanied by protein synthesis, specifically synthesis of synaptic vesicle proteins, in the entorhinal cortex. We also show that protein synthesis is decreased in the entorhinal cortex of aged rats and a strain of rat which is genetically hypertensive, both of which exhibited impaired LTP. We propose that that the observed increase in protein synthesis in the entorhinal cortex, which accompanied LTP in the dentate gyrus, contributes to the reported changes in morphology in the presynaptic terminal.
Aging↗
Typical Friedreich's ataxia without GAA expansions and GAA expansion without typical Friedreich's ataxia.
We clinically assessed and performed polymerase chain reaction analysis for the GAA trinucleotide repeat expansion in 103 patients from 73 families in Ireland, with a prior clinical diagnosis of Friedreich's ataxia (FA) or an unclassified progressive ataxic syndrome. The patients were classified as "typical" or "atypical" FA according to Harding's mandatory clinical diagnostic criteria. All patients underwent blood glucose analysis, and electrocardiography and echocardiography was performed in 99 and 101 patients, respectively. Mutation screening for expanded CAG trinucleotide repeats, associated with spinocerebellar ataxia (SCA) 1, 2, 3 and 6 was performed in 86 patients overall, including all GAA negative patients. Forty-nine of 56 typical patients and 13 of 47 atypical patients were either homozygous or heterozygous for the GAA expansion. Seven patients with a typical FA phenotype were negative for the GAA expansion. Although one of these patients had vitamin E deficiency, and two had raised alpha-fetoprotein levels, three other GAA negative patients with a typical FA phenotype had no other identifiable cause for their ataxia, once again raising the possibility of locus heterogeneity in FA. It is also possible that these patients have two point mutations in the X25 gene, or that they have another ataxic syndrome mimicking the FA phenotype. Two families who were homozygous for the GAA expansion exhibited intrafamilial phenotypic variability. Only one GAA negative patient had the SCA 3 mutation, and this was the only patient in the study with a possible autosomal dominant inheritance pattern. In the homozygous GAA population typical patients had significantly more repeats on the smaller allele than atypical patients, and there was an inverse relationship between the number of repeats on the smaller allele and the age at presentation. There was also an inverse relationship between the repeat size on both the larger and the smaller of the two alleles and the age at becoming wheelchair bound. There was no significant relationship between repeat size and the other indices of disease severity, including the presence or absence of diabetes or cardiomyopathy. This is the first large study of an Irish population with progressive ataxia that has shown a similar phenotype/genotype relationship to studies of FA in other European and non-European populations. The relatively low sensitivity and specificity of Harding's clinical diagnostic criteria must be appreciated when clinically assessing patients with a progressive ataxic syndrome. Although molecular genetic analysis now plays an essential role in diagnosis and classification, patients with a typical FA phenotype without any identifiable cause for their ataxia exist.
Adolescent↗
Deficits in nerve growth factor release and tyrosine receptor kinase phosphorylation are associated with age-related impairment in long-term potentiation in the dentate gyrus.
Previous findings have indicated that nerve growth factor may play a role in the expression of long-term potentiation in perforant path-granule cell synapses and that nerve growth factor treatment restores the ability of aged rats to sustain long-term potentiation. In this study, we have attempted to analyse the changes which occur in nerve growth factor release and tyrosine receptor kinase phosphorylation following tetanization in tissue prepared from dentate gyrus of young rats, as well as aged rats which did or did not sustain long-term potentiation. We report that KCl-stimulated nerve growth factor release was significantly increased in slices of the dentate gyrus or whole hippocampus, but not in synaptosomes prepared from the dentate gyrus. KCl-induced nerve growth factor release was also significantly enhanced in slices prepared from tetanized, compared with untetanized, tissue obtained from young rats and aged rats which sustained long-term potentiation; this response was absent in tissue prepared from aged rats which failed to sustain long-term potentiation, perhaps due to the enhanced basal nerve growth factor release observed in this tissue. Tetanization increased tyrosine receptor kinase phosphorylation in the dentate gyrus of young rats and aged rats which sustained long-term potentiation. In parallel with the changes in nerve growth factor release, tyrosine receptor kinase phosphorylation was markedly increased in untetanized tissue, which may contribute to the lack of effect in tetanized tissue prepared from aged rats which failed to sustain long-term potentiation. We observed that nerve growth factor concentration and tyrosine receptor kinase expression were decreased in aged, compared with young, rats. The data suggest that deficits in nerve growth factor release and subsequent signalling may contribute to age-related deficits in long-term potentiation.
Aging↗
Randomized comparison of unfractionated heparin with corticosteroids in severe active inflammatory bowel disease.
BACKGROUND: Heparin therapy may be effective in steroid resistant inflammatory bowel disease. AIM: A randomized pilot study, to compare unfractionated heparin as a first-line therapy with corticosteroids in colonic inflammatory bowel disease. METHODS: Twenty patients with severe inflammatory bowel disease (ulcerative colitis, n=17; Crohn's colitis, n=3) were randomized to either intravenous heparin for 5 days, followed by subcutaneous heparin for 5 weeks (n=8), or high-dose intravenous hydrocortisone for 5 days followed by oral prednisolone 40 mg daily, reducing by 5 mg per day each week (n=12). After 5 days, non-responders in each treatment group were commenced on combination therapy. Response to therapy was monitored by: clinical disease activity (ulcerative colitis: Truelove and Witt Index; Crohn's colitis: Harvey and Bradshaw Index), stool frequency, serum C-reactive protein and alpha1 acid glycoprotein, endoscopic and histopathological grading. RESULTS: The response rates were similar in both treatment groups: clinical activity index (heparin vs. steroid; 75% vs. 67%; P=0.23), stool frequency (75% vs. 67%; P=0.61), endoscopic (75% vs. 67%; P=0.4) and histopathological grading (63% vs. 50%; P=0.67). Both treatments were well-tolerated with no serious adverse events. CONCLUSION: Heparin as a first line therapy is as effective as corticosteroids in the treatment of colonic inflammatory bowel disease. Large multicentre randomized comparative studies are required to determine the role of heparin in the management of inflammatory bowel disease.
Administration, Oral↗
Drug interactions avoided-a useful indicator of good prescribing practice.
AIMS: To develop an index of quality prescribing in general practice by investigating the incidence of potential drug interactions when medicines were coprescribed within the State supported General Medical Services (GMS) in Ireland. METHODS: We determined an odds ratio (OR), as a measure of the relative risk of being exposed to a potential interaction, comparing the use of the H2-receptor antagonist, cimetidine, with that of the noninteracting agents ranitidine, famotidine and nizatidine in users and nonusers of warfarin, phenytoin and theophylline. RESULTS AND CONCLUSIONS: In 86 510 prescriptions for the H2-receptor antagonists potentially interacting drugs were dispensed to 8188 (9%) patients in the Eastern Health Board Region of the GMS. We found that prescribers were significantly less likely to use cimetidine (OR = 0.20,95% CI 0. 17-0.21, P < 0.001) in those patients who were coprescribed warfarin, suggesting good prescribing practice within the GMS. Similarly there was preferential use of the noninteracting H2-receptor antagonists in patients receiving phenytoin or theophylline and the extent of this selective prescribing was in keeping with the rank order of severity of interaction with these drugs. This novel pharmacological index may be a sensitive marker of good prescribing practice.
Anticoagulants↗