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Biomedical subjects

A Kelly

Publications and source records attributed to A Kelly.

At least 37 records · Page 2Linked to original sources
PubMed2001

Lack of symptom benefit following presumptive Helicobacter pylori eradication therapy in primary care.

BACKGROUND: Helicobacter pylori eradication regimens have failure rates under 10%, however little information is available on the effect of treatment success in reducing the subsequent prescription of anti-ulcer medications in primary care. AIMS: To determine, using a large prescription database in eastern Ireland, the success of presumptive eradication therapy in improving symptoms of dyspepsia in primary care, as judged by a reduction in the subsequent prescription of anti-ulcer medications. METHODS: In a cross-sectional study, we identified 3847 patients who received a prescription for eradication therapy for Helicobacter pylori, including 826 who were followed for 9-11 months. Those who subsequently received anti-ulcer medications were deemed failures to obtain symptom relief. RESULTS: For 3847 patients with a median follow-up of 8 months, the failure rate was 49%. Of 826 patients, followed for a longer period (9-11 months), the overall failure rate was 56% (range 44-62% depending on the eradication regimen used). Age over 65 years (hazard ratio=1.57, 95% confidence interval= 1.29-1.91, P < 0.001), prior use of anti-ulcer medications (hazard ratio=1.97, 95% confidence interval=1.63-2.37, P < 0.001) and prior use of aspirin/NSAIDs (hazard ratio=1.43, 95% confidence interval=1.18-1.73, P < 0.001) all predicted failure to obtain relief of symptoms of dyspepsia from eradication therapy. CONCLUSIONS: Such high failure rates of eradication therapy in reducing the subsequent consumption of anti-ulcer medications have both clinical and economic implications for the use of eradication therapy for Helicobacter pylori in primary care.

Adult↗
PubMed2001

Protein-sensitive and fasting hypoglycemia in children with the hyperinsulinism/hyperammonemia syndrome.

OBJECTIVE: Because the hyperinsulinism/hyperammonemia (HI/HA) syndrome is associated with gain of function mutations in the leucine-stimulated insulin secretion pathway, we examined whether protein feeding or fasting was responsible for hypoglycemia in affected patients. STUDY DESIGN: Patients with HI/HA (8 children and 6 adults) were studied. All had dominantly expressed mutations of glutamate dehydrogenase and plasma concentrations of ammonium that were 2 to 5 times normal. The responses to a 24-hour fasting test were determined in 7 patients. Responses to a 1.5 gm/kg oral protein tolerance test in 12 patients were compared with responses of 5 control subjects. RESULTS: The median age at onset of hypoglycemia in the 14 patients was 9 months; diagnosis was delayed beyond age 2 years in 6 patients, and 4 were not given a diagnosis until adulthood. Fasting tests revealed unequivocal evidence of hyperinsulinism in only 1 of 7 patients. Three did not develop hypoglycemia until 12 to 24 hours of fasting; however, all 7 demonstrated inappropriate glycemic responses to glucagon that were characteristic of hyperinsulinism. In response to oral protein, all 12 patients with HI/HA showed a fall in blood glucose compared with none of 5 control subjects. Insulin responses to protein loading were similar in the patients with HI/HA and control subjects. CONCLUSION: The postprandial blood glucose response to a protein meal is more sensitive than prolonged fasting for detecting hypoglycemia in the HI/HA syndrome.

Adolescent↗
PubMed2001

Hyponatremia and polyuria in children with central diabetes insipidus: challenges in diagnosis and management.

Five patients with well-controlled, long-standing, central diabetes insipidus had acute development of dehydration, hyponatremia, and inappropriate natriuresis in the setting of polyuria resistant to exogenous antidiuretic hormone. Hyponatremia and dehydration worsened with fluid restriction or use of exogenous antidiuretic hormone. We discuss the challenges in diagnosis and management of probable salt wasting in children with central diabetes insipidus.

Adolescent↗
PubMed2001

Acarbose treatment of postprandial hypoglycemia in children after Nissen fundoplication.

Dumping syndrome and postprandial hypoglycemia have been reported after Nissen fundoplication. The physiopathologic mechanisms are poorly understood and a variety of therapies have failed to control the hypoglycemia in these patients. We report a series of 6 infants with postprandial hypoglycemia after Nissen fundoplication who were treated successfully with acarbose.

Acarbose↗
PubMed2001

Response-time dynamics: evidence for linear and low-dimensional nonlinear structure in human choice sequences.

Response time (RT) is a commonly used measure of cognitive performance, which is usually characterized as stochastic. However, useful information may be hidden in the apparently random fluctuations of RT. Dynamical systems analysis techniques allow an exploration of the alternative hypothesis that RT fluctuations are deterministic, albeit in a complex manner. We applied careful task construction and noise-reduction and surrogate series tests to show that RT series from a forced-pace serial response-time task have low-dimensional chaotic characteristics. In Experiment 1, 80% of subjects' filtered RT series had low dimensionality, sensitive dependence on initial conditions, spectra close to 1/f, and stable attractor geometry across sessions. In Experiment 2, we showed that the size of the inter-stimulus interval (ISI) determined the number of subjects with low-dimensional chaotic series. A small ISI caused 100% of subjects to respond in the chaotic regime, whereas only 25% had a low-dimensional chaotic RT component when the ISI was large. We argue that demanding task requirements cause a reduction in the dimensionality of the dynamics, producing RT fluctuations that may reflect a response strategy for controlling RT.

Adult↗
PubMed2001

A pathological study of tumour regression in oesophageal adenocarcinoma treated with preoperative chemoradiotherapy.

AIMS: To measure residual tumour in oesophageal adenocarcinoma treated with preoperative chemoradiotherapy, to correlate specific pathological variables with survival, and to describe morphological changes in tumour and non-neoplastic tissue resulting from preoperative treatment. METHODS: Resection specimens from 47 cases of oesophageal adenocarcinoma treated with preoperative 5-fluorouracil/cisplatin and radiotherapy were reviewed. Residual tumour was assessed in terms of tumour regression grade (TRG), pTNM stage, lymphovascular space invasion, and resection margin involvement. Survival analysis was performed using the Kaplan-Meier method and log rank test. Cox's proportional hazard model was used for multivariate analysis. RESULTS: A complete pathological response (TRG1) was present in eight cases. The absence of residual tumour was confirmed by negative immunohistochemical staining for MNF116. Tumour corresponding to TRG2 was present in five cases, to TRG3 in nine, to TRG4 in 22, and to TRG5 in three. By multivariate analysis, pN0 status (n = 35) had a positive effect on survival (p = 0.04) and TRG had no significant effect on survival (p = 0.06). Patients with pN0 tumours had a median survival of 48 months versus eight months for those with pN1 tumours (log rank test, p < 0.0001). We found that giant fibroblasts were discernible from single large residual tumour cells on haematoxylin and eosin alone. CONCLUSION: Response to preoperative chemoradiotherapy in oesophageal adenocarcinoma is variable. Although there are as yet no reliable predictors of response to treatment, patients who are identified at diagnosis as having negative loco-regional lymph nodes should benefit considerably from this treatment approach.

Adenocarcinoma↗
PubMed2001

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↗
PubMed2001

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↗
PubMed2001

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↗
PubMed2001

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↗
PubMed2001

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↗
PubMed2001

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↗
PubMed2001

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↗
PubMed2000

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↗
PubMed2000

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↗