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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.)

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.

Aims: To investigate secular trends in the incidence of Type 1 diabetes in Northern Ireland over the period 1989-2003. To highlight geographical variations in the incidence of Type 1 diabetes by producing disease maps and to compare incidence rates by relevant area characteristics., Methods: New cases of Type 1 diabetes in children aged 0-14 years in Northern Ireland were prospectively registered from 1989 to 2003. Standardized incidence rates were calculated and secular trends investigated. Bayesian methodology was used to produce maps of disease incidence using small geographical areas (582 electoral wards). Ecological analyses were conducted using Poisson regression to investigate incidence rates by area characteristics at a finer geographical subdivision (5022 census output areas)., Results: In Northern Ireland during 1989-2003, there were 1433 new cases, giving a directly standardized incidence rate of 24.7 per 100,000 person-years. This incidence rate increased by a mean of 4.2% per annum. Disease maps highlighted higher incidence rates in the predominately rural north-east of the province and lower incidence rates in the urban areas around Belfast in the east and Derry in the north-west of the province. Ecological analysis identified higher incidence in rural areas (P < 0.001), areas with low migration rates (P = 0.002), affluent areas (P < 0.0001), sparsely populated areas (P = 0.0001) and remote areas (P = 0.005). CONCLUSIONS In Northern Ireland the incidence of Type 1 diabetes is increasing. The observed higher incidence in rural, affluent, sparsely populated and remote areas may reflect a reduced or delayed exposure to infections in these areas.

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.

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.

During the period 1989-1994, 462 cases of insulin-dependent diabetes mellitus were registered among children from Northern Ireland aged under 15 years. The estimated completeness of the register was 98.8% (95% confidence interval (CI) 97.7%, 99.9%). A standardised rate of 19.6 (95% CI 17.8, 21.4) per 100 000 person years was obtained, placing Northern Ireland near the top of the range of published incidence in the United Kingdom, with a rate close to that reported for Scotland. In an analysis based on 217 postcode sectors, areas with a high population density and the most material deprivation were observed to have the lowest incidence rates. After inclusion of population density in a Poisson regression analysis, the component of deprivation which was found to be most significant was household crowding. Relative to children living in areas of low population density, there was a reduced risk for children in medium (relative incidence 0.85 (95% confidence limits CI 0.67, 1.09)) and high (0.62 (95% CI 0.48,0.80)) population density areas. Similarly, relative to children living in areas with low levels of household crowding, there was a reduced risk for children in medium (relative incidence 0.73 (95% CI 0.58,0.93)) and high (0.67 (95% CI 0.53, 0.83)) levels of household crowding. Tests for space-time clustering at diagnosis and at birth were negative. A possible explanation for the differences in incidence rate observed in this study is that exposure to infections very early in childhood is a protective factor. Later infections may act as either initiators or promoters of diabetes, but the absence of space-time clustering suggests that no single specific infectious agent is responsible.

In the first phase of the Northern Ireland PKU Study, we used automated sequencing to identify the spectrum of mutations in a random group of 32 unrelated phenylketonuria (PKU) families. We also investigated 7 Northern Irish patients with mild hyperphenylalaninaemia not requiring dietary intervention (MHP, previously referred to as non-PKU HPA). Disease-causing mutations were identified on all 78 investigated chromosomes. We found 23 different mutations, including 20 missense, 1 nonsense and 2 splice site mutations. All mutations were located within exons or at intron-exon boundaries of the phenylalanine hydroxylase gene. Seven mutations occurred at CpG sites, confirming these sites as mutation hot-spots in PKU. Mutations R408W and I65T are the two commonest PKU mutations in the Northern Irish population. Two mutations (T380M and V245A) can be characterized as MHP mutations; they are quasi dominant markers for MHP since they cause mild hyperphenylalaninaemia even when occurring in conjunction with the most severe PKU mutations. The results have proven valuable for the development of a routine PKU mutation analysis system in Northern Ireland.

Objective: To identify perinatal risk factors for childhood insulin-dependent diabetes mellitus (IDDM) and determine if they differ between early-onset and late-onset disease., Research Design and Methods: We selected 258 diabetic children in Northern Ireland and 271 diabetic children in Scotland from population-based registers. For each diabetic child, five matched control subjects were drawn from the same population. All perinatal data were recorded routinely at birth. Odds ratios (ORs) were estimated for parental age, social class, breast-feeding, deprivation measures, and other perinatal variables., Results: Scottish data indicated an increased risk among children born to older mothers (OR = 2.43, 95% confidence interval [CI] 1.49-3.97 for mothers > or = 35 years of age relative to those < 25 years of age). Northern Ireland data showed no such effect. Only Northern Ireland data showed an excess risk in children of professional or managerial families (OR = 1.51, 95% CI 1.11-2.04). A small but nonsignificant reduction in risk among breast-fed children was observed only after adjustment for social class (OR = 0.76, 95% CI 0.54-1.07). Deprivation measures were associated with reductions in risk. Children delivered by cesarean section were at increased risk in both Northern Ireland (OR = 1.66, 95% CI 1.10-2.50) and Scottish (OR = 1.70, 95% CI 1.12-2.59) data. In Northern Ireland data only, children of first pregnancies were at increased risk (OR = 1.41, 95% CI 1.03-1.93). Both data sets indicated that a first pregnancy was a more important risk factor for early-onset disease than for late-onset disease., Conclusions: Many reported risk factors are weak and show inconsistencies between studies. They may be secondary to more direct, as-yet-undiscovered risk factors. Although irrelevant in the majority of cases, the increased risk associated with delivery by cesarean section deserves further study.

Paraquat, the most important of the bipyridyl group of herbicides, has proved a most effective weedkiller and is now in world-wide use. When used as intended, the compound is quite safe, but misuse has led to a significant number of deaths. If taken orally in significant amounts a fatal outcome is likely and there is as yet no effective antidote. Deaths from paraquat poisoning have been proportionately higher in Ireland than elsewhere. The present paper analyses 26 fatal and 7 non-fatal poisonings occurring in Northern Ireland during the period 1967-1975. The history, clinical features, length of survival and pathological findings are discussed. Extensive toxicological analyses have been performed on samples taken during life, and on a wide range of body fluids and tissues obtained at autopsy. These data are presented and show the progressive but slow fall-off in paraquat recovery after ingestion, with detectable levels still present for up to 21 days. The increasing incidence of suicidal, as opposed to accidental, paraquat poisoning is stressed. The decline in accidental poisoning suggests that the measures taken to prevent accidental ingestion are proving successful. The swing from accident to suicide is reflected in the shorter survival times, differing autopsy findings and significantly higher tissue and body fluid levels encountered in suicidal poisonings.

Data from 30 fatal cases of dextropropoxphene poisoning occurring in Northern Ireland over three years have been studied. All the victims had ingested more than therapeutic amounts, and many had also taken alcohol or other drugs. Most of the deaths were probably suicides. Death occurred very rapidly suggesting that the narcotic effects of dextropropoxyphene predominated, and this may explain the scarcity of clinical reports, It is suggested that many doctors are unaware of the danger of dextropropoxyphene in overdosage and that the problem of dextropropoxyphene poisoning in the United Kingdom has not been fully appreciated. This supposition, if correct, highlights the absence of a satisfactory early-warning system for serious drug effects including death.

In 1967 the first patient in Northern Ireland commenced growth hormone treatment for short stature. By the end of December 1988 a total of 89 patients had been treated. Thirty-two had idiopathic isolated growth hormone deficiency, an incidence of 1.5 new cases per year (in a population of 1.5 million with approximately 30,000 births per year). Since 1967 the mean age at starting treatment has fallen from 18 years to 10 years and the height standard deviation score has fallen from -4.7 +/- 0.6 to -3.4 +/- 0.3. The group with classical growth hormone deficiency (maximum GH less than 7 mU/l during insulin-induced hypoglycaemia) had a greater increase in height velocity over the first year of treatment, 3.8 +/- 0.4 cm, than those with a partial deficiency (maximum growth hormone 7.1 - 20 mU/l), 1.9 +/- 0.4 cm. All pre-pubertal children responded with a rise in the height velocity standard deviation score from -1.8 +/- 0.3 before treatment to +3.5 +/- 0.4 over the first year of treatment. 58% of the adult males and 25% of adult females have attained an adult height within the normal range (3rd centile or above). There have been three deaths, one each from Fanconi's aplastic anaemia which predated growth hormone treatment, an accidental fire injury and a relapsing craniopharyngioma. There have been no deaths from Creutzfeldt-Jakob disease. Growth hormone therapy is safe and effective, but continues to be commenced late in terms both of age and height standard deviation score.