William F. Kelly

Diabetes prevalence and socioeconomic status: a population based study showing increased prevalence of type 2 diabetes mellitus in deprived areas

OBJECTIVE To establish the relation between socioeconomic status and the age-sex specific prevalence of type 1 and type 2 diabetes mellitus. The hypothesis was that prevalence of type 2 diabetes would be inversely related to socioeconomic status but there would be no association with the prevalence of type 1 diabetes and socioeconomic status. SETTING Middlesbrough and East Cleveland, United Kingdom, district population 287 157. PATIENTS 4313 persons with diabetes identified from primary care and hospital records. RESULTS The overall age adjusted prevalence was 15.60 per 1000 population. There was a significant trend between the prevalence of type 2 diabetes and quintile of deprivation score in men and women (χ2 for linear trend, p<0.001). In men the prevalence in the least deprived quintile was 13.4 per 1000 (95% confidence intervals (95% CI) 11.44, 15.36) compared with 17.22 per 1000 (95% CI 15.51, 18.92) in the most deprived. For women the prevalence was 10.84 per 1000 (95% CI 9.00, 12.69) compared with 15.48 per 1000 (95% CI 13.84, 17.11) in the most deprived. The increased prevalence of diabetes in the most deprived areas was accounted for by increased prevalence of type 2 diabetes in the age band 40–69 years. There was no association between the prevalence of type 1 diabetes and socioeconomic status. CONCLUSION These data confirm an inverse association between socioeconomic status and the prevalence of type 2 diabetes in the middle years of life. This finding suggests that exposure to factors that are implicated in the causation of diabetes is more common in deprived areas.

Excess mortality in a population with diabetes and the impact of material deprivation: longitudinal, population based study

Abstract Objectives: To establish the age and sex specific mortality for people with diabetes in comparison with local and national background populations; to investigate the relationship between mortality and material deprivation in an unselected population with diabetes. Design: Longitudinal study, using a population based district diabetes register. Setting: South Tees, United Kingdom. Participants: All people known to have diabetes living in Middlesbrough and Redcar and Cleveland local authorities on 1 January 1994. Main outcome measure: Death, from any cause, between 1 January 1994 and 31 December 1999. Results: Over the six years of the study 1205 (24.9%) of 4842 participants died. All cause standardised mortality ratios for type 1 diabetes were 641 (95% confidence interval 406 to 962) in women and 294 (200 to 418) in men, and those for type 2 diabetes were 160 (147 to 174) in women and 141 (130 to 152) in men. Cause specific standardised mortality ratios were increased for ischaemic heart disease, cerebrovascular disease, and renal disease; no reductions in mortality from other causes were seen. The risk of premature death increased significantly with increasing material deprivation (P<0.001). Conclusions: Diabetes is associated with excess mortality, even in an area with high background death rates from cardiovascular disease. This excess mortality is evident in all age groups, most pronounced in young people with type 1 diabetes, and exacerbated by material deprivation. Aggressive approaches to the management of cardiovascular risk factors could reduce the excess mortality in people with diabetes. What is already known on this topic Mortality, mainly from cardiovascular disease, is increased in people with diabetes, but this excess varies considerably by country and ethnic group Previous British studies have reported no excess mortality in old age, a reduction in deaths from non-cardiovascular causes, and that mortality may be adversely affected by deprivation What this study adds Mortality is increased, across all ages, in an unselected population with diabetes compared with the local population without diabetes, which itself has high mortality Most of the excess is from cardiovascular causes, but there are no reductions in other causes of death Mortality among people with diabetes is increased even in the most affluent group, and this excess increases with worsening material deprivation

Pituitary Apoplexy: A Review of Clinical Presentation, Management and Outcome in 45 Cases

Objective: To review clinical presentation, management and outcomes following different therapies in patients with pituitary apoplexy. Methods: Retrospective analysis of case-records of patients with classical pituitary apoplexy treated in our hospitals between 1983–2004. Results: Forty-five patients (28 men; mean age 49 years, range 16–72 years) were identified. Only 8 (18%) were known to have pituitary adenomas at presentation. Thirty-four (81%) patients had hypopituitarism at presentation. CT and MRI identified pituitary apoplexy in 28% and 91% cases, respectively. Twenty-seven (60%) patients underwent surgical decompression, whilst 18 (40%) were managed conservatively. Median time from presentation to surgery was 6 days (range 1–121 days). Patients with visual field defects were more likely than those without these signs to be managed surgically (p = 0.01). Complete or near-complete resolution occurred in 93% (13/14), 94% (15/16) and 93% (13/14) of the surgically treated patients with reduced visual acuity, visual field deficit and ocular palsy, respectively. All patients with reduced visual acuity (4/4), visual field deficit (4/4) and ocular palsy (8/8) in the conservative group had complete or near-complete recovery. Only 5 (19%) patients in the surgical group and 2 (11%) in the conservative group had normal pituitary function at follow up. One (4%) patient in the surgical group and 4 (22%) in the conservative group had a recurrence of pituitary adenoma. Conclusions: This large series suggests that the patients with classical pituitary apoplexy, who are without neuro-ophthalmic signs or exhibit mild and non-progressive signs, can be managed conservatively in the acute stage.

Diabetes- and Nondiabetes-Related Lower Extremity Amputation Incidence Before and After the Introduction of Better Organized Diabetes Foot Care: Continuous longitudinal monitoring using a standard method

OBJECTIVE—There is a lack of continuous longitudinal population-based data on lower extremity amputation (LEA) in the U.K. We present here accurate data on trends in diabetes-related (DR) LEAs and non-DRLEAs in the South Tees area over a continuous 5-year period. RESEARCH DESIGN AND METHODS—All cases of LEA from 1 July 1995 to 30 June 2000 within the area were identified. Estimated ascertainment using capture-recapture analysis approached 100% for LEAs in the area. Data were collected longitudinally using the standard method of the Global Lower Extremity Amputation Study protocol. RESULTS—Over 5 years there were 454 LEAs (66.3% men) in the South Tees area, of which 223 were diabetes related (49.1%). Among individuals with diabetes, LEA rates went from 564.3 in the first year to 176.0 of 100,000 persons with diabetes in the fifth year. Over the same period, non-DRLEAs increased from 12.3 to 22.8 of 100,000 persons without diabetes. The relative risk of a person with diabetes undergoing an LEA went from being 46 times that of a person without diabetes to 7.7 at the end of the 5 years. The biggest improvement in LEA incidence was seen in the reduction of repeat major DRLEAs. CONCLUSIONS—Our data show that in the South Tees area at a time when major non-DRLEA rates increased, major DRLEA rates have fallen. These diverging trends mark a significant improvement in care for patients with diabetic foot disease as a result of better organized diabetes care.

Gsα and Gi2α mutations in clinically non-functioning pituitary tumours

BACKGROUND AND OBJECTIVE Activating mutations of Gsα (gsp) and Gi2α (gip) have been described in various endocrine neoplastic conditions. The objective of this study was to assess the prevalence of gsp and gip mutations in clinically non‐functioning pituitary tumours (NFTs) and to compare the clinical phenotypic characteristics of tumours bearing G protein gene mutations with wild‐type tumours.

A prospective study of psychiatric and psychological aspects of Cushing's syndrome

OBJECTIVE Cushings syndrome is associated with psychiatric and psychological disturbances. The aim of this study was to ascertain the extent of mental illness in patients before and after treatment for Cushings syndrome.

Sexual dimorphism in 11 β hydroxysteroid dehydrogenase activity and its relation to fat distribution and insulin sensitivity; a study in hypopituitary subjects

Sexual dimorphism of 11 β hydroxysteroid dehydrogenase activity (11 β HSD) as measured by the urinary 11‐OH/11‐oxo cortisol metabolite ratio has been documented in healthy subjects. Since body composition, fat distribution and insulin sensitivity vary between the sexes we have investigated whether these factors may account for the observed difference. Studies were performed in ACTH deficient hypopituitary subjects to eliminate the effect of feedback modulation of cortisol secretion.

Evidence for a New Graves Disease Susceptibility Locus at Chromosome 18q21

Graves disease (GD) is a common autoimmune thyroid disorder that is inherited as a complex multigenic trait. By using a single microsatellite marker at each locus, we screened the type 1 diabetes loci IDDM4, IDDM5, IDDM6, IDDM8, and IDDM10 and the fucosyltransferase-2 locus for linkage in sib pairs with GD. This showed a two-point nonparametric linkage (NPL) score of 1.57 (P=.06) at the IDDM6 marker D18S41, but NPL scores were <1.0 at the other five loci. Thus, the investigation of the IDDM6 locus was extended by genotyping 11 microsatellite markers spanning 48 cM across chromosome 18q12-q22 in 81 sib pairs affected with autoimmune thyroid disease (AITD). Multipoint analysis, designating all AITD sib pairs as affected, showed a peak NPL score of 3.46 (P=.0003), at the marker D18S487. Designation of only GD cases as affected (74 sib pairs) showed a peak NPL score of 3.09 (P=.001). Linkage to this region has been demonstrated in type 1 diabetes (IDDM6), rheumatoid arthritis, and systemic lupus erythematosus, which suggests that this locus may have a role in several forms of autoimmunity.

Further Evidence for a Susceptibility Locus on Chromosome 20q13.11 in Families with Dominant Transmission of Graves Disease

To the Editor: The susceptibility loci for Graves disease (GD [MIM 275000]), which is a common complex trait (Brix et al. 1998), have been difficult to define (Roman et al. 1992; McLachlan 1993; Davies 1998; Farid 1998; Vaidya et al. 1999). Tomer et al. (1998) recently found evidence for linkage of GD to markers on the long arm of chromosome 20 (MIM 603388), with a peak multipoint LOD score of 3.5 at the marker D20S195. Their linkage analysis was performed by both parametric and nonparametric methods, and their cohort of 53 families with at least two first-degree relatives affected with autoimmune thyroid disease (AITD) was derived from the North American, Italian, Israeli, and British populations (Tomer et al. 1998). We have examined this chromosomal region in a homogeneous cohort of 71 affected GD sib pairs derived from 64 multiplex British GD kindreds (146 subjects with GD, 20 with autoimmune hypothyroidism [MIM 140300], and 72 unaffected). In six families, an additional sibling had autoimmune hypothyroidism, resulting in a total of 77 affected sib pairs with AITD (i.e., either GD or autoimmune hypothyroidism) (table 1). Parents (n=49) and unaffected sibs (n=36) were studied wherever available. All subjects were white, and >95% of the grandparents were from the mainland United Kingdom or were of Irish origin. The clinical definitions of GD and autoimmune hypothyroidism were identical to those described elsewhere (Tomer et al. 1998). Fifty-four (37%) of the patients with GD had significant thyroid-associated orbitopathy (class 3 or worse) (Werner 1977). Background allele frequencies were derived from typing of DNA obtained from local subjects without evidence of autoimmune disease. Nonparametric, parametric, and exclusion-mapping analyses were performed with the use of the GENEHUNTER package, version 2.0 (Kruglyak et al. 1996). For parametric analyses, a population frequency of 1% for GD was assumed, with a nonsusceptibility-genotype penetrance of .005, and allele frequencies were varied, according to Hardy-Weinberg equilibrium, for each susceptibility-genotype penetrance studied. Table 1 Phenotypes of Affected Sib Pairs with AITD Multipoint nonparametric analysis with the use of five microsatellite markers spanning a 21-cM area of 20q13.11 showed no evidence to support linkage in the 71 GD sib pairs, with a peak NPL (nonparametric linkage) score of 0.1 occurring at the marker D20S884 (fig. 1). We were able to formally exclude (LOD score 2.5 from this entire region (fig. 1). Parametric analysis was performed both with and without the assumption of heterogeneity, with both recessive and dominant models. There was no evidence for linkage of GD to this region at disease penetrances of 30%, 60%, or 90%, with either model of inheritance, in the 71 sib pairs (table 2). Figure 1 Linkage analysis in all 64 affected GD kindreds. A, Percentage information content shown at each of the map positions. B, Multipoint nonparametric linkage analysis of kindreds with GD for chromosome 20q13.11 markers. Genotyping was performed by PCR with ... Table 2 Peak Multipoint Parametric LOD Scores for the Chromosome 20q13.11 Markers in the 64 Families with GD and in the Subset of 12 Kindreds with Dominant Transmission of GD The ascertainment strategy (at least two affected sibs with GD) used to recruit families for our study was different from that (at least two affected first-degree relatives with AITD) used by Tomer et al., such that their cohort of families was likely to contain many more affected parent-offspring kindreds (Tomer et al. 1998). We speculated that such affected parent-offspring kindreds might have enriched their cohort for families segregating dominant loci and that this difference in ascertainment might explain the apparent discrepancy between our findings, if the susceptibility locus segregated as a dominant (McCarthy et al. 1998). Therefore, we investigated linkage both in a subgroup of 12 families (38 subjects with GD) who had apparent dominant transmission of GD from parent to offspring and in a subgroup of 28 families with dominant transmission of AITD from parent to offspring (75 subjects with GD and 17 with autoimmune hypothyroid). Multipoint nonparametric analysis in the 12 families with dominant transmission of GD showed a 4-cM plateau suggestive of linkage, with a peak NPL score of 2.02 (P=.023) occurring at the marker D20S106 (fig. 2). This was not observed in the larger subgroup of 28 families with parent-to-offspring transmission of AITD (fig. 2). Parametric analysis in the subgroup with dominant transmission of GD, with the assumption of heterogeneity, showed a peak LOD score of 1.06 occurring at the marker D20S884 with a dominant model (table 2). Figure 2 Linkage analysis of the subset of 12 GD kindreds with dominant transmission of GD, and other groups. A, Percentage information content for the 12 families with dominant transmission of GD is shown at each of the map positions. B, Multipoint nonparametric ... Our study provides some evidence to support the presence of a GD-susceptibility locus in this region of 20q13.11 (Tomer et al. 1998), and we show that this locus appears to be important only in families with dominant inheritance of GD. The small number of such kindreds that we have studied precludes a reliable estimate of the strength of effect of this locus, but our ability to detect the effect using only 12 families with this structure, coupled with the 1:0 allele-sharing ratio of 69% between the sib pairs with GD, suggests that it may have a strong effect. In contrast, our families with affected subjects with GD in only one generation and our families with dominant transmission of AITD do not show evidence of linkage to this locus (figs. 1 and ​and2).2). Analysis of a larger cohort of kindreds with dominant transmission of GD is necessary to confirm the presence of this susceptibility locus for GD. However, the recent mapping of a susceptibility locus for systemic lupus erythematosus (MIM 152700) to this region of chromosome 20 in two different mixed American cohorts (Gaffney et al. 1998; Moser et al. 1998) suggests that this region may harbor a polymorphism(s) that is important in other autoimmune disorders. In addition, our study illustrates that the ascertainment strategies employed in the collection of cohorts of kindreds with complex disorders may have a marked effect on the ability to detect a given susceptibility locus (McCarthy et al. 1998).

The relationships between cardiovascular risk factors and socio-economic status in people with diabetes

The hypothesis that the prevalence of cardiovascular risk factors in people with diabetes is inversely related to socio‐economic status was tested. Demographic and biochemical data were collected on 1246 patients, aged 20–69 years, attending a hospital diabetes clinic. This is estimated to represent between 71 % and 78 % of all people of this age with a diagnosis of diabetes in the health authority. In total, 296 people were classified as Type 1 (insulin‐dependent) diabetic patients (age of onset <31, now on insulin). Using data from the 1991 census a deprivation score was ascribed to each individual according to their area (enumeration district) of residence. The total study population was ranked by deprivation score and divided into quintiles. The relationships between means and quintiles of deprivation were assessed by ANOVA for linear trend, and between proportions and quintiles of deprivation by the chi‐squared test for trend. In Type 1 diabetes increasing quintiles of deprivation were significantly related to mean serum cholesterol (p < 0.01) and proportion smoking (p < 0.01), and in Type 2 (non‐insulin‐dependent) diabetes to mean body mass index (p < 0.001), proportion smoking (p < 0.001), and proportion with proteinuria (p < 0.05). The need for health measures to prevent cardiovascular disease in people with diabetes is greatest in deprived areas.