Tm Greenaway

Brain Atrophy in Type 2 Diabetes Regional distribution and influence on cognition

OBJECTIVE Type 2 diabetes (T2DM) is associated with brain atrophy and cerebrovascular disease. We aimed to define the regional distribution of brain atrophy in T2DM and to examine whether atrophy or cerebrovascular lesions are feasible links between T2DM and cognitive function. RESEARCH DESIGN AND METHODS This cross-sectional study used magnetic resonance imaging (MRI) scans and cognitive tests in 350 participants with T2DM and 363 participants without T2DM. With voxel-based morphometry, we studied the regional distribution of atrophy in T2DM. We measured cerebrovascular lesions (infarcts, microbleeds, and white matter hyperintensity [WMH] volume) and atrophy (gray matter, white matter, and hippocampal volumes) while blinded to T2DM status. With use of multivariable regression, we examined for mediation or effect modification of the association between T2DM and cognitive measures by MRI measures. RESULTS T2DM was associated with more cerebral infarcts and lower total gray, white, and hippocampal volumes (all P < 0.05) but not with microbleeds or WMH. T2DM-related gray matter loss was distributed mainly in medial temporal, anterior cingulate, and medial frontal lobes, and white matter loss was distributed in frontal and temporal regions. T2DM was associated with poorer visuospatial construction, planning, visual memory, and speed (P ≤ 0.05) independent of age, sex, education, and vascular risk factors. The strength of these associations was attenuated by almost one-half when adjusted for hippocampal and total gray volumes but was unchanged by adjustment for cerebrovascular lesions or white matter volume. CONCLUSIONS Cortical atrophy in T2DM resembles patterns seen in preclinical Alzheimer disease. Neurodegeneration rather than cerebrovascular lesions may play a key role in T2DM-related cognitive impairment.

Phenotype and phenocopy: the relationship between genotype and clinical phenotype in a single large family with multiple endocrine neoplasia type 1 (MEN 1).

The majority of reports describing the natural history and prognosis of multiple endocrine neoplasia type 1 (MEN 1) utilize phenotypic rather than molecular genetic criteria to establish a diagnosis of MEN 1.

Vitamin D levels in prepubertal children in Southern Tasmania: prevalence and determinants.

Objective: To describe the prevalence and determinants of 25-hydroxy D3(25(OH)D) in children.Design: Cross-sectional study.Setting: Southern Tasmania between June and November 1997.Subjects: Two hundred and one 8-y old male and female children taking part in a cohort study whose principal endpoints were blood pressure and high-density lipoprotein (HDL) cholesterol.Results: The mean 25(OH)D level was 79 nmol/l (s.d. 29.5, median 73, range 12–222). Boys had higher levels than girls (82.1 vs 72.8 nmol/l, P=0.02). 25(OH)D was associated with sunlight exposure in winter school holidays (r=0.20, P=0.005) and winter weekends (r=0.16, P=0.02), the month after school holidays (87.5 vs 69.5 nmol, P<0.0001) and body mass index (r=−0.23, P=0.001). Dietary intake of vitamin D was low (mean 40 IU/day, range 5.2–384) and was not associated with 25(OH)D levels (r=0.01, P=0.91). Variation in skin melanin density was weakly associated with 25(OH)D (r=0.09, P=0.19).Conclusions: Sunlight is the major determinant of vitamin D stores in our population. Neither variation in skin type within Caucasians nor diet modified this association to any significant extent. Extrapolation of these findings to sunlight bone mass associations in a very similar population suggests that a minimum level of around 50 nmol/l in the population is required for optimal bone development in prepubertal children but this needs to be confirmed with further controlled trials of vitamin D supplementation and bone mass.Sponsorship: Arthritis Foundation of Australia, Roche Pharmaceuticals.

A population-based study of the relationship between salt intake, bone resorption and bone mass

Objective: To explore the relationship between urinary sodium (the best measure of salt intake), urinary calcium, urinary deoxypyridinoline (DPYR) and bone mass. Design: Cross-sectional study. Setting: Population based sample of healthy Hobart residents. Subjects: One hundred and fifty-four (M=34, F=120) subjects invited to take part from a systematic sample of the electoral roll and a single newspaper advertisement. Results: In both sexes, urinary sodium correlated moderately with urinary DPYR (r=0.32, P<0.0001) and urinary calcium (r=0.37, P<0.0001). In multivariate analysis, the combination of urinary sodium, total body bone area, age and sex explained 22% of the variation in log-transformed DPYR (P<0.00001). In univariate analysis, both urinary sodium and urinary DPYR were strongly associated with bone mineral content and bone mineral density at all sites but this association disappeared after adjustment for confounders particularly body weight. Conclusions: This study has shown that salt intake is associated with markers of bone resorption in a population-based sample of males and females and appears likely to be a risk factor for osteoporosis despite the lack of a demonstrable association between bone mass and a single measure of urinary sodium excretion. Further studies are needed to define the effect of salt intake on bone mass and fractures more clearly. These studies will need to be either longitudinal or interventional in design with repeated measures of urinary sodium so that habitual sodium intake can be accurately assessed and regression dilution bias can be minimised. Sponsorship: Arthritis Foundation of Australia, Royal Hobart Hospital Acute Care Program.

Methylglyoxal, Cognitive Function and Cerebral Atrophy in Older People

BACKGROUND The effects of advanced glycation endproducts on cognition and brain structure are poorly understood. We studied associations of the advanced glycation endproduct precursor methylglyoxal (MGO) with cognitive function and brain volumes in older people. METHODS Nondemented participants in the Tasmanian Study of Cognition and Gait underwent cognitive testing and brain magnetic resonance imaging scans. Brain volumes were obtained by magnetic resonance imaging scan segmentation and statistical parametric mapping procedures. Serum MGO was measured after derivatization to methylquinoxaline by high pressure liquid chromatography and UV detection. Linear regression was used to examine associations of log-transformed MGO with cognitive scores and brain volumes adjusting for potential confounding by age, sex, education, mood, insulin resistance, history of stroke, vascular risk factors, alcohol intake, and psychoactive medication use. RESULTS There were 378 participants, mean age 72.1 years (SD 7.1), 55% male. Greater MGO was associated with poorer memory (β = -.12, 95% confidence interval: -0.22, -0.02, p = .02) and executive function, the latter being greater among those with a history of stroke (MGO × stroke β = .48, 95% confidence interval: 0.17, 0.79, p = .002). Greater MGO was associated with lower grey matter volume (β = -6.42, 95% confidence interval -11.82, -1.11, p = .02) but not with white matter volume, white matter lesion volume, or hippocampal volume. CONCLUSIONS These results support the investigation of the role of the advanced glycation endproduct precursor methylglyoxal in cognitive decline and neurodegeneration in older people.

Enteropancreatic malignancy associated with multiple endocrine neoplasia type 1

Enteropancreatic malignancy is an important cause of morbidity and mortality associated with multiple endocrine neoplasia type 1 (MEN 1). However, the risk factors and mechanisms of the tumorigenesis of this malignancy are poorly understood.

The effect of a fracture protocol on hospital prescriptions after minimal trauma fractured neck of the femur : a retrospective audit

Effective therapies for the treatment of osteoporosis and fracture have been available for a number of years. Despite this, there are numerous reports indicating very low uptake rates in those admitted to hospital with fracture. The aim of this retrospective audit was to assess the impact of a fracture protocol on inpatient prescriptions of osteoporosis therapy. A fracture protocol was arrived at by consensus and was based on recommendations from the Australian Fracture Prevention Summit, which included specific advice on the commencement in hospital of calcium, vitamin D, synthetic estrogen receptor modulators (SERMs) and bisphosphonates. We studied subjects who were treated for fractured neck of the femur at Royal Hobart Hospital from March 2002 to March 2004 and included 161 prior to the start of the protocol and 93 after. As compared to the baseline period, subjects after the introduction of the protocol had higher rates of in-hospital prescription for any treatment (58 vs. 36%, P <0.01), calcium (51 vs. 26%, P <0.01), vitamin D (48 vs. 29%, P <0.01) and oral bisphosphonates (24 vs. 5%, P <0.01), but not SERMs as expected (1 vs. 1%, P =0.70). Additional factors affecting the decision to start any treatment included in-hospital death (OR 0.16, 95% CI 0.05–0.49), dementia (OR 0.39, 95% CI 0.21–0.74), a trend for female sex (OR 1.79, 95%CI 0.96–3.36), but not age. In conclusion, a structural approach to changing hospital policy from the top down is effective at substantially increasing the usage of effective therapy after fractured neck of the femur.

Review of management of type 2 diabetes mellitus

Background: Commonly used drugs for type 2 diabetes are not ideal. The sulphonylureas, especially potent and long‐acting agents such as glibenclamide, can induce hypoglycaemia, while metformin carries the risk of lactic acidosis. Aim: To review the management of type 2 diabetes at the major teaching hospital in Tasmania, Australia, principally to determine the extent of use of glibenclamide and metformin in the elderly and patients where published contraindications are present. Methods: A retrospective review of the medical records for 150 consecutive patients with type 2 diabetes admitted to the hospital in mid‐1997, was performed. An extensive range of demographic and clinical variables was recorded for each patient. These included the duration of type 2 diabetes, the presence of other medical conditions, medication history, presence of any contraindications to the use of metformin or sulphonylureas, biochemical measures of diabetic control, and the presence of any diabetic complications. Results: The mean (±SD) age of the 150 patients included in the study was 70·1±11·8 years. The mean body mass index was 28·7±6·2 kg/m2 and the mean recent HbA1c level was 8·6±2·1%; only 24·7% of patients had a HbA1c level of 7% or lower. Of the 45 patients using glibenclamide, 40 (88·9%) had one or more risk factors for hypoglycaemia: over 65 years of age, renal impairment, or cognitive impairment and living alone. The study also found an extensive use of metformin in patients with contraindications and at highest risk of developing lactic acidosis. Sixty‐six out of 70 patients (94%) using metformin had at least one contraindication according to the manufacturers prescribing information, 57% of patients had two or three contraindications and 14% of patients had more than three contraindications. More than 20% of the patients had a renal function below published exclusion criteria. Conclusions: There was evidence of over‐utilization of metformin and glibenclamide in type 2 diabetes patients most at risk of adverse reactions. Insulin therapy could be a safer and more effective management strategy in many of these patients.

A randomized controlled trial of phytoestrogen supplementation, growth and bone turnover in adolescent males

Objective: To assess the effect of phytoestrogens on bone turnover and growth in adolescent boys.Design: Randomized double-blind placebo-controlled trial.Setting: Single school in northwest Tasmania.Participants: Adolescent boys (treatment n=69, placebo n=59, mean age 16.8 y).Interventions: Six weeks of isoflavone supplementation (Novasoy, 50 mg daily of isoflavone equivalents). Bone turnover markers (bone specific alkaline phosphatase (BAP) and pyridinoline creatinine ratio (PYR)) were measured at baseline and follow-up.Results: Despite marked increases in urinary genistein and daidzein in the treatment arm (both P<0.001), there were no significant differences in BAP, PYR or short-term height or weight change. This applied to both intention-to-treat and per protocol analysis. Neither was there a significant correlation between urinary genistein and daidzein levels and BAP or PYR.Conclusions: Phytoestrogen supplementation to the level of usual Japanese dietary intake has no measurable effect on bone turnover in adolescent boys. Longer-term studies of bone density may be desirable but it is unlikely that there will be a large effect in either girls or boys given the lower endogenous oestrogen levels in boys.Sponsorship: National Health and Medical Research Council of Australia, Arthritis Foundation of Australia.

Somatotrophinomas in multiple endocrine neoplasia type 1: A review of clinical phenotype and insulin-like growth factor-1 levels in a large multiple endocrine neoplasia type 1 kindred

PURPOSE Within the spectrum of pituitary disease in multiple endocrine neoplasia type 1 (MEN-1), widely disparate prevalence rates for somatotrophinomas have been described. Studies that combine multiple, small MEN-1 kindreds report pituitary disease in 60% to 65% of patients, somatotrophinomas accounting for 27% to 37% of total pituitary lesions. However, reports based on large MEN-1 family screening programs have produced lower prevalence rates for pituitary adenomas (9% to 40%), of which somatotrophinomas comprise up to 14%. We sought to determine the prevalence of both biochemical and clinically overt growth hormone (GH) hypersecretion in the largest reported MEN-1 genealogy, the Tasman 1 kindred. PATIENTS AND METHODS The Tasman 1 MEN-1 kindred contains 165 members with established MEN-1. We reviewed the records of 124 MEN-1 patients for evidence of acromegaly or gigantism. To determine if clinical criteria underestimate the occurrence of biochemical GH hypersecretion, a subset of 33 patients was assessed for elevated levels of serum insulin-like growth factor-1 (IGF-1). RESULTS No cases of acromegaly or gigantism were detected in the 124 patients reviewed. Of the 33 patients screened with IGF-1, 13 had previously diagnosed pituitary lesions--11 prolactinomas and 2 nonsecretory lesions. The IGF-1 levels were normal in all patients studied. There were no significant differences in mean IGF-1 values between patients with and without pituitary lesions. CONCLUSIONS This report represents the largest study of growth hormone secretion patterns thus far described in MEN-1. The apparent absence of somatotrophinomas in a kindred of this size is unexpected. These results support the existence of kindred-specific MEN-1 phenotypes. We conclude that the pathogenesis of GH-secreting adenomas in MEN-1 is influenced by secondary factors acting in synergy with the well-documented primary MEN-1 gene defect on chromosome 11q13.