Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial

Context  The worldwide explosive increase in type 2 diabetes mellitus and its cardiovascular morbidity are becoming major health concerns. Objective  To evaluate the effect of decreasing postprandial hyperglycemia with acarbose, an -glucosidase inhibitor, on the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance (IGT). Design, Setting, and Participants  International, multicenter double-blind, placebo-controlled, randomized trial, undertaken in hospitals in Canada, Germany, Austria, Norway, Denmark, Sweden, Finland, Israel, and Spain from July 1998 through August 2001. A total of 1429 patients with IGT were randomized with 61 patients (4%) excluded because they did not have IGT or had no postrandomization data, leaving 1368 patients for a modified intent-to-treat analysis. Both men (49%) and women (51%) participated with a mean (SD) age of 54.5 (7.9) years and body mass index of 30.9 (4.2). These patients were followed up for a mean (SD) of 3.3 (1.2) years. Intervention  Patients with IGT were randomized to receive either placebo (n = 715) or 100 mg of acarbose 3 times a day (n = 714). Main Outcome Measures  The development of major cardiovascular events (coronary heart disease, cardiovascular death, congestive heart failure, cerebrovascular event, and peripheral vascular disease) and hypertension (=" BORDER="0">140/90 mm Hg). Results  Three hundred forty-one patients (24%) discontinued their participation prematurely, 211 in the acarbose-treated group and 130 in the placebo group; these patients were also followed up for outcome parameters. Decreasing postprandial hyperglycemia with acarbose was associated with a 49% relative risk reduction in the development of cardiovascular events (hazard ratio [HR], 0.51; 95% confidence interval [CI]; 0.28-0.95; P = .03) and a 2.5% absolute risk reduction. Among cardiovascular events, the major reduction was in the risk of myocardial infarction (HR, 0.09; 95% CI, 0.01-0.72; P = .02). Acarbose was also associated with a 34% relative risk reduction in the incidence of new cases of hypertension (HR, 0.66; 95% CI, 0.49-0.89; P = .006) and a 5.3% absolute risk reduction. Even after adjusting for major risk factors, the reduction in the risk of cardiovascular events (HR, 0.47; 95% CI, 0.24-0.90; P = .02) and hypertension (HR, 0.62; 95% CI, 0.45-0.86; P = .004) associated with acarbose treatment was still statistically significant. Conclusion  This study suggests that treating IGT patients with acarbose is associated with a significant reduction in the risk of cardiovascular disease and hypertension.      

Decreased brain creatine levels in elderly apolipoprotein E ε4 carriers

Summary. Apolipoprotein E (ApoE) genotype has been shown to influence results in neuroimaging studies using a number of various imaging modalities. No in vivo data exists on whether or not there are ApoE-related changes observable by proton magnetic resonance spectroscopy (MRS). In this study we measured absolute peak areas of proton MR spectra obtained from the occipital cortex in 22 non-demented elderly with (n = 8) or without (n = 14) the ApoE ε4 allele. No statistically significant differences were found in levels of N-acetyl aspartate, myo-inositol, or choline containing compounds between the groups. Instead, compared with the non-carriers, the levels of creatine were significantly lower in the ε4 carriers, suggesting increased metabolic demands in the brain of the ε4 carriers. The levels of creatine also correlated significantly with age and performance on the Mini-Mental State Examination test in the ε4 carriers, but not in the non-carriers. These findings may be of significant clinical interest as potential indicator of incipient AD, and also from therapeutical point of view given the potential neuroprotective effects of creatine. Received February 18, 2002; accepted August 5, 2002 Published online December 9, 2002 Acknowledgements This study was supported by the Research Council for Health of the Academy of Finland, the Finnish Neurology Foundation, the Instrumentarium Research Foundation, and the Farmos Research Foundation. Authors' address: M. Laakso, Department of Neurology, Bldg. 5, Kuopio University Hospital, P.O.Box 1777, 70211 Kuopio, Finland, e-mail: mikko.laakso@uku.fi Abbreviations AD Alzheimer's disease, ApoE apolipoprotein E, MI myo-inositol, MMSE Mini-Mental State Examination, MRI magnetic resonance imaging, MRS magnetic resonance spectroscopy, NAA N-acetyl aspartate.     

Postprandial responses of individual fatty acids in subjects homozygous for the threonine- or alanine-encoding allele in codon 54 of the intestinal fatty acid binding protein 2 gene

BACKGROUND: The affinity of intestinal fatty acid binding protein (FABP) for fatty acids is regulated by the polymorphism at codon 54 of the FABP2 gene (alanine-to-threonine shift). We found earlier that the threonine-encoding allele (Thr54) is associated with an increased postprandial lipemic response. OBJECTIVE: We studied the postprandial responses of individual fatty acids in subjects homozygous for the Thr54 or alanine-encoding allele (Ala54). DESIGN: Oral-fat-loading tests were performed in 8 subjects homozygous for Thr54 and in 7 subjects homozygous for Ala54. RESULTS: The postprandial responses of most of the 14-18-carbon fatty acids in chylomicron and VLDL triacylglycerols were significantly elevated in the Thr54 homozygotes whereas the relative increases in these fatty acids were not significantly different in both groups. The amounts of 20- and 22-carbon polyunsaturated fatty acids started to increase later than the amounts of shorter ones after the test meal, and the differences between the groups were mostly insignificant. The responses of chylomicron fatty acids correlated positively with postprandial insulin response in the Thr54 homozygotes and inversely in the Ala54 homozygotes. VLDL fatty acid responses correlated with fasting triacylglycerol concentrations in the Ala54 homozygotes but not in the Thr54 homozygotes. CONCLUSION: The threonine-encoding allele of the FABP2 gene is associated with an increased postprandial response of 14-18-carbon fatty acids but not with changes in the relative amounts of individual fatty acids introduced to chylomicron triacylglycerols.     

Psychopathy and the posterior hippocampus

Neurobiology of psychopathy is of interest, not only because neural underpinnings of psychopathy remain obscure, but also because psychopaths may provide a model to study violent behavior, neurology of morals and impaired decision-making. Medial temporal lobe pathology has been suggested to be a part of the neural systems dysfunction which manifests as violent and psychopathic behavior. Yet, so far no sound evidence of neuroanatomical correlates for psychopathic behavior has been found. In this study regional hippocampal volumes were measured using magnetic resonance imaging in 18 habitually violent offenders with antisocial personality disorder and type 2 alcoholism (derived from forensic psychiatric evaluation). The regional volumes along the anteroposterior axis of the hippocampus were correlated with the subjects' degree of psychopathy as evaluated by the Psychopathy Checklist-Revised. Strong negative correlations, up to -0.79, were observed, among the study subjects, between the psychopathy scores and the posterior half of the hippocampi bilaterally. These data are in accordance with experimental studies proposing that lesions of the dorsal hippocampus impair acquisition of conditioned fear, and with theories on psychopathology according to which one of the central features in the birth of psychopathy is a deficit in acquisition of conditioned fear.     

Alpha-synuclein pathology is highly dependent on the case selection

Lewy bodies and dystrophic neurites have been considered a common substrate for dementia, but they are also frequently found in the normal elderly population. The primary component of this pathology involves alpha-synuclein. The main objective of the present study was to estimate the prevalence of alpha-synuclein pathology in aged population, and to assess its relative significance in relation to dementia. The study also investigated whether differences could be detected in alpha-synuclein pathology in relation to age, gender or concomitant Alzheimer's pathology. Furthermore, the influence of sampling strategies was analysed. Alpha-synuclein pathology was assessed using immunohistochemistry in well-characterized post-mortem material. The investigation included patients from a longitudinal study of dementia of Alzheimer's type (n = 103, 85% demented), subjects from a prospective longitudinal clinical study of ageing (n = 69, 29% demented), a cohort of consecutive clinical post-mortem cases collected for 1 year (n = 262, 12% demented), a sample of forensic post-mortem cases collected for 6 months (n = 121, 15% demented) and a sample of Brain Bank material (n = 234, 26% demented). Overall, alpha-synuclein pathology was found in 14% of all 774 subjects over 40 years of age, and this percentage varied from 8% to 27% according to sampling strategies. These results indicate that the prevalence of alpha-synuclein pathology clearly depends on the selection of material. Furthermore alpha-synuclein pathology was found in 23% of clinically demented patients and in 11% of non-demented subjects. The load of alpha-synuclein pathology was significantly greater in the demented patients versus non-demented subjects indicating that alpha-synuclein pathology is indeed of importance in the pathogenesis of dementia.     

A morphometric MRI study of the hippocampus in first-episode, neuroleptic-naïve schizophrenia

Magnetic resonance imaging (MRI) studies have frequently, although not unambiguously, reported hippocampal volume deficit in schizophrenia. Data on the hippocampal volumes in first-episode schizophrenia, however, are sparse. In addition, a recent topographic MRI study proposed a regionally specific volume loss in the hippocampus of chronic schizophrenics, but to date no reports have replicated this finding. In this study two-dimensional MRI-based topographic brain mapping was used to study the possibility of regional changes in the hippocampus of 22 controls and 18 patients with first-episode, neuroleptic-na?ve schizophrenia. Compared to controls, there were no significant differences between hippocampal volumes, regional volumes, or length of the hippocampus in the patients with schizophrenia. These data are at odds with the previous reports on hippocampal volume loss in first-episode schizophrenia, and with the hypothesis of regionally specific hippocampal volume deficit in schizophrenia.     

Intron 4 polymorphism of the endothelial nitric oxide synthase gene is associated with elevated blood pressure in type 2 diabetic patients with coronary heart disease

The endothelial nitric oxide synthase (eNOS) gene is responsible for constitutive nitric oxide synthesis and arterial vasodilatation. Recently two polymorphisms, the 27-bp repeat sequence in intron 4 and the Glu298Asp substitution in exon 7 of the eNOS gene have been reported to be related to coronary heart disease (CHD). We screened these polymorphisms of the eNOS gene in 308 unrelated nondiabetic subjects with CHD, in 251 unrelated patients with type 2 diabetes with CHD, and in 110 randomly selected healthy subjects without CHD. The 4a and Asp298 allele frequencies of the eNOS gene were 0.19 and 0.36 in nondiabetic patients with CHD, 0.21 and 0.27 in type 2 diabetic patients with CHD, and 0.16 and 0.31 in nondiabetic subjects without CHD (n.s. between the groups). The Asp298 allele in exon 7 of the eNOS gene was not associated with elevated blood pressure in any of the study groups. Among type 2 diabetic patients with CHD the 4a allele in intron 4 of the eNOS gene was associated with elevated levels of systolic (P=0.035) and mean arterial blood pressure (P=0.040). In nondiabetic subjects these associations were not statistically significant. When all study groups were pooled in statistical analysis the 4a allele of the eNOS gene was associated with elevated diastolic (P=0.032) and mean (P=0.030) arterial blood pressure even after adjustment for confounding factors. We conclude that the 4a allele of the eNOS gene is not associated with CHD or type 2 diabetes, but that it is related to elevated blood pressure levels particularly among type 2 diabetic patients with CHD.     

Reactive microglia in aging and dementia: an immunohistochemical study of postmortem human brain tissue

Significantly increased up-regulation of HLA DR (major histocompatibility complex class II antigen) was seen using immunohistochemistry in postmortem brain tissue from demented patients with Alzheimer’s disease (AD) (73 cases, 61 females/12 males, mean age 84 ± 9 years) compared to controls (22 cases, 10 females/12 males, mean age 78 ± 9 years). The counts of HLA DR-expressing activated microglia were significantly higher in female AD patients compared to males, significantly higher in AD patients with the age at death greater than 75 years compared to those dying younger and higher, although not statistically significantly, in AD patients with the apolipoprotein E (ApoE) ɛ4 allele compared to those patients not carrying this allele. In contrast to the situation in AD patients, in the control cases the HLA DR expression was higher in males compared to females. Furthermore, in the very old non-demented patients (age at death > 80 years), a decrease in the up-regulation of HLA DR expression was observed. A significant correlation between activated microglia and neurofibrillary tangles was seen in female AD patients compared to males, in AD cases without ApoE ɛ4 allele compared to those with this allele, in sporadic cases compared to familial and in cases with senile rather than presenile onset of the disease. Our results indicate that there is an age- and/or sex-related variability in up-regulation of HLA DR expression of microglia and that the linkage between this up-regulation and AD lesions is significantly influenced by the ApoE ɛ4 allele, gender of subjects, age at onset and familiality of the disease. Received: 20 May 1998 / Revised: 5 August 1998, 4 October 1998 / Accepted: 21 October 1998     

Repeatability of C-peptide response in glucagon stimulation test

Measurement of the plasma C-peptide level before and after iv administration of 1 mg of glucagon was repeated four times in 10 elderly non-diabetic subjects and in 20 elderly non-insulin-dependent diabetics treated with diet or oral drugs to assess the repeatability of the C-peptide responses. Plasma C-peptide levels before and after glucagon administration and C-peptide glucose ratios in the four measurements did not differ significantly from test to test either in diabetic or non-diabetic subjects. The results of the present study indicate that the repeatability of C-peptide response to glucagon is very good both in non-insulin-dependent diabetics and in non-diabetic subjects.