Voxel-based morphometry study on monozygotic twins discordant for Alzheimer's disease.

OBJECTIVES: We set to investigate the possible role of genes and environment in developing Alzheimer's disease (AD) in monozygotic twin pairs discordant for AD. METHODS: Three pairs of twins discordant for AD, who were enrolled in the Finnish Twin Cohort, were used in the study and compared with 13 controls. Gray matter changes were assessed with magnetic resonance images using voxel-based morphometry with statistical parametric mapping. RESULTS: In the affected twins, the peaks of volume loss were located bilaterally in the temporal (including the hippocampus), the frontal, and the parietal lobes, while in the unaffected siblings, the peaks were located in the frontal gyri and in the parietal lobule. Thus, in the unaffected twins, the pattern of volume loss overlaps with the neocortical but not with the medial temporal areas. DISCUSSION: These findings suggest that genetic factors more largely control neocortical regions, whereas environmental factors more strongly affect medial temporal regions.

Early detection of Alzheimer disease: ¹¹C-PiB PET in twins discordant for cognitive impairment.

OBJECTIVE: The aim of this study was to investigate whether cognitively preserved monozygotic or dizygotic cotwins of persons with Alzheimer disease (AD) exhibit increased brain amyloid accumulation. METHODS: We performed a cross-sectional carbon-11 labeled 2-(4'-methylaminophenyl)-6-hydroxybenzothiazole ((11)C)-Pittsburgh compound B (PiB) PET study on 9 monozygotic and 8 dizygotic twin pairs discordant for cognitive impairment as well as on 9 healthy elderly control subjects. (11)C-PiB uptake was analyzed with Statistical Parametric Mapping and with region of interest analysis with the region-to-cerebellum ratio as a measure of tracer uptake. RESULTS: Cognitively preserved monozygotic cotwins of cognitively impaired probands had increased cortical (11)C-PiB uptake (117%-121% of control mean) in their temporal and parietal cortices and the posterior cingulate. Cognitively preserved dizygotic subjects did not differ from the controls. Further, the cognitively preserved monozygotic subjects showed similar (11)C-PiB uptake patterns as their cognitively impaired cotwins. The cognitively impaired subjects (monozygotic and dizygotic individuals combined) showed typical Alzheimer-like patterns of (11)C-PiB uptake. CONCLUSIONS: Genetic factors appear to influence the development of Alzheimer-like ß-amyloid plaque pathology. The dissociation between cognitive impairment and brain ß-amyloidosis in monozygotic twins implies that there may be important environmental/acquired factors that modulate the relationship between brain amyloidosis and neurodegeneration. AD may be detectable in high-risk individuals in its presymptomatic stage with (11)C-PiB PET, but clinical follow-up will be needed to confirm this.

Association and causal relationship of midlife obesity and related metabolic disorders with old age cognition.

OBJECTIVE: Epidemiological studies suggest a relationship between midlife metabolism and old age cognition. We examined the effect of midlife BMI and related metabolic conditions on old age cognitive performance and whether there was evidence from direct causal pathways behind these associations in a large sample of Finnish twins. DESIGN: Midlife variables of 2606 twin individuals were based on postal questionnaires and registry records. Old age cognitive status was measured by using a validated telephone interview. RESULTS: Midlife BMI, cardiovascular disease, hypertension and diabetes were each associated with old age cognition when adjusted for sex, education, birth year and age at the interview. Similarly, overweight increased the risk for categories of mild impairment of cognitive function and likely dementia. Cardiovascular disease diminished the mean cognitive score also among discordant twin pairs (ß-estimate=1.10, p-value= 0.012). Weight gain more than 1.7 kg/m(2) and loss more than 2 kg/m(2) within an average of 5.6 years were associated with lower cognitive performance independently of BMI. An additive genetic correlation explained the association between BMI and old age cognition (r(A)=-0.12, 95% CI -0.21; -0.03), but adjustment for education led to loss of significance (r(A)=-0.06, 95% CI -0.16; 0.03). CONCLUSIONS: Midlife metabolic diseases, especially diabetes, are independently associated with impaired cognition in old age. Even a more subtle weight change than suggested previously was associated with lower old age cognition. There was evidence from direct causal pathway between cardiovascular disease and old age cognition, while the correlation between midlife BMI and old age cognition was explained mostly by genetic factors.

The metabolic syndrome defined by modified International Diabetes Federation criteria and mortality: a 9-year follow-up of the aged in Finland.

AIM: The aim of this study was to investigate the relationship between the metabolic syndrome (MetS) and mortality in the aged population. METHODS: In this prospective population-based study with a 9-year follow-up, the participants were all residents of the municipality of Lieto, Finland, aged 64 and over in 1998-99 (n=1529). Altogether, 1260 (82%) were included in the study. Cox proportional-hazard models were used to estimate hazard ratios (HRs) for all-cause, cardiovascular (CVD), coronary heart disease (CHD) and cerebrovascular (CV) mortality as predicted by MetS (defined by modified International Diabetes Federation criteria). RESULTS: At baseline, 17% of the men and 21% of the women had MetS. During the 9-year follow-up, 422 deaths occurred. After multivariable adjustment, no significant differences were found between subjects with and without MetS for all-cause, CVD, CHD or CV mortality in all study participants or by gender. On evaluating MetS components separately, elevated blood pressure was found to predict lower all-cause mortality in all participants [HR: 0.65; 95% confidence interval (CI): 0.47-0.89], and lower CHD mortality in men (HR: 0.42; 95% CI: 0.18-0.97). In women, high triglyceride levels predicted lower all-cause mortality (HR: 0.67; 95% CI: 0.47-0.95), whereas low HDL cholesterol predicted higher all-cause (HR: 1.61; 95% CI: 1.15-2.24) and CV (HR: 2.44; 95% CI: 1.05-5.67) mortality. CONCLUSION: These findings suggest that MetS does not predict mortality later in life and, of the separate components of MetS, only low HDL cholesterol is predictive of mortality in women. Also, even markedly higher blood pressure values than those included in the criteria for MetS fail to predict mortality in this age group.

Voxel-based analysis of cerebral glucose metabolism in mono- and dizygotic twins discordant for Alzheimer disease.

BACKGROUND: Sporadic Alzheimer disease (AD) is a multifactorial disease to which both genetic and environmental factors contribute. Therefore, twin pairs are useful in studying its pathogenesis and aetiology. Cerebral glucose metabolism has been found to be reduced in AD patients. METHODS: Cerebral glucose metabolism was studied in seven monozygotic (MZ) and nine same-sexed dizygotic (DZ) twin pairs discordant for AD using positron emission tomography. To obtain objective and explorative results concerning differences in glucose metabolism, the analysis was performed utilising modern voxel-based analysis methodology statistical parametric mapping and automated region-of-interest analysis. RESULTS: In the demented MZ and DZ co-twins, cerebral glucose metabolism was extensively reduced compared with controls. The non-demented MZ co-twins showed reduced metabolism in inferior frontal, lateral temporal, parietal and medial temporal cortices as well as in the thalamus, putamen and right amygdala. In contrast, no reductions were found in the non-demented DZ co-twins. The reduction found in the non-demented MZ co-twins may be an indicator of genetic susceptibility to AD.

Measuring case-mix and outcome for older people in acute hospital care across Europe: the development and potential of the ACMEplus instrument.

AIM: To identify case-mix variables measured shortly after admission to be included in a patient classification system (ACMEplus) that best explains hospital outcome for older people in different health care systems. DESIGN: Observational prospective cohort study collecting patient factors (sociodemographics, functional, mental, clinical, administrative and perceived health) at different time assessments. METHODS: Multicentre study involving eight hospitals in six European countries (United Kingdom, Spain, Italy, Finland, Greece and Poland). It included consecutive patients aged 65 years or older admitted to hospital for acute medical problems. MAIN OUTCOME MEASURES: discharge status, hospital readmission, mortality and length of stay. RESULTS: Of the 1667 included patients (mean age = 78.1 years; male gender = 43.5%) two-third had at least one 'Geriatric Giant' (immobility, confusion, incontinence or falls) on admission or shortly after. The most frequently affected system was cardiovascular (29.2%) and 31% of patients declared poor or very poor health. Mean length of stay was 17.9 days, 79% of patients were discharged to their usual residence; in-hospital and 1-month follow up mortality were 7.4% and 11.6%, respectively. Physical function explained the highest variation (between 8% and 21%), followed by cognitive status and number of Geriatric Giants, for almost all outcomes except readmission. CONCLUSION: Factors other than diagnosis (physical function, cognition and presenting problems) are important in predicting key outcomes of acute hospital care for older people and are consistent across countries. Their inclusion in a standardized system of measurement may be a way of improving quality and equity of medical care in older people.

Hippocampal MRI volumetry in cognitively discordant monozygotic twin pairs.

OBJECTIVE: To investigate whether hippocampal atrophy, a proxy for incipient Alzheimer's disease, can be detected in non-demented monozygotic co-twins of demented twins by using volumetric magnetic resonance imaging (MRI). METHODS: Seven pairs of monozygotic female twins discordant for cognitive function (mean (SD) age 75 (4) years), and 10 age and education matched healthy controls (seven women, three men; mean age 73 (3) years) were studied with volumetric MRI. RESULTS: The mean normalised right hippocampal volume was 31% lower (p = 0.002) in the demented twins, and 6% lower (p = 0.45) in the non-demented twins than in the controls. In the left hippocampus, the mean normalised volume was 36% lower (p<0.001) in the demented twins, and 9% lower (p = 0.13) in the non-demented twins than in the controls. CONCLUSIONS: Significant hippocampal atrophy was detected in the demented twins compared with the controls. This is in line with previous imaging and pathological studies, with hippocampus showing the early changes in Alzheimer's disease. In the non-demented twins, only a minor, non-significant reduction was observed in the hippocampal volumes compared with the controls. This could reflect gene-environment interactions that have protected the non-demented twins longer than their demented co-twins and contributed to the relative preservation of their hippocampal volumes, or it could be a sign of preclinical Alzheimer's disease in the non-demented twins.

Qt dispersion and mortality in the elderly.

BACKGROUND: The prognostic value of QT interval dispersion measured from a standard 12-lead electrocardiogram (ECG) in the general population is not well established. The purpose of the present study was primarily to assess the value of QT interval dispersion obtained from 12-lead ECG in the prediction of total, cardiac, stroke, and cancer mortality in the elderly. METHODS: A random population sample of community-living elderly people (n = 330, age > or = 65 years, mean 74 +/- 6 years) underwent a comprehensive clinical evaluation, laboratory tests, and 12-lead ECG recordings. RESULTS: By the end of the 10-year follow-up, 180 subjects (55%) had died and 150 (45%) were still alive. Heart rate corrected QT (QTc) dispersion had been longer in those who had died than in the survivors (75 +/- 32 ms vs 63 +/- 35 ms, P = 0.01). After adjustment for age and sex in the Cox proportional hazards model, prolonged QTc dispersion (> or = 70 msec) predicted all-cause mortality (relative risk [RR] 1.38, 95% confidence interval [CI] 1.02-1.86) and particularly stroke mortality (RR 2.7, 95% CI 1.29-5.73), but not cardiac (RR 1.38, 95% CI 0.87-2.18) or cancer (RR 1.51, 95% CI 0.91-2.50) mortality. After adjustment for age, sex, body mass index, blood pressure, blood glucose and cholesterol concentrations, functional class, history of cerebrovascular disease, diabetes, smoking, previous myocardial infarction, angina pectoris, congestive heart failure, medication, left ventricular hypertrophy on ECG, presence of atrial fibrillation and R-R interval, increased QTc dispersion still predicted stroke mortality (RR 3.21, 95% CI 1.09-9.47), but not total mortality or mortality from other causes. The combination of increased QTc dispersion and left ventricular hypertrophy on ECG was a powerful independent predictor of stroke mortality in the present elderly population (RR 16.52, 95% CI 3.37-80.89). QTcmin (the shortest QTc interval among the 12 leads of ECG) independently predicted total mortality (RR 1.0082, 95% CI 1.0028-1.0136, P = 0.003), cardiac mortality (RR 1.0191, 95% CI 1.0102-1.0281, P < 0.0001) and cancer mortality (RR 1.0162, 95% CI 1.0049-1.0277, P = 0.005). CONCLUSIONS: Increased QTc dispersion yields independent information on the risk of dying from stroke among the elderly and its component, QTcmin, from the other causes of death.

Poor performance in the mini-mental state examination due to causes other than dementia.

OBJECTIVE: The aim of this study was to examine the extent to which causes other than dementia contribute to poor performance on the Mini-Mental State Examination (MMSE). DESIGN: Cross-sectional population-based study. SETTING: Municipality of Lieto, Finland. SUBJECTS: The study population consisted of all individuals residing in Lieto and born in or before 1926. A total of 1196 individuals, 93% of those eligible, participated. MAIN OUTCOME MEASURES: The MMSE was implemented following interviews and clinical examinations. Whenever an individual was unable to complete any individual item on the MMSE, the nurse recorded causes and assessed whether poor performance was mainly caused by dementia or other reasons. RESULTS: Poor test performance due to causes other than dementia was recorded in 122 (10.2%) individuals (4% of those in the 64-74 years group, 15% in the 75-84 years group and 42% in the group of 85 years of age or older). The most common causes were poor vision and hearing, deficient schooling and consequences of stroke. CONCLUSION: Ten percent of the elderly population had symptoms contributing to poor performance on the MMSE. Physicians should therefore consider and record co-morbidity in the testing situation, especially in very old individuals.

Increase in T-cell subsets of oral mucosa: a late immune response in patients with treated coeliac disease?

BACKGROUND AND AIMS: In coeliac disease, the gut involvement is gluten-dependent. Following the introduction of a gluten-free diet, inflammatory cell infiltration decreases in the small intestinal mucosa. Our hypothesis was that the oral mucosa might mirror the changes found in coeliac disease similarly to the mucosa of the small intestine. Thus, the number of inflammatory cells in the oral mucosa would decrease in patients with coeliac disease on a gluten-free diet. METHODS: The distribution CD45RO+ and CD3(+) T cells, T-cell subpopulations (CD4(+), CD8(+), T-cell receptor (TCR)alpha beta+ and TCR gamma delta+ cells) and HLA DR expression were studied in the buccal mucosa of 15 untreated and 44 gluten-free diet treated coeliac disease patients, and of 19 controls. All 15 patients with untreated coeliac disease were immunglobulin (Ig)A endomysial antibody positive and all 44 patients on gluten-free diet except one were endomysial antibody negative, as were all control subjects. RESULTS: Untreated coeliac disease patients did not differ from controls in the densities of CD45RO+ cells, CD3(+) cells or of T-cell subsets. In contrast, in treated coeliac disease patients, a significant increase in the numbers of mast cells, CD3(+) and CD4(+) lymphocytes was found in the lamina propria of oral mucosa as compared with patients with untreated coeliac disease and controls. The increase in CD3(+) T cells was in part owing to an increase in lymphocytes expressing no TCR. No differences were found in the expression of human leucocyte antigen (HLA) DR in the epithelium or in the lamina propria in the patient groups studied or in the controls. In treated coeliac disease patients only a few TCR gamma delta+ T cells were found intraepithelially and in the lamina propria, but these cells were not detected in the lamina propria of oral mucosa of patients with untreated coeliac disease or in the controls. CONCLUSIONS: The infiltration of T cells into oral mucosa was increased in treated coeliac disease patients in spite of adherence to a gluten-free diet. Because the CD3(+) T cell count was higher than those of the TCR alpha beta+ and TCR gamma delta+ T cells, there must be other cells involved, probably natural killer (NK) cells. The increase in T-cell subsets in the treated coeliac disease patients seems not to result from poor dietary compliance, but might occur as a late immune response in coeliac disease and reflect chronic immunologic stimulation followed by regeneration of memory T cells.

Local challenge on oral mucosa with an alpha-gliadin related synthetic peptide in patients with celiac disease.

OBJECTIVE: Gluten-derived peptides (e.g., amino-acids 31-49 of alpha-gliadin) have been shown to cause changes typical of celiac disease in the gut. Gluten-derived peptides have mostly been used in in vitro studies. The easiest access to the gastrointestinal system may be the mouth. In the present study we were interested to see whether a synthetic peptide corresponding to amino-acids 31-49 of alpha-gliadin could induce inflammatory changes in the oral mucosa after a local challenge in celiac disease patients. METHODS: The challenge was made by injecting the peptide solution at a concentration of 10 microg/ml submucosally into the oral mucosa of 10 celiac disease patients after a gluten-free diet (GFD) and 12 healthy control subjects. B and CD45RO+ T cells, mast cells, CD3+, CD4+, CD8+ lymphocytes, and alphabeta and gammadelta T-cell receptor-bearing (TcR alphabeta, TcR gammadelta) lymphocytes were counted and HLA DR expression was determined. The expression of CD25 and Ki-67 antigen was also examined. RESULTS: The peptide significantly increased the total number of T cells in the lamina propria of the celiac disease patients. The expression of T-cell activation marker CD25 (IL-2 receptor), but not that of cell proliferation marker Ki-67, was also significantly increased in the lamina propria after peptide challenge. Such a reaction was not observed in the controls. The numbers of CD3+ and CD4+ T cells in the lamina propria were also increased in celiac disease patients after the challenge. The count of TcR gammadelta+ cells was very small in the oral mucosa in celiac disease and showed no increase when the oral mucosa was challenged with the peptide. The expression of HLA DR staining was enhanced after the submucosal peptide challenge in celiac disease; however, the difference was not statistically significant. CONCLUSIONS: The results show that in the celiac disease patients after the peptide challenge the oral mucosal lamina propria responds with a nonproliferative increase of lymphocytes. Thus, submucosal challenge with the peptide 31-49 can be used as an aid in the diagnosis of celiac disease. However, further studies with optimized methodology, including various concentrations of the peptide, adjuvants, other peptides, etc., are warranted, especially because the oral mucosa provides the easiest access to an in vivo peptide challenge in celiac disease.

Salivary antigliadin and antiendomysium antibodies in coeliac disease.

The definitive diagnosis of coeliac disease is based on typical changes in the small intestine biopsy specimens. To screen individuals for coeliac disease serum IgA and IgG antigliadin (AGA), IgA antireticulin (ARA) and IgA antiendomysium (EmA) antibodies are used. The aim of this study was to investigate whether these antibodies can also be detected in saliva as diagnostic markers of coeliac disease. The study population comprised 30 patients with coeliac disease treated with a gluten-free diet, 14 patients with untreated coeliac disease and 13 healthy control subjects. Sera and saliva were tested simultaneously for the presence of IgA and IgG AGA and IgA EmA. None of patients studied had a selective IgA deficiency. There was no significant difference in salivary IgA AGA levels between the three groups tested and there was no correlation between the individual serum and salivary values of IgA AGA. Salivary IgG AGA levels were very low or undetectable. Serum IgA AGA showed a low sensitivity (36.4%) to detect an untreated patient with coeliac disease. All salivary samples, regardless of the study group were negative for IgA EmA. Serum IgA EmAs were universally detected in the sera of patients with newly diagnosed coeliac disease and also in the sera of five of 30 patients with treated coeliac disease. No IgA EmA was detected in the sera of controls. None of the patients studied had a selective IgA deficiency either. Serum IgA EmA is the most sensitive, and IgA and IgG AGA are good indicators for coeliac disease, but salivary IgA or IgG AGA and salivary IgA EmA are not helpful for the diagnosis or follow-up of coeliac disease patients.

Cardiac interbeat interval dynamics from childhood to senescence : comparison of conventional and new measures based on fractals and chaos theory.

BACKGROUND: New methods of R-R interval variability based on fractal scaling and nonlinear dynamics ("chaos theory") may give new insights into heart rate dynamics. The aims of this study were to (1) systematically characterize and quantify the effects of aging from early childhood to advanced age on 24-hour heart rate dynamics in healthy subjects; (2) compare age-related changes in conventional time- and frequency-domain measures with changes in newly derived measures based on fractal scaling and complexity (chaos) theory; and (3) further test the hypothesis that there is loss of complexity and altered fractal scaling of heart rate dynamics with advanced age. METHODS AND RESULTS: The relationship between age and cardiac interbeat (R-R) interval dynamics from childhood to senescence was studied in 114 healthy subjects (age range, 1 to 82 years) by measurement of the slope, beta, of the power-law regression line (log power-log frequency) of R-R interval variability (10(-4) to 10(-2) Hz), approximate entropy (ApEn), short-term (alpha(1)) and intermediate-term (alpha(2)) fractal scaling exponents obtained by detrended fluctuation analysis, and traditional time- and frequency-domain measures from 24-hour ECG recordings. Compared with young adults (<40 years old, n=29), children (<15 years old, n=27) showed similar complexity (ApEn) and fractal correlation properties (alpha(1), alpha(2), beta) of R-R interval dynamics despite lower spectral and time-domain measures. Progressive loss of complexity (decreased ApEn, r=-0.69, P<0.001) and alterations of long-term fractal-like heart rate behavior (increased alpha(2), r=0.63, decreased beta, r=-0.60, P<0.001 for both) were observed thereafter from middle age (40 to 60 years, n=29) to old age (>60 years, n=29). CONCLUSIONS: Cardiac interbeat interval dynamics change markedly from childhood to old age in healthy subjects. Children show complexity and fractal correlation properties of R-R interval time series comparable to those of young adults, despite lower overall heart rate variability. Healthy aging is associated with R-R interval dynamics showing higher regularity and altered fractal scaling consistent with a loss of complex variability.

Blood vitamins, mineral elements and inflammation markers as risk factors of vascular and non-vascular disease mortality in an elderly population.

BACKGROUND: The need for protecting agents against degenerative processes of the body has been proposed to be especially high in elderly people. In order to evaluate the prognostic value of various biochemical factors in ageing the associations of blood concentrations of several vitamins, mineral elements and some other suggested risk factors with vascular and non-vascular mortality were studied in an elderly population. METHODS: A large health survey with complete clinical evaluation was carried out in the City of Turku in 1982-1983. A random sample of 344 community-living elderly individuals aged 65 years or older, stratified into four age groups, was studied. During the 13 years follow-up 225 subjects had died. Calcium, magnesium, copper, ceruloplasmin, zinc, selenium, iron, ferritin, transferrin, alpha-tocopherol, retinol, folate, vitamin B12, malondialdehyde, orosomucoid and insulin levels were analysed from the blood specimens. The relations between the compounds measured and relative mortality risks during the 13-year follow-up were analysed by Cox proportional hazards model adjusting for other known risk factors. RESULTS AND CONCLUSIONS: High concentrations of serum copper, orosomucoid and insulin were associated with increased risk of vascular mortality. The relative risks within the subjects of the highest tertile of serum concentrations were 2.2 for copper, 1.8 for orosomucoid, and 1.8 for insulin when adjusted for many confounding risk factors. Low serum vitamin B12 concentrations appeared to be significantly (P = 0.01) associated with increased vascular mortality. The associations were essentially not more significant when adjusted only for age. Contrary to earlier observations concentrations of serum magnesium, selenium, alpha-tocopherol, iron and its binding proteins or plasma and erythrocyte folate were not associated with increased mortality risk when adjusted for confounding risk factors. The authors suggest that in elderly subjects these elements and compounds are at the most weak, and probably non-independent risk factors for vascular mortality.

Environmental differences in twin pairs discordant for Alzheimer's disease.

The aim of this study was to examine the contribution of environmental factors to the pathogenesis of Alzheimer's disease by comparing environmental differences in twin pairs discordant for Alzheimer's disease. Seventy four twin pairs discordant for Alzheimer's disease were found by linking the Finnish twin cohort and the Hospital Discharge Register from years 1972-91. In 50 pairs (25 monozygotic and 25 dizygotic pairs), both co-twins had responded to a questionnaire survey in 1975. Exposure differences were compared between these pairs. A reduced risk of Alzheimer's disease was significantly associated with a higher level of schooling (relative risk 0.3; 95% confidence interval 0.1-0.9, p=0.029). In addition, a reduced risk was suggestively associated with ambidextrousness or left handedness (p=0.083) and an increased risk with marriage (p=0.052), widowhood (p=0.074), and a history of cholelithiasis (p=0.071). In conclusion, a reduced risk of Alzheimer's disease was associated with a higher level of schooling.

Oral mucosal changes in coeliac patients on a gluten-free diet.

Oral mucosal lesions or dental enamel defects may be the only presenting features of coeliac disease. A series of 128 patients with coeliac disease (CD) on a gluten-free diet (GFD), 8 patients with a newly diagnosed CD, and 30 healthy controls participated in a clinical and histopathological study of their oral mucosa. Oral mucosal lesions occurred in 71/128 GFD-treated CD patients. in 4/8 untreated and in 10/30 controls, and oral symptoms in 85/128, in 6/8 and in 10/30, respectively. Five CD patients had aphthous ulcers. Moderate to severe lymphocytic inflammation occurred in 36/117 and in 14/117 of the biopsy specimens of GFD-treated CD patients, in 1/8 and 2/8 of untreated CD patients, and in 3/30 and in 1/30 of controls, respectively. Intraepithelial T-cells were significantly more frequent in GFD-treated CD patients than in controls. There was no difference between untreated CD patients and controls. In the lamina propria of the GFD-treated CD patients, T-cells were more frequent than in the other groups. Mast cells were significantly more frequent in patients with GFD-treated CD. Nine GFD-treated CD patients had raised serum endomysium IgA antibody titres, although five of them reported to follow a strict GFD. A lack of strict compliance with a GFD may be related to the high prevalence of oral changes and symptoms. In addition, T-cell infiltration in the oral mucosa tends to increase with a longer duration of CD, independent of GFD-treatment. Clinically, it is important to study the oral cavity of patients suspected of having CD where the only clue to the disease may reside, since no less than 66% of the patients in this study had oral symptoms.

Power-law relationship of heart rate variability as a predictor of mortality in the elderly.

BACKGROUND: The prognostic role of heart rate (HR) variability analyzed from 24-hour ECG recordings in the general population is not well known. We studied whether analysis of 24-hour HR behavior is able to predict mortality in a random population of elderly subjects. METHODS AND RESULTS: A random sample of 347 subjects of > or =65 years of age (mean, 73+/-6 years) underwent a comprehensive clinical evaluation, laboratory tests, and 24-hour ECG recordings and were subsequently followed up for 10 years. Various spectral and nonspectral measures of HR variability were analyzed from the baseline 24-hour ECG recordings. Risk factors for all-cause, cardiac, cerebrovascular, cancer, and other causes of death were assessed. By the end of 10-year follow-up, 184 subjects (53%) had died and 163 (47%) were still alive. Seventy-four subjects (21%) had died of cardiac disease, 37 of cancer (11%), 25 of cerebrovascular disease (7%), and 48 (14%) of various other causes. Among all analyzed variables, a steep slope of the power-law regression line of HR variability (< -1.50) was the best univariate predictor of all-cause mortality (odds ratio, 7.9; 95% confidence interval [CI], 3.7 to 17.0; P<.0001). After adjusting for age and sex and including all univariate predictors of mortality in the proportional hazards analysis, ie, measures of HR variability, history of heart disease, functional class, smoking, medication, and blood cholesterol and glucose concentrations, all-cause mortality was predicted only by the slope of HR variability (adjusted relative risk, 1.74; 95% CI, 1.42 to 2.13; P<.0001) and a history of congestive heart failure (adjusted relative risk, 1.70; P=.0002). The slope of HR variability predicted both cardiac (adjusted relative risk, 2.05; P=.0002) and cerebrovascular death (adjusted relative risk, 2.84; P=.0001) but not cancer or other causes of death. CONCLUSIONS: Power-law relationship of 24-hour HR variability is a more powerful predictor of death than the traditional risk markers in elderly subjects. Altered long-term behavior of HR implies an increased risk of vascular causes of death rather than being a marker of any disease or frailty leading to death.

Lifestyle, stress, and genes in peptic ulcer disease: a nationwide twin cohort study.

BACKGROUND: The familial accumulation of peptic ulcer disease observed in several studies may be attributable to genetic effects, aggregation of environmental exposure (shared environment), or both. The intrafamilial spread of Helicobacter pylori infection has raised the question whether shared environment could explain the familial aggregation of peptic ulcer disease rather than genetic similarity of family members. OBJECTIVE: To examine the contribution of genetic and environmental factors to the pathogenesis of peptic ulcer disease in a nationwide population-based cohort of adult twins. METHODS: The Finnish Twin Cohort consists of all same-sexed twin pairs born before 1958 with both twins alive in 1975. The total number of twin pairs is 13888, of whom 4307 are monozygotic (MZ) and 9581 are dizygotic (DZ) twins. Questionnaire surveys of twins were carried out in 1975, 1981, and 1990, including medical and psychosocial questions. One question asked whether a physician had ever made a diagnosis of gastric or duodenal ulcer. In addition, hospital discharge data from 1972 to 1991 were linked with the twin cohort to obtain those twin individuals who had been treated for gastric or duodenal ulcer. The prevalence of and concordance for peptic ulcer disease were examined in MZ and DZ twins. Model-fitting analysis was used to specify the relative roles of genetic and environmental factors. The contribution of lifestyle factors and stress was examined prospectively in an incidence study and by comparison of discordant pairs. RESULTS: The prevalence of peptic ulcer disease was 6.2% in men and 2.8% in women in 1975. There were 63 MZ and 86 DZ pairs concordant for peptic ulcer disease. Concordance for disease was significantly higher in MZ than in DZ twin pairs; the probandwise concordance rate was 23.6% (95% confidence interval [CI], 20.9%-26.3%) in MZ twins and 14.8% (95% CI, 13.3%-16.3%) in DZ twins. In the model-fitting analysis, a model with both additive genetic and unshared environmental effects had the best goodness-of-fit. Thirty-nine percent (95% CI, 32%-47%) of the liability to peptic ulcer disease was explained by genetic factors and 61% (95% CI, 53%-68%) by individual environmental factors. In the incidence study (logistic regression analysis of the entire cohort initially free of peptic ulcer disease, with subjects diagnosed as having peptic ulcer after 1975 as cases), current smoking (relative risk, 2.2; 95% CI, 1.5-3.2) and high stress levels (relative risk, 3.2; 95% CI, 1.4-7.6) in men and regular use of analgesics (relative risk, 3.3; 95% CI, 1.3-8.1) in women predicted peptic ulcer disease during the follow-up from 1976 to 1991. In the analysis of discordant pairs, smoking in men and regular use of analgesics in both sexes were predictors of peptic ulcer disease. CONCLUSIONS: The questionnaire and hospital usage data on peptic ulcer disease in the population-based twin cohort suggest that the familial aggregation of the disease is modest, and attributable almost solely to genetic factors. Environmental effects not shared by family members were significant predictors of disease, and they were attributable to smoking and stress in men and the use of analgesics in women. The minor effects of shared environment to disease liability do not support the concept that the clustering of risk factors, such as H pylori infection, would explain the familial accumulation of peptic ulcer disease.

Cerebrospinal fluid tau protein as a biochemical marker for Alzheimer's disease: a community based follow up study.

OBJECTIVES: Biochemical markers for Alzheimer's disease would be of great value, especially to help in diagnosis early in the course of the disease. A pronounced increase in CSF tau protein (CSF-tau) is found in most patients with Alzheimer's disease. However, the specificity has to be further studied, as an increase in CSF-tau has also been found in other dementias, especially in vascular dementia. As most previous CSF studies have been based on selected inpatients, it was considered of special interest to examine the diagnostic potential of CSF-tau in a community population based sample of consecutive patients with dementia. Such patient material has been examined at the Piteå River Valley Hospital in Northern Sweden since 1986, and includes all those with memory disturbances in the community. The aim was also to study if an increase in CSF-tau is found early in the disease process, and whether CSF-tau changes during the progression of disease. PARTICIPANTS: Community population based sample of 75 demented patients (43 with Alzheimer's disease, 21 with vascular dementia, and 11 with mixed Alzheimer's disease/vascular dementia), 18 healthy subjects, and 18 neurological controls. A follow up investigation (including analysis of a new CSF sample) was performed in all patients after about one year. MAIN OUTCOME MEASURES: Concentrations of total (both normal tau and PHF-tau) tau in CSF, clinical measures (duration and severity of dementia), and apoE polymorphism. RESULTS: CSF-tau was markedly increased in Alzheimer's disease, 41/43 (95%) patients had values above the cut off level (mean+2 SD) in controls (306 pg/ml). High CSF-tau concentrations were also found in most patients with vascular dementia, preferentially in patients with vascular dementia without progressive leukoaraiosis on CT, whereas patients with vascular dementia with progressive leukoaraiosis had normal CSF-tau. Concentrations of CSF-tau were stable at one year follow up in both patients with Alzheimer's disease and patients with vascular dementia, and there was no correlation between CSF-tau and either duration or severity of dementia. CONCLUSIONS: The findings confirm the high sensitivity of CSF-tau for the diagnosis of Alzheimer's disease, but high CSF-tau was also found in vascular dementia, resulting in a lower specificity. However, high CSF-tau is preferentially found in patients with vascular dementia without progressive leukoaraiosis, which may constitute a group with concomitant Alzheimer's disease pathology. High CSF-tau may be present during the whole course of the disease in Alzheimer's disease. Possibly, therefore, the same high CSF-tau concentrations may be present before the onset of clinical dementia. Follow up studies on such patients will tell whether analysis of CSF-tau is useful as a biochemical marker for early Alzheimer's disease.