Accumulation of Lewy-Related Pathology Starts in Middle Age: The Tampere Sudden Death Study.

When effective treatments against neurodegenerative diseases become a reality, it will be important to know the age these pathologies begin to develop. We investigated alpha-synuclein pathology in brain tissue of the Tampere Sudden Death Study-unselected forensic autopsies on individuals living outside hospital institutions in Finland. Of 562 (16-95 years) participants, 42 were positive for Lewy-related pathology (LRP). The youngest LRP case was aged 54 years, and the frequency of LRP in individuals aged ≥50 years was 9%. This forensic autopsy study indicates LRP starts already in middle age and is more common than expected in the ≥50 years-of-age non-hospitalized population. ANN NEUROL 2024;95:843-848.

Sex differences in coronary atherosclerosis during the pre- and postmenopausal period: The Tampere Sudden Death Study.

BACKGROUND AND AIMS: Women are believed to be protected from coronary heart disease (CHD) by the effects of estrogen but detailed studies on the vessel wall level are missing. We aimed to measure sex differences in atherosclerosis during the premenopausal and postmenopausal periods directly at the coronary arteries. METHODS: We analyzed statistics for sex differences in CHD mortality in Finland in 2020. Coronary atherosclerosis was measured using computer-assisted morphometry in 10-year age groups of 185 white Caucasian women and 515 men from the Tampere Sudden Death Study. RESULTS: CHD mortality was rare in both women and men before 50 years of age. After 50 years of age, male mortality increased rapidly, with women reaching equal levels in the oldest age groups. In the autopsy series, there were no differences in fatty streak, fibrotic or calcified plaque areas, nor in the plaque area or stenosis percentage in coronary arteries between premenopausal women and men in the same age group. The plaque area remained 25 % smaller in both coronaries in postmenopausal women aged 51-70 years compared to men. In the oldest postmenopausal group (≥70 years), plaque area reached the level of men. In the postmenopausal period, coronary stenosis in the left anterior descending (LAD) artery remained lower among women. CONCLUSION: We did not detect any major sex-difference in coronary atherosclerosis in the premenopausal period when women are considered to be protected from CHD. However, in line with CHD mortality statistics, postmenopausal women showed a slower speed of coronary atherosclerosis development compared to men.

Thrombus Aspirates From Patients With Acute Ischemic Stroke Are Infiltrated by Viridans Streptococci.

BACKGROUND: Acute ischemic stroke may be due to embolism from ruptured atherosclerotic carotid arteries. DNA of oral bacteria, mainly the viridans streptococci group, has been detected in thrombus aspirates of patients with ischemic stroke as well as in carotid endarterectomy samples. Because viridans streptococci are known to possess thrombogenic properties, we studied whether their presence in thrombus aspirates and in carotid artery specimens can be confirmed using bacterial immunohistochemistry. METHODS AND RESULTS: Thrombus aspirates from 61 patients with ischemic stroke (70.5% men; mean age, 66.8 years) treated with mechanical thrombectomy, as well as carotid endarterectomy samples from 20 symptomatic patients (65.0% men; mean age, 66.2 years) and 48 carotid artery samples from nonstroke autopsy cases (62.5% men; mean age, 66.4 years), were immunostained with an antibody cocktail against 3 species (Streptococcus sanguinis, Streptococcus mitis, and Streptococcus gordonii) of viridans streptococci. Of the thrombus aspirates, 84.8% were immunopositive for viridans streptococci group bacteria, as were 80.0% of the carotid endarterectomy samples, whereas immunopositivity was observed in 31.3% of the carotid artery samples from nonstroke autopsies. Most streptococci were detected inside neutrophil granulocytes, but there were also remnants of bacterial biofilm as well as free bacterial infiltrates in some samples. CONCLUSIONS: Oral streptococci were found in aspirated thrombi of patients with acute ischemic stroke as well as in carotid artery samples. Our results suggest that viridans streptococci group bacteria may play a role in the pathophysiology of ischemic stroke.

The prognostic significance of the electrical QRS axis on long-term mortality in acute coronary syndrome patients - The TACOS study.

INTRODUCTION: There are several potential causes of QRS-axis deviation in the ECG, but there is limited data on the prognostic significance of QRS-axis deviation in ACS patients. SUBJECTS AND METHODS: We evaluated the long-term prognostic significance of acute phase frontal plane QRS-axis deviation and its shift during hospital stay in ACS patients. A total of 1026 patients who met the inclusion criteria were divided into three categories: normal (n = 823), left (n = 166) and right/extreme axis (n = 37). RESULTS: The median survival time was 9.0 years (95% CI 7.9-10.0) in the normal, 3.6 years (95% CI 2.4-4.7) in the left and 1.3 years (95% CI 0.2-2.4) in the right/extreme axis category. Both short and long-term all-cause mortality was lowest in the normal axis category and highest in the right/extreme axis category. Compared to normal axis, both admission phase QRS-axis deviation groups were independently associated with a higher risk of all-cause mortality. When including left ventricular hypertrophy in the ECG, only the right/extreme axis retained its statistical significance (aHR 1.76; 95% CI 1.16-2.66, p = 0.007). Axis shift to another axis category had no effect on mortality. CONCLUSION: In ACS patients, acute phase QRS-axis deviation was associated with higher risk of all-cause mortality. Among the axis deviation groups, right/extreme QRS-axis deviation was the strongest predictor of mortality in the multivariable analysis. Further studies are required to investigate to what extent this association is caused by pre-existing or by ACS-induced axis deviations. QRS-axis shift during hospital stay had no effect on all-cause mortality.

Association between Oral Pathology, Carotid Stenosis, and Oral Bacterial DNA in Cerebral Thrombi of Patients with Stroke.

METHODS: Thrombus aspirates and control arterial blood were taken from 71 patients (70.4% male; mean age, 67.4 years) with acute ischemic stroke. Tooth pathology was registered using CT scans. Carotid stenosis was estimated with CTA and ultrasonography. The presence of bacterial DNA from aspirated thrombi was determined using quantitative PCR. We also analyzed the presence of these bacterial DNAs in carotid endarterectomies from patients with peripheral arterial disease. RESULTS: Bacterial DNA was found in 59 (83.1%) of the thrombus aspirates (median, 8.6-fold). Oral streptococcal DNA was found in 56 (78.9%) of the thrombus aspirates (median, 5.1-fold). DNA from A. actinomycetemcomitans and P. gingivalis was not found. Most patients suffered from poor oral health and had in median 19.0 teeth left. Paradoxically, patients with better oral health had more oral streptococcal DNA in their thrombus than the group with the worst pathology (p = 0.028). There was a trend (OR 7.122; p = 0.083) in the association of ≥50% carotid artery stenosis with more severe dental pathology. Oral streptococcal DNA was detected in 2/6 of carotid endarterectomies. CONCLUSIONS: Stroke patients had poor oral health which tended to associate with their carotid artery stenosis. Although oral streptococcal DNA was found in thrombus aspirates and carotid endarterectomy samples, the amount of oral streptococcal DNA in thrombus aspirates was the lowest among those with the most severe oral pathology. These results suggest that the association between poor oral health and acute ischemic stroke is linked to carotid artery atherosclerosis.

The Effect of Atrial Fibrillation on the Long-Term Mortality of Patients with Acute Coronary Syndrome: The TACOS Study.

INTRODUCTION: Atrial fibrillation (AF) is a frequent finding in acute coronary syndrome (ACS), but there is conflicting scientific evidence regarding its long-term impact on patient outcome. The aim of this study was to survey and compare the ≥10-year mortality of ACS patients with sinus rhythm (SR) and AF. METHODS: Patients were divided into 2 groups based on rhythm in their 12-lead ECGs: (1) SR (n = 788) at hospital admission and discharge (including sinus bradycardia, physiological sinus arrhythmia, and sinus tachycardia) and (2) AF/atrial flutter (n = 245) at both hospital admission and discharge, or SR and AF combination. Patients who failed to match the inclusion criteria were excluded from the final analysis. The main outcome surveyed was long-term all-cause mortality between AF and SR groups during the whole follow-up time. RESULTS: Consecutive ACS patients (n = 1,188, median age 73 years, male/female 58/42%) were included and followed up for ≥10 years. AF patients were older (median age 77 vs. 71 years, p < 0.001) and more often female than SR patients. AF patients more often presented with non-ST-elevation myocardial infarction (69.8 vs. 50.4%, p < 0.001), had a higher rate of diabetes (31.0 vs. 22.8%, p = 0.009), and were more often using warfarin (32.2 vs. 5.1%, p < 0.001) or diuretic medication (55.1 vs. 25.8%, p < 0.001) on admission than patients with SR. The use of warfarin at discharge was also more frequent in the AF group (55.5 vs. 14.8%, p < 0.001). The rates of all-cause and cardiovascular mortality were higher in the AF group (80.9 vs. 50.3%, p < 0.001, and 73.8 vs. 69.6%, p = 0.285, respectively). In multivariable analysis, AF was independently associated with higher mortality when compared to SR (adjusted HR 1.662; 95% CI: 1.387-1.992, p < 0.001). CONCLUSION: AF/atrial flutter at admission and/or discharge independently predicted poorer long-term outcome in ACS patients, with 66% higher mortality within the ≥10-year follow-up time when compared to patients with SR.

Changes in the metabolic profile of human male postmortem frontal cortex and cerebrospinal fluid samples associated with heavy alcohol use.

Heavy alcohol use is one of the top causes of disease and death in the world. The brain is a key organ affected by heavy alcohol use. Here, our aim was to measure changes caused by heavy alcohol use in the human brain metabolic profile. We analyzed human postmortem frontal cortex and cerebrospinal fluid (CSF) samples from males with a history of heavy alcohol use (n = 74) and controls (n = 74) of the Tampere Sudden Death Series cohort. We used a nontargeted liquid chromatography mass spectrometry-based metabolomics method. We observed differences between the study groups in the metabolite levels of both frontal cortex and CSF samples, for example, in amino acids and derivatives, and acylcarnitines. There were more significant alterations in the metabolites of frontal cortex than in CSF. In the frontal cortex, significant alterations were seen in the levels of neurotransmitters (e.g., decreased levels of GABA and acetylcholine), acylcarnitines (e.g., increased levels of acylcarnitine 4:0), and in some metabolites associated with alcohol metabolizing enzymes (e.g., increased levels of 2-piperidone). Some of these changes were also significant in the CSF samples (e.g., elevated 2-piperidone levels). Overall, these results show the metabolites associated with neurotransmitters, energy metabolism and alcohol metabolism, were altered in human postmortem frontal cortex and CSF samples of persons with a history of heavy alcohol use.

Poor long-term outcome in acute coronary syndrome in a real-life setting: Ten-year outcome of the TACOS study.

BACKGROUND: Long-term outcome of the three categories of acute coronary syndrome (ACS) in real-life patient cohorts is not well known. The objective of this study was to survey the 10-year outcome of an ACS patient cohort admitted to a university hospital and to explore factors affecting the outcome. METHODS: A total of 1188 consecutive patients (median age 73 years) with ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI) or unstable angina pectoris (UA) in 2002-2003 were included and followed up for ≥ 10 years. RESULTS: Mortality for STEMI, NSTEMI and UA patients during the follow-up period was 52.5%, 69.9% and 41.0% (p < 0.001), respectively. In multivariable Cox regression analysis, only age and creatinine level at admission were independently associated with patient outcome in all the three ACS categories when analyzed separately. CONCLUSIONS: All the three ACS categories proved to have high mortality rates during long-term followup in a real-life patient cohort. NSTEMI patients had worse outcome than STEMI and UA patients during the whole follow-up period. Our study results indicate clear differences in the prognostic significance of various demographic and therapeutic parameters within the three ACS categories.

Long-term outcome of pre-specified ECG patterns in acute coronary syndrome.

BACKGROUND: Long-term outcome of real-life acute coronary syndrome (ACS) patients with selected ECG patterns is not well known. PURPOSE: To survey the 10-year outcome of pre-specified ECG patterns in ACS patients admitted to a university hospital. METHODS: A total of 1184 consecutive acute coronary syndrome patients in 2002-2003 were included and followed up for 10 years. The patients were classified into nine pre-specified ECG categories: 1) ST elevation; 2) pathological Q waves without ST elevation; 3) left bundle branch block (LBBB); 4) right bundle branch block (RBBB) 5) left ventricular hypertrophy (LVH) without ST elevation except in leads aVR and/or V1; 6) global ischemia ECG (ST depression ≥0.5 mm in 6 leads, maximally in leads V4-5 with inverted T waves and ST elevation ≥0.5 mm in lead aVR); 7) other ST depression and/or T wave inversion; 8) other findings and 9) normal ECG. RESULTS: Any abnormality in the ECG, especially Q waves, LBBB, LVH and global ischemia, had negative effect on outcome. In age- and gender adjusted Cox regression analysis, pathological Q waves (HR 2.28, 95%CI 1.20-4.32, p = .012), LBBB (HR 3.25, 95%CI 1.65-6.40, p = .001), LVH (HR 2.53, 95%CI 1.29-4.97, p = .007), global ischemia (HR 2.22, 95%CI 1.14-4.31, p = .019) and the combined group of other findings (HR 3.01, 95%CI 1.56-6.09, p = .001) were independently associated with worse outcome. CONCLUSIONS: During long-term follow-up of ACS patients, LBBB, ECG-LVH, global ischemia, and Q waves were associated with worse outcome than a normal ECG, RBBB, ST elevation or ST depression with or without associated T-wave inversion. LBBB was associated with the highest mortality rates.

The prognostic significance of a positive or isoelectric T wave in lead aVR in patients with acute coronary syndrome and ischemic ECG changes in the presenting ECG - Long-term follow-up data of the TACOS study.

BACKGROUND: A positive T wave in lead aVR (aVRT+) is an independent prognostic predictor of cardiovascular mortality in the general population as well as in cardiovascular disease. SUBJECTS AND METHODS: We evaluated the prognostic impact of aVRT+ in an ECG recorded as close to hospital discharge as possible in acute coronary syndrome patients (n = 527). We divided the patients into three categories based on the findings in the admission ECG: ST elevation, global ischemia and other ST/T changes. RESULTS: In the whole study population, and in all the three ECG subgroups, the 10-year all-cause mortality rate was higher in the aVRT+ group than in the aVRT- group. In Cox regression analysis, the age and gender adjusted hazard ratio (HR) for aVRT+ to predict all-cause mortality in the whole study population was 1.43 (95% confidence interval [CI] 1.12-1.83; p = 0.004). To predict cardiovascular mortality, the age and gender adjusted HR for aVRT+ was 1.54 (95% CI 1.14-2.07; p = 0.005) in the whole study population and 2.07 (95% CI 1.07-4.03; p = 0.032) in the category with other ST/T changes. CONCLUSION: In ACS patients with or without ST elevation, but with ischemic ST/T changes in their presenting ECG, a positive or isoelectric T wave in lead aVR in an ECG recorded in the subacute in-hospital stage is associated with all-cause and cardiovascular mortality during long-term follow-up. Clinicians should pay attention to this simple ECG finding at hospital discharge.

Age-dependent association of gut bacteria with coronary atherosclerosis: Tampere Sudden Death Study.

BACKGROUND: The gut microbiome is thought to remain stable into old age. Gut bacteria and their translocation may play a role in the development of coronary heart disease (CHD) by modulating cholesterol levels and immune responses, as well as by producing toxic metabolites and bacterial endotoxins. The association of changes in the gut microbiome with the severity of coronary atherosclerosis and the ability of gut bacteria themselves to translocate into coronary plaques has not been studied. MATERIALS AND METHODS: As a part of the Tampere Sudden Death Study, we measured age-dependent changes in the relative ratios of major intestinal bacterial communities (Bacteroides species [spp.], the Clostridium leptum group, the Clostridium coccoides group, Bifidobacterium spp., Enterobactericeae, Lactobacillus spp.) and Streptococcus spp. in both feces and coronary plaques of the same male autopsy cases (n = 67, age range 44-95) using real-time quantitative PCR (qPCR). The area of coronary atherosclerotic lesions were measured by computer-assisted morphometry. Fecal bacterial DNA measurements from healthy volunteers served as a control for gut bacterial analyses of autopsy cases. The relative amount of bacterial DNA in a sample was determined with the comparative Cq method. RESULTS: The relative ratios of fecal Lactobacillus spp., Bifidobacterium spp., the Clostridium coccoides group, and Bacteroides spp. did not differ between controls and autopsy cases and showed no age-dependence. In contrast, the ratios of the Clostridium leptum group, Enterobactericeae, and Streptococcus spp. increased with age. Elevated relative ratios of fecal Enterobactericeae associated with a larger coronary plaque fibrotic area (p = 0.001), and the Clostridium leptum group with a larger calcification area (p = 0.015). Intestinal bacterial DNA could be amplified in 67.6% of the coronary plaques, the most common being Streptococcus spp. (41.0%), followed by Enterobactericeae (12.1%), Clostridium leptum (2.4%), and Lactobacillus spp. (2.4%). The percentages of Streptococcus spp. DNA decreased, and those of Enterobactericeae increased in coronary plaques along with age. CONCLUSIONS: DNA of the Clostridium leptum group and pathogenic Enterobactericeae increase in the gut microbiome with age and can be detected in the same individual's coronary plaques along with pathogenic Streptococcus spp., associating with more severe coronary atherosclerosis.

Oral Bacterial Signatures in Cerebral Thrombi of Patients With Acute Ischemic Stroke Treated With Thrombectomy.

Background Chronic infections have been reported to be risk factors for both coronary heart disease and ischemic stroke. DNA of oral bacteria, mainly from the viridans streptococci group, has been detected in coronary thrombus aspirates of myocardial infarction and cerebral aneurysms. Viridans streptococci are known to cause infective endocarditis and possess thrombogenic properties. We studied the presence of oral bacterial DNA in thrombus aspirates of patients with acute ischemic stroke treated with mechanical thrombectomy. Methods and Results Thrombus aspirates and arterial blood were taken from 75 patients (69% men; mean age, 67 years) with acute ischemic stroke. The presence of Streptococcus species, mainly the Streptococcus mitis group, belonging to viridans streptococci as well as Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans in samples were determined using a quantitative polymerase chain reaction with specific primers and probes. The relative amount of bacterial DNA in a sample was determined with the comparative threshold cycle method. Bacterial DNA was detected in 84% (n=63) of aspired thrombi, and 16% (n=12) of samples were considered bacterial DNA negative. DNA of Streptococcus species, mainly the S mitis group, was found in 79% (n=59) of samples. The median relative amount of Streptococcus species DNA was 5.10-fold higher compared with the control blood samples from the same patients. All thrombi were negative for both P gingivalis and A actinomycetemcomitans. Conclusions This is the first study showing the common presence of bacterial DNA from viridans streptococci in aspired thrombi of patients with acute ischemic stroke. Streptococcal bacteria, mostly of oral origin, may contribute to the progression and thrombotic events of cerebrovascular diseases.

Bacterial signatures in thrombus aspirates of patients with lower limb arterial and venous thrombosis.

OBJECTIVE: Increasing data supports the role of bacterial inflammation in adverse events of cardiovascular and cerebrovascular diseases. In our previous research, DNA of bacterial species found in coronary artery thrombus aspirates and ruptured cerebral aneurysms were mostly of endodontic and periodontal origin, where Streptococcus mitis group DNA was the most common. We hypothesized that the genomes of S mitis group could be identified in thrombus aspirates of patients with lower limb arterial and deep venous thrombosis. METHODS: Thrombus aspirates and control blood samples taken from 42 patients with acute or acute-on-chronic lower limb ischemia (Rutherford I-IIb) owing to arterial or graft thrombosis (n = 31) or lower limb deep venous thrombosis (n = 11) were examined using a quantitative real-time polymerase chain reaction to detect all possible bacterial DNA and DNA of S mitis group in particular. The samples were considered positive, if the amount of bacterial DNA in the thrombus aspirates was 2-fold or greater in comparison with control blood samples. RESULTS: In the positive samples the mean difference for the total bacterial DNA was 12.1-fold (median, 7.1), whereas the differences for S mitis group DNA were a mean of 29.1 and a median of 5.2-fold. Of the arterial thrombus aspirates, 57.9% were positive for bacterial DNA, whereas bacterial genomes were found in 75% of bypass graft thrombosis with 77.8% of the prosthetic grafts being positive. Of the deep vein thrombus aspirates, 45.5% contained bacterial genomes. Most (80%) of bacterial DNA-positive cases contained DNA from the S mitis group. Previous arterial interventions were significantly associated with the occurrence of S mitis group DNA (P = .049, Fisher's exact test). CONCLUSIONS: This is the first study to report the presence of bacterial DNA, predominantly of S mitis group origin, in the thrombus aspirates of surgical patients with lower limb arterial and deep venous thrombosis, suggesting their possible role in the pathogenesis of thrombotic events. Additional studies will, however, be needed to reach a final conclusion.

A Validation Study of Vascular Cognitive Impairment Genetics Meta-Analysis Findings in an Independent Collaborative Cohort.

Vascular cognitive impairment (VCI), including its severe form, vascular dementia (VaD), is the second most common form of dementia. The genetic etiology of sporadic VCI remains largely unknown. We previously conducted a systematic review and meta-analysis of all published genetic association studies of sporadic VCI prior to 6 July 2012, which demonstrated that APOE (ɛ4, ɛ2) and MTHFR (rs1801133) variants were associated with susceptibility for VCI. De novo genotyping was conducted in a new independent relatively large collaborative European cohort of VaD (nmax = 549) and elderly non-demented samples (nmax = 552). Where available, genotype data derived from Illumina's 610-quad array for 1210 GERAD1 control samples were also included in analyses of genes examined. Associations were tested using the Cochran-Armitage trend test: MTHFR rs1801133 (OR = 1.36, 95% CI 1.16-1.58, p = <0.0001), APOE rs7412 (OR = 0.62, 95% CI 0.42-0.90, p = 0.01), and APOE rs429358 (OR = 1.59, 95% CI 1.17-2.16, p = 0.003). Association was also observed with APOE epsilon alleles; ɛ4 (OR = 1.85, 95% CI 1.35-2.52, p = <0.0001) and ɛ2 (OR = 0.67, 95% CI 0.46-0.98, p = 0.03). Logistic regression and Bonferroni correction in a subgroup of the cohort adjusted for gender, age, and population maintained the association of APOE rs429358 and ɛ4 allele.

Predicting sudden cardiac death using common genetic risk variants for coronary artery disease.

AIMS: Genome-wide association studies (GWAS) have identified many variants associating with an increased risk of coronary artery disease (CAD). We studied the possible association between these variants and the risk of sudden cardiac death (SCD). METHODS AND RESULTS: A weighted genetic risk score (GRSCAD) was formed from variants most strongly associating with CAD identified by the CARDIoGRAMplusC4D Consortium explaining 10.6% of the heritability of CAD [153 single-nucleotide polymorphisms with r(2) < 0.2]. The association between GRSCAD and the occurrence of SCD was studied in three independent autopsy series of consecutive cases combining altogether 1035 autopsies with 306 SCDs due to CAD (SCDCAD). The results were replicated in a prospective follow-up study of 2321 patients (mean follow-up time of 6.2 years with 48 incident SCDs of which 39 due to CAD) undergoing clinical exercise test at baseline. In a meta-analysis of the autopsy series, GRSCAD associated significantly with the risk of SCDCAD with age, body mass index, and sex adjusted odds ratio (OR) of 1.042 (1.023-1.061, P = 9.1 × 10(-6)) for one allele increase in GRSCAD. The same association was seen in both sexes. GRSCAD predicted significantly the risk of SCDCAD also in a prospective study setting (Cox regression analysis adjusted with all relevant clinical data): hazard ratio 1.049 (1.010-1.090, P = 0.014). In meta-analysis of all cohorts (adjusting further for other genetic markers related to traditional risk factors and QT-interval), the association was highly significant [OR 1.045 (1.028-1.063), P = 1.7 × 10(-7)]. CONCLUSION: Genetic risk estimate for CAD may also be used to predict SCD.

Βeta-fibrinogen gene promoter A -455 allele associated with poor longterm survival among 55-71 years old Caucasian women in Finnish stroke cohort.

BACKGROUND: Women die of stroke more often than men. After menopause, the incidence of ischemic stroke increases rapidly. Elevated fibrinogen levels and smoking have been associated with an increased risk of stroke. In gene-cluster haplotype analyses, the beta-fibrinogen (FGB) promoter -455 G/A polymorphic locus was most strongly associated with elevated plasma fibrinogen levels. We investigated whether the FGB -455 G/A polymorphism and smoking might interact with sex on longterm survival of acute stroke sufferers. METHODS: The Stroke Aging Memory (SAM) cohort comprising 486 consecutive stroke patients (55-85 years, 246 men, 240 women) subjected to clinical and MRI examination was followed over 12.5 years. During this period 347 (71.4%) patients died. The genotypes of the FGB -455 G/A polymorphism were determined by PCR. RESULTS: The FGB -455 G/A polymorphism genotype distributions were 64.7%, 32.1%, and 3.2% for GG, GA, and AA, respectively. During the follow-up, the FGB -455 A + genotype did not associate with survival, nor was there any genotype-by-smoking interaction on poor outcome in the total study population. However, women aged 55-71 years who carried the FGB -455 A-allele showed worse survival regardless of smoking status compared to non-smoking FGB -455 GG homozygotes (non-smokers, crude HR = 5.21, 95% CI: 1.38-19.7; smokers, crude HR = 7.03, 95% CI: 1.81-27.3). This association persisted in adjusted analyses. No such association was observed for women in the oldest age-group, nor among men. CONCLUSION: The A + genotype of the FGB -455 G/A polymorphism associated with poor survival among 55-71 years old Caucasian women in the Finnish stroke cohort.

Enterovirus RNA in blood is linked to the development of type 1 diabetes.

OBJECTIVE: To assess whether the detection of enterovirus RNA in blood predicts the development of clinical type 1 diabetes in a prospective birth cohort study. Further, to study the role of enteroviruses in both the initiation of the process and the progression to type 1 diabetes. RESEARCH DESIGN AND METHODS: This was a nested case-control study where all case children (N = 38) have progressed to clinical type 1 diabetes. Nondiabetic control children (N = 140) were pairwise matched for sex, date of birth, hospital district, and HLA-DQ-conferred genetic susceptibility to type 1 diabetes. Serum samples, drawn at 3- to 12-month intervals, were screened for enterovirus RNA using RT-PCR. RESULTS: Enterovirus RNA-positive samples were more frequent among the case subjects than among the control subjects. A total of 5.1% of the samples (17 of 333) in the case group were enterovirus RNA-positive compared with 1.9% of the samples (19 of 993) in the control group (P < 0.01). The strongest risk for type 1 diabetes was related to enterovirus RNA positivity during the 6-month period preceding the first autoantibody-positive sample (odds ratio 7.7 [95% CI 1.9-31.5]). This risk effect was stronger in boys than in girls. CONCLUSIONS: The present study supports the hypothesis that enteroviruses play a role in the pathogenesis of type 1 diabetes, especially in the initiation of the ß-cell damaging process. The enterovirus-associated risk for type 1 diabetes may be stronger in boys than in girls.

Human parechovirus 1 infections in young children--no association with type 1 diabetes.

The epidemiology, transmission and clinical symptoms of human parechoviruses [HPeV, classified earlier as enteroviruses; echovirus 22 (HPeV1) and echovirus 23 (HPeV2)] remain poorly characterized. Enteroviruses and one parechovirus species, the Ljungan virus, have been associated with type 1 diabetes in humans and rodents. The occurrence of human parechovirus 1 (HPeV1) infections in young children and their possible association with type 1 diabetes was evaluated. The prospective birth cohort study comprised 221 Finnish children carrying genetic type 1 diabetes susceptibility and who were observed from birth. Thirty-four children developed multiple diabetes-associated autoantibodies, and 18 children progressed to clinical type 1 diabetes during the follow-up. HPeV1 infections were diagnosed by measuring neutralizing antibodies from the follow-up sera taken every 3-12 months. In addition, viral RNA was analysed by RT-PCR from stool samples taken every month from six of the participants. HPeV1 infections were found to occur early in childhood. The median age of infection was 18 months and 20% of the children had had an infection by the age of 1 year. The number of infections started to increase from the age of 6 months and most children had their first infection by 36 months. Nearly all (99%) mothers were HPeV1 antibody positive. No difference was found in infection frequency between boys and girls, nor between prediabetic, diabetic and control subjects. Most infections (87%) occurred during autumn, winter and spring.