Multivariable Analysis of Pre-operative Brain Atrophy as a Predictor of Long Term Mortality After Carotid Endarterectomy.

OBJECTIVE: Brain atrophy is associated with an increased mortality rate in elderly trauma patients and in patients treated with mechanical thrombectomy for acute ischaemic stroke. In the setting of ischaemic stroke, the association between brain atrophy and death is stronger than that of sarcopenia. It has previously been shown that lower masseter area, as a marker of sarcopenia, is linked to lower survival after carotid endarterectomy (CEA). The aim of this study was to investigate whether brain atrophy is also associated with long term mortality in patients undergoing CEA. METHODS: A cohort of patients treated with CEA between 2004 and 2010 was retrieved from the Tampere University Hospital vascular registry and those with available pre-operative computed tomography (CT) imaging were analysed retrospectively. CT images were evaluated for brain atrophy index (BAI) and masseter muscle surface area and density. The association between BAI and mortality was investigated with Cox regression. RESULTS: Two hundred and thirty-three patients with a median (interquartile range [IQR]) age of 71 years (64.0, 77.0) were included. Most patients were operated on for symptomatic stenosis (n = 203; 87.1%). The median (IQR) duration of follow up was 115.0 months (66.0, 153.0), and 155 patients (66.5%) died during follow up. BAI was statistically significantly correlated with age (r = .489), average masseter density (r = -.202), and smoking (r = -.186; all p <.005). Increased BAI was statistically significantly associated with overall mortality (hazard ratio [HR] 1.45, 95% confidence interval [CI] 1.25 - 1.68, per one standard deviation [SD] increase) in the univariable analysis, and the association remained (HR 1.23, 95% CI 1.04 - 1.46, per one SD increase) in the multivariable models. Age, peripheral artery disease, and chronic obstructive pulmonary disease were also independently associated with mortality. The optimal cutoff value for BAI was 0.133. CONCLUSION: Brain atrophy independently predicts the long term post-operative mortality rate after CEA in a cohort containing mainly symptomatic patients. Future studies are needed to validate the results in prospective settings and in asymptomatic patients.

Pre-Operative Masseter Area is an Independent Predictor of Long-Term Survival after Carotid Endarterectomy.

OBJECTIVE/BACKGROUND: Sarcopenia is a predictor of mortality in elderly patients. Masseter area (MA) reflects sarcopenia in trauma patients. It was hypothesised that MA and Masseter density (MD) could be evaluated reliably from pre-operative computed tomography angiography (CTA) scans and that they predict post-operative survival in carotid endarterectomy (CEA) patients. METHODS: This was an observational registry study. Patients (n = 242) were operated on for asymptomatic stenosis (n = 32; 13.2%), amaurosis fugax (n = 41; 16.9%), transient ischaemic attack (n = 85; 35.1%), or ischaemic stroke (n = 84; 34.7%). Internal carotid artery stenoses were graded angiographically. Intraclass correlation coefficient (ICC) was used to analyse measurement reliability by three independent observers. Cox regression analysis was used to study the effect of MA and MD on survival (hazard ratio [HR]). RESULTS: Median patient age was 71.0 years (interquartile range [IQR] 13.0) and follow up time was 68.5 months (range 3-163 months); at the end of follow up (1 October 2017), 104 (43.0%) patients had died according to the National Population Register. The average MA (MAavg, the mean of left and right MA [median 394.0 mm2; IQR 110.1 mm2]) and MD (MDavg, the mean of left and right MD [median 53.5 HU; IQR 16.5 HU]) could be measured with excellent reliability (ICC > 0.865, p < .001 for all). In multivariable analyses only body surface area (BSA) (p < .001) and dental status were associated with MAavg (p = .021). Increased MAavg predicted lower mortality (HR 0.76, 95% confidence interval [CI] 0.61-0.96; p = .023) independent of age (HR 1.05, 95% CI 1.02-1.07; p = 0.001), female sex, body mass index, renal insufficiency, ipsilateral stenosis, indication category, and presence of teeth. MDavg was not associated with mortality. After further adjustment, BSA (the most significant determinant of MAavg) did not alter the association between MAavg and mortality (0.75, 95% CI 0.58-0.97; p = .031). CONCLUSION: Average MA but not MD measured from the pre-operative CTA scan provides a reliable estimate of post-operative long-term survival in CEA patients independent of other risk factors, anthropometric measurements, and dental status.

Chronic Kidney Diseases Among Patients Undergoing Elective Arthroplasty: Risk Groups and the Value of Serum Creatinine.

BACKGROUND: In arthroplasty clinics, we tend to evaluate patient's kidney function looking at serum creatinine (SCr), while estimated glomerular filtration rate (eGFR) is recommended. We reported the prevalence of chronic kidney disease (CKD; eGFR <60 mL/min/1.73 m2) in different patient groups and investigated whether CKD is missed by evaluation based on SCr. METHODS: Preoperative SCr values were used to calculate eGFR in 20,575 consecutive hip or knee arthroplasties. RESULTS: Prevalence of CKD was 9%-12%. It was higher among older women, knee arthroplasty patients, and patients with hypertension, diabetes, or coronary disease. Using SCr instead of eGFR leads to missing CKD in up to 7% of the cases. In older women and older patients with body mass index <25 kg/m2, half of CKD cases were missed. CONCLUSION: Use of eGFR instead of SCr to detect CKD more accurately is recommended.

White matter lesions are associated with hospital admissions because of hip-fractures and trauma after ischemic stroke.

BACKGROUND AND PURPOSE: Cerebral white matter lesions (WMLs), a surrogate for cerebral small-vessel disease, have been shown to be associated with decreasing mobility, gait instability, and falls. The aim of this study was to investigate whether WMLs of the brain are associated with increased incidence of hospital admissions because of any trauma and hip-fractures in a cohort of patients with stroke. METHODS: We included 383 consecutive patients aged 55 to 85 years with ischemic stroke admitted to the Helsinki University Central Hospital (The Stroke Aging Memory cohort) with a 12-year follow-up. National register data were reviewed for hip-fractures, other traumatic injuries, survival data, and causes of death. WMLs were rated using MRI and dichotomized as none to mild and moderate to severe. The data were analyzed using Kaplan-Meier plots (log-rank) and a complex Cox multivariable hazards models for multiple cases per subject to assess hazard ratios with their 95% confidence intervals. RESULTS: During the 12-year follow-up, there were more hip-fractures (13.5% versus 6.5%; log-rank, P=0.01) and more hospital admissions because of traumatic injury (22.2% versus 16.7%; log-rank, P=0.04) in the moderate-to-severe than in the none-to-mild WMLs group. In the complex samples, Cox multivariable model adjusting for age, sex, National Institutes of Health Stroke Scale, infarct size, and poststroke dementia, moderate-to-severe WMLs were associated with increased incidences of hospital admissions because of hip-fractures (hazard ratio, 3.98; 95% confidence interval, 1.55-10.21) and traumatic injuries including hip-fractures (hazard ratio, 1.72; 95% confidence interval, 1.03-2.87). CONCLUSIONS: Patients with ischemic stroke and moderate-to-severe WMLs are at high risk, who experience serious traumatic injuries and especially hip-fractures requiring hospital treatment.

Detection of prostate cancer by an electronic nose: a proof of principle study.

PURPOSE: We evaluate the ability of an electronic nose to discriminate prostate cancer from benign prostatic hyperplasia using urine headspace, potentially offering a clinically applicable noninvasive and rapid diagnostic method. MATERIALS AND METHODS: The ChemPro® 100-eNose was used to discriminate prostate cancer from benign prostatic hyperplasia using urine sample headspace. Its performance was tested with 50 patients with confirmed prostate cancer and 24 samples from 15 patients with benign prostatic hyperplasia (15 patients provided urine preoperatively and 9 patients provided samples 3 months postoperatively) scheduled to undergo robotic assisted laparoscopic radical prostatectomy or transurethral resection of prostate, respectively. The patients provided urine sample preoperatively and those with benign prostatic hyperplasia also provided samples 3 months postoperatively to be used as a pooled control sample population. A discrimination classifier was identified for eNose and subsequently, sensitivity and specificity values were determined. Leave-one-out cross-validation was performed. RESULTS: Using leave-one-out cross-validation the eNose reached a sensitivity of 78%, a specificity of 67% and AUC 0.77. CONCLUSIONS: The electronic nose is capable of rapidly and noninvasively discriminating prostate cancer and benign prostatic hyperplasia using urine headspace in patients undergoing surgery.

Poststroke dementia is associated with recurrent ischaemic stroke.

OBJECTIVE: To investigate whether poststroke dementia (PSD) diagnosed after ischaemic stroke predicts recurrent ischaemic stroke in long-term follow-up. METHODS: We included 486 consecutive patients with ischaemic stroke (388 with first-ever stroke) admitted to Helsinki University Central Hospital who were followed-up for 12 years. Dementia was diagnosed in 115 patients using the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition (DSM-III) criteria. The effects of risk factors and  PSD on survival free of recurrent stroke were estimated using Kaplan-Meier log-rank analyses, and the HRs for stroke recurrence were calculated using Cox proportional hazards models. RESULTS: In the entire cohort, patients with PSD had a shorter mean time to recurrent stroke (7.13 years, 95% CI 6.20 to 8.06) than patients without dementia (9.41 years, 8.89 to 9.92; log rank p<0.001). This finding was replicated in patients with first-ever stroke (6.89 years, 5.85 to 7.93 vs 9.68 years, 9.12 to 10.24; p<0.001). In Cox univariate analysis, PSD was associated with increased risk for recurrent stroke both in the entire cohort (HR 2.02; 95% CI 1.47 to 2.77) and in those with first-ever stroke (2.40; 1.68 to 3.42). After adjustment for the significant covariates of age, atrial fibrillation, peripheral arterial disease and hypertension, PSD was associated with increased risk for recurrent stroke both in the entire cohort (1.84; 1.34 to 2.54) and in those with first-ever stroke (2.16; 1.51 to 3.10). CONCLUSIONS: Poststroke dementia predicts recurrence of ischaemic stroke in long-term follow-up and should be considered when estimating prognosis.

Post-stroke depression and depression-executive dysfunction syndrome are associated with recurrence of ischaemic stroke.

BACKGROUND: Depression and depression-executive dysfunction syndrome (DES) are common neuropsychiatric consequences of stroke. We hypothesized that if stroke as a cerebrovascular event causes depression, this so-called post-stroke depression will further increase the risk of recurrent stroke. The objective of the study was to investigate whether patients with post-stroke depression or DES have increased rates of stroke recurrence. METHODS: We included 223 patients from the Helsinki Stroke Aging Memory cohort (n = 486) admitted to Helsinki University Central Hospital with a follow-up of 12 years. We included only patients with first-ever ischaemic stroke who were testable for depression and executive dysfunction. For follow-up, national register data were reviewed for all diagnosis codes of ischaemic stroke, survival data and causes of death. Neuropsychological and neuropsychiatric evaluations for depression and executive functions were performed 12-20 weeks after the index stroke. Univariate analysis was performed using χ(2), Mantel-Haenszel, ANOVA, and Kaplan-Meier log rank analyses. A Cox multivariable model with forced entry was used to adjust for stroke risk factors (age, gender, smoking, atrial fibrillation, hypertension, diabetes, peripheral arterial disease, hypercholesterolaemia). RESULTS: The mean time to first recurrent stroke was shorter for the depressed patient group (8.15, 95% CI 7.11-9.19 vs. 9.63, 8.89-10.38 years) and even shorter for patients with DES (7.15, 5.55-8.75 vs. 9.75, 9.09-10.41 years) compared to the remaining groups, respectively. The cumulative risk for recurrent ischaemic stroke in the 12-year follow-up was higher for the depression group (log rank p = 0.04) and for the DES group (log rank p = 0.01) compared to the remaining groups, respectively. Cox multivariable analyses revealed that the older age of the patient (1.05; 1.01-1.08/year), the absence of hypercholesterolaemia (0.24; 0.09-0.59), depression (1.68; 1.07-2.63), and DES (1.95; 1.14-3.33) were all associated with recurrent stroke. CONCLUSIONS: Depression and especially DES are associated with a shorter interval to recurrence of ischaemic stroke but executive dysfunction alone is not associated with a more rapid stroke recurrence. Diagnosis and treatment of depressive syndromes should be considered as a part of secondary prevention in patients with ischaemic stroke.

Detection of smell print differences between nonmalignant and malignant prostate cells with an electronic nose.

AIM: To determine whether an electronic nose can differentiate cultured nonmalignant and malignant prostatic cells from each other and whether the smell print is secreted to the surrounding medium. MATERIALS & METHODS: Prostatic nonmalignant (EP-156T and controls) and malignant (LNCaP) cell lines, as well as conditioned and unconditioned media, were collected. The smell prints of the samples were analyzed by a ChemPro(®) 100 electronic nose device. The data were normalized and dimension reduction was conducted. The samples were classified and misclassification rates were calculated. RESULTS: The electronic nose differentiated the nonmalignant and malignant cell lines from each other, achieving misclassification rates of 2.9-3.6%. Cells did not differ from the conditioned medium but differed from the unconditioned medium (misclassification rates: 0.0-25.6%). CONCLUSION: Malignant and nonmalignant prostatic cell lines have distinct smell prints. Prostatic cancer cells seem to modify the smell print of their medium.

Short stature is associated with coronary heart disease: a systematic review of the literature and a meta-analysis.

AIMS: The aim of this study was to assess the relationship between short stature and coronary heart disease (CHD) morbidity and mortality. METHODS AND RESULTS: We performed a systematic search from MEDLINE, PREMEDLINE, and All EBM Reviews as well as from a reference list of relevant articles. We used SPICO (Study design, Patient, Intervention, Control-intervention, Outcome) criteria. The methodological quality of studies was analysed by modified Borghoust criteria. From a total of 1907 articles, we selected 52 studies comprising population-based follow-up studies and patient cohorts followed after a CHD event, as well as case-control studies with height either as a continuous or categorical variable, totalling 3 012 747 individuals. The short ones were below 160.5 cm and tall ones over 173.9 cm on average. Among the shortest height category, the relative risks were 1.35 (95% CI 1.25-1.44) for all-cause mortality, 1.55 (1.37-1.74) for all cardiovascular disease (CVD) mortality, 1.49 (1.33-1.67) for CHD, and 1.52 (1.28-1.81) for myocardial infarction when compared with those within the highest height category. The mean relative risk was 1.46 (1.37-1.55). Short stature was associated with increased cardiovascular morbidity and mortality in both genders. CONCLUSION: The relationship between short stature and CVD appears to be a real one. On the basis of comparison, adults within the shortest category had an approximately 50% higher risk of CHD morbidity and mortality than tall individuals.

Post-stroke dementia and permanent institutionalization.

BACKGROUND: Dementia is among the most frequent causes of institutionalization. To serve the purpose of preventive strategies, there are no follow-up studies that have evaluated the actual impact of post-stroke dementia on institutionalization. We therefore compared the institutionalization rate and length of stay in an institutional care facility of patients with post-stroke dementia with stroke patients without dementia. METHODS: We included 410 consecutive patients aged 55 to 85 years with ischemic stroke who were admitted to Helsinki University Hospital (The SAM cohort). Hospitalization and nursing home admissions were reviewed from national registries. Dementia was diagnosed using the Diagnostic and Statistical Manual of Mental Disorders 3rd edition (DSM-III) criteria using extensive clinical assessments performed 3 months post-stroke. The cohort had a follow-up 21 years later. RESULTS: Compared to patients without dementia, post-stroke dementia was associated with shorter survival time (6.60 vs 10.10 years, p < 0.001), shorter time spent not institutionalized (5.40 vs 9.37 years, p < 0.001), but not with time spent permanently institutionalized (0.73 vs 1.10 years, p = 0.08). Post-stroke dementia was associated with higher rates and earlier permanent institutionalization compared to absence of post-stroke dementia (HR 1.53, 95% CI 1.07-2.18) in a Cox regression model adjusting for age, status of living alone at baseline, modified Rankin Scale at baseline, history of atrial fibrillation, and cardiac failure. CONCLUSIONS: Post-stroke dementia is associated with earlier permanent institutionalization. Due to significantly shorter survival, the time spent in nursing homes was not significantly longer in patients with post-stroke dementia compared with patients without post-stroke dementia.

Cerebral small vessel disease and kidney function predict long-term survival in patients with acute stroke.

BACKGROUND AND PURPOSE: Cerebral small vessel disease reflected by white matter lesions (WMLs) in MRI and kidney function reflected by estimated glomerular filtration rate (eGFR) is closely associated in patients without stroke. We studied whether eGFR and WMLs predict long-term survival in patients with acute stroke. METHODS: After exclusion of patients with low eGFR (N=5 [1.3%]; <30 mL/min/1.73 m(2)), consecutive patients with acute stroke (N=378) subjected to MRI and serum creatinine determination were included in the study and prospectively followed-up up to 12 years. RESULTS: Of the patients, 71.2% had died during the follow-up, 152 (40.2%) had moderate (eGFR <60 mL/min/1.73 m(2)), and 226 (59.8%) had normal or mildly impaired eGFR (>or=60 mL/min/1.73 m(2)). Of the patients, 108 (28.6%) had mild, 68 (18.0%) had moderate, and 202 (53.4%) had severe WMLs. In logistic regression analysis adjusted with age and sex, eGFR <60 mL/min/1.73 m(2) was associated with severe WMLs (relative risk 2.77, 95% CI 1.10 to 6.98, P=0.030). In Cox regression survival analysis adjusted with significant covariates, eGFR <60 mL/min/1.73 m(2) (1.30, 95% CI 1.00 to 1.68, P=0.047) and severe WMLs (hazard ratio 1.32, 95% CI 1.02 to 1.71, P=0.033) were associated with poor survival, whereas they were not independent from each other. In further analyses, presence of either eGFR >or=60 mL/min/1.73 m(2) or only mild to moderate WMLs, or both, was associated with improved survival compared with all other combinations. CONCLUSIONS: Cerebral small vessel disease is closely associated with kidney function in patients with acute stroke. Cerebral small vessel disease and kidney function are closely associated predictors of poor poststroke survival.

Depression-executive dysfunction syndrome relates to poor poststroke survival.

BACKGROUND: The aim of this study was to investigate the influence of poststroke depression and executive dysfunction on long-term survival after acute stroke. METHODS: A total of 257 consecutive acute ischemic stroke patients were included in the study and followed up to 12 years. Depression was diagnosed 3 months after stroke in 99 patients (38.5%). FINDINGS: In Kaplan-Meier analysis, there was no difference in survival of patients with and without poststroke depression (8.7 versus 8.3 years). Instead, patients with both depression and executive dysfunction had shorter median survival than patients with neither depression nor executive dysfunction (6.6 versus 10.3 years). Comparison between all patients with executive dysfunction and patients without it, not regarding depressive status, showed that executive dysfunction in itself was strongly associated with poor poststroke survival (6.4 versus 10.6 years). In stepwise Cox regression proportional hazards analysis adjusted with covariates, poststroke depression with executive dysfunction (hazard ratio [HR] 1.63) and advanced age (HR 1.11) remained as independent predictors of poor long-term survival. INTERPRETATION: The authors' well-defined poststroke cohort with long-term follow-up indicates that in poststroke depression, the depression-executive dysfunction syndrome is the predictor of poor long-term survival rather than depression in itself.

Alpha-lipoic acid does not alter stress protein response to acute exercise in diabetic brain.

Heat shock proteins (HSPs) are molecular chaperones which may act protective in cerebrovascular insults and peripheral diabetic neuropathy. We hypothesized that alpha-lipoic acid (LA), a natural thiol antioxidant, may enhance brain HSP response in diabetes. Rats with or without streptozotocin-induced diabetes were treated with LA or saline for 8 weeks. Half of the rats were subjected to exhaustive exercise to investigate HSP induction, and the brain tissue was analyzed. Diabetes increased constitutive HSC70 mRNA, and decreased HSP90 and glucose-regulated protein 75 (GRP75) mRNA without affecting protein levels. Exercise increased HSP90 protein and mRNA, and also GRP75 and heme oxygenase-1 (HO-1) mRNA only in non-diabetic animals. LA had no significant effect on brain HSPs, although LA increased HSC70 and HO-1 mRNA in diabetic animals and decreased HSC70 mRNA in non-diabetic animals. Eukaryotic translation elongation factor-2, essential for protein synthesis, was decreased by diabetes and suggesting a mechanism for the impaired HSP response related to translocation of the nascent chain during protein synthesis. LA supplementation does not offset the adverse effects of diabetes on brain HSP mRNA expression. Diabetes may impair HSP translation through elongation factors related to nascent chain translocation and subsequent responses to acute stress.

Diabetes impairs exercise training-associated thioredoxin response and glutathione status in rat brain.

Regular exercise plays an important preventive and therapeutic role in oxidative stress-associated diseases such as diabetes and its complications. Thiol antioxidants including thioredoxin (TRX) and glutathione (GSH) have a crucial role in controlling cellular redox status. In this study, the effects of 8 wk of exercise training on brain TRX and GSH systems, and antioxidant enzymes were tested in rats with or without streptozotocin-induced diabetes. We found that in untrained animals, the levels of TRX-1 (TRX1) protein and activity, and thioredoxin-interacting protein (TXNip) were similar in diabetic and nondiabetic animals. Exercise training, however, increased TRX1 protein in nondiabetic animals without affecting TXNip levels, whereas diabetes inhibited the effect of training on TRX1 protein and also increased TXNip mRNA. In addition, the proportion of oxidized glutathione (GSSG) to total GSH was increased in animals with diabetes, indicating altered redox status and possibly increased oxidative stress. Glutathione peroxidase-1 (GPX1) levels were not affected by diabetes or exercise training, although diabetes increased total GPX activity. Both diabetes and exercise training decreased glutathione reductase (GRD) activity and cytosolic superoxide dismutase (Cu,Zn-SOD) levels. Nevertheless, diabetes or training had no effect on Cu,Zn-SOD mRNA, Mn-SOD protein, total SOD activity, or catalase mRNA, protein, or activity. Our findings suggest that exercise training increases TRX1 levels in brain without a concomitant rise in TXNip, and that experimental diabetes is associated with an incomplete TRX response to training. Increased oxidative stress may be both a cause and a consequence of perturbed antioxidant defenses in the diabetic brain.

Smoking and the platelet fibrinogen receptor glycoprotein IIb/IIIA PlA1/A2 polymorphism interact in the risk of lacunar stroke and midterm survival.

BACKGROUND AND PURPOSE: Smoking, increased fibrinogen levels, and platelet activation are related to the risk of ischemic stroke. The platelet fibrinogen receptor glycoprotein (Gp) IIb/IIIa Pl(A1/A2) polymorphism affects the binding of platelets to fibrinogen and is suggested to interact with smoking. METHODS: We explored the association of smoking and the Pl(A1/A2) polymorphism with ischemic stroke and survival in the Stroke Aging Memory cohort, comprising 486 consecutive patients (55 to 85 years old) who were analyzed 3 months after an ischemic stroke and followed up for 15 months. Stroke subtype determined by magnetic resonance imaging and GpIIb/IIIa Pl(A1/A2) genotype data were available for 272 patients. RESULTS: In multivariate analysis, smoking was the only factor related to the risk of lacunar infarcts (odds ratio [OR]=1.87, 95% CI=1.05 to 3.31; P=0.033), and it was also a predictor of death (n=24, 8.8%) at 15 months (OR=5.13, 95% CI=1.61 to 16.36; P=0.006), along with age (OR=1.10, 95% CI=1.01 to 1.19; P=0.008). The GpIIb/IIIa Pl(A1/A2) polymorphism alone showed no association with stroke subtype or survival. However, there was a smoking-by-genotype association with the risk of lacunar infarcts (OR=2.10, 95% CI=0.90 to 4.89; P=0.087) and with survival (OR=2.78, 95% CI=0.89 to 8.61; P=0.077). Among younger (55 to 69 years) stroke patients, smokers carrying the Pl(A2) allele were at a higher (OR=5.81, 95% CI=1.26 to 26.80; P=0.024) risk of lacunar infarcts than noncarrier smokers (OR=3.12, 95% CI=1.06 to 9.24; P=0.039). The effect of Pl(A2) and smoking combined on survival was also stronger (OR=8.86, 95% CI=1.68 to 46.55; P=0.010) than the effect of smoking alone (OR=5.06, 95% CI=1.20 to 21.35; P=0.027). CONCLUSIONS: Our results indicate that prothrombotic genetic factors may interact with smoking by modifying the stroke phenotype and affecting midterm survival.

Alpha-lipoic Acid modulates heat shock factor-1 expression in streptozotocin-induced diabetic rat kidney.

Increased oxidative stress and impaired heat shock protein (HSP) synthesis may contribute to diabetic nephropathy. The question of whether 8-week thiol antioxidant alpha-lipoic acid (LA) supplementation modulates HSP response and oxidative stress was studied in the kidney of streptozotocin-induced diabetic (SID) and nondiabetic rats. SID caused a histological mesangial expansion, tubular dilatation, and increased levels of transforming growth factor-beta (TGF-beta), a mediator of glomerulosclerosis. SID increased 4-hydroxynonenal (4-HNE) protein adduct formation, a marker of lipid peroxidation, and heme oxygenase-1 (HO-1), also a marker of oxidative stress. Moreover, SID increased the DNA-binding activity of heat shock factor-1 (HSF-1) and expression of heat shock protein 60 (HSP60). In contrast, LA supplementation partially reversed histological findings of glomerulosclerosis and decreased TGF-beta. LA also increased HSF-1 and decreased HO-1 protein expression, without affecting 4-HNE protein adduct levels. At the mRNA level, LA increased expression of HSF-1, HSP90, and glucose-regulated protein (GRP75) in both control and diabetic animals and HSP72 in SID rats. However, LA supplementation did not affect these HSPs at the protein level. These findings suggest that in addition to its antiglomerulosclerotic effects, LA can induce cytoprotective response in SID.

Heat shock protein 60 response to exercise in diabetes: effects of alpha-lipoic acid supplementation.

The pathophysiology of diabetes includes oxidative stress and impaired heat shock protein (HSP) expression. We studied the effects of alpha-lipoic acid (LA) supplementation for 8 weeks and acute exercise on HSP60 expression and the oxidative stress marker 4-hydroxynonenal adducts (4-HNE) in streptozotocin-induced diabetic (SID) and nondiabetic control rats. Diabetes was associated with decreased HSP60 in the heart and increased levels of HSP60 and 4-HNE in the liver. LA increased HSP60 in the liver of control and diabetic rats and decreased 4-HNE in the liver and heart. Acute exercise increased liver 4-HNE, which was offset by LA. In conclusion, diabetes induced oxidative stress and impaired myocardial HSP60 expression, while LA partially offsets these alterations in a tissue-specific manner.

Antireflux surgery and esophageal mucosal DNA damage.

Gastroesophageal reflux disease (GERD) is characterized by reflux of gastroduodenal contents, esophagitis and oxidative tissue damage in the distal esophagus. It may ultimately lead to the development of a pre-malignant Barrett's esophagus and subsequently to carcinoma. Antireflux surgery is an effective therapeutic tool to relieve GERD symptoms and to normalize the reflux to the distal esophagus. However, antireflux surgery may be insufficient to restore oxidative insult, which can promote DNA adduct formation and subsequent initiation of carcinogenesis. Controversy exists whether antireflux surgery can reverse the development of carcinoma in the mucosa. We aimed to test the effect of antireflux surgery on DNA adduct formation in the esophagus. Patients (n = 19) with objectively confirmed GERD underwent antireflux surgery and were followed up for 6 months after which a symptom evaluation, control endoscopy, biopsy and pH-measurements were performed. The amounts of DNA adducts in the proximal and distal mucosa of the esophagus were measured using the 32-P-postlabelling method. After the surgery, esophageal acid exposure was normalized in all the patients and symptoms were relieved in all but one patient. Endoscopic examinations showed that erosive esophagitis had healed in all the cases 6 months after the surgery. Barrett's esophagus was found in six cases in preoperative biopsies. The amount of DNA adducts in the distal esophagus was higher than in the proximal esophagus both pre- and postoperatively. Antireflux surgery did not change this pattern and was thus not capable of reducing DNA adduct formation. The level of DNA damage was similar in the patients having Barrett's esophagus compared to the rest of the patients. Antireflux surgery is insufficient to normalize DNA damage due to GERD. Our observations suggest that antireflux surgery is perhaps not effective in the prevention of carcinogenesis because of the persisting DNA damage.

Severe cerebral white matter lesions in ischemic stroke patients are associated with less time spent at home and early institutionalization.

BACKGROUND: Cerebral white matter lesions are one imaging surrogate for cerebral small vessel disease. These white matter lesions are associated with increased morbidity and mortality in both the general population and ischemic stroke patients. AIMS: To investigate whether severe white matter lesions in a cohort of ischemic stroke patients are associated with fewer days spent at home and earlier permanent institutionalization. METHODS: We included 391 consecutive patients aged 55-85 years with ischemic stroke admitted to the Helsinki University Central Hospital (the Stroke Aging Memory cohort) with a 21-year follow-up. Hospitalization and nursing home admissions were reviewed from national registers.white matter lesions were rated using magnetic resonance imaging performed three-months poststroke, dichotomized as none-to-moderate and severe. Kaplan-Meier plots log-rank and binary logistic regression (odds ratio) and Cox multivariable proportional hazards model were used to study the association of white matter lesions with days spent at home and the time of permanent institutionalization. Hazards and odds ratio with their 95% confidence intervals are reported. RESULTS: Severe white matter lesions were associated with fewer days spent at home, and more frequent, and earlier permanent institutionalization (1487 vs. 2354 days; log-rank P < 0·001).After adjusting for significant covariates from univariable analyses, severe white matter lesions were associated with fewer days spent at home (odds ratio 1·62; confidence interval 1·16-2·25), permanent institutionalization within five-years (odds ratio 2·29; confidence interval 1·23-4·29), and increased hazards ratio of permanent institutionalization during 21 years of follow-up (1·64; confidence interval 1·119-2·26). CONCLUSIONS: After ischemic stroke, patients with severe white matter lesions spend fewer days at home and become permanently institutionalized earlier, especially within the first five-years.

Heat shock preconditioning modulates proliferation and apoptosis after superficial injury in isolated guinea pig gastric mucosa via an eicosanoid and protein synthesis-dependent mechanism.

AIM: In restitution after superficial injury of the gastric mucosa, the epithelial continuity is restored by cellular migration. We have shown that heat shock preconditioning inhibits restitution after superficial injury. This study investigates the effect of heat shock preconditioning on tissue proliferation and apoptosis. EXPERIMENTAL DESIGN: Paired guinea pig gastric mucosae were mounted and perfused in Ussing chambers (37 degrees C). After heat shock preconditioning (42 degrees C) (30 min) and normothermic recovery (37 degrees C) (150 min) or normothermic perfusion, a superficial injury was induced by luminal exposure to 1.25 mol/L NaCl (5 min) followed by a 3 h restitution. During perfusion, the mucosa was exposed to 30 micromol/L arachidonic acid (AA) to enhance heat shock response, to 50 micromol/L quercetin (Q) to inhibit the metabolism of arachidonic acid via lipoxygenases, to 50 micromol/L indomethacin (In) to inhibit the metabolism of arachidonic acid via cyclo-oxygenases, or to 150 micromol/L cycloheximide (CHX) to inhibit de novo protein synthesis. After the experiment the mucosa was prepared for immunohistochemical analysis of the expression of Mib-1 proliferation antigen and pro-apoptotic protein Bax. RESULTS: Heat shock decreased Mib-1/Bax ratio and this effect was maintained after superficial injury and exposure to Q, to AA+CHX or to In+CHX. Exposure to CHX, to AA, to In+Q, to In+AA, In+AA+Q or to In+AA+CHX, however, blocked the effect of heat shock preconditioning. The decreasing effect of heat shock preconditioning on Mib-1/Bax ratio could be reversed by exposure to AA+Q or to In. CONCLUSION: The heat-preconditioning-induced effects on the mucosa are reversible and sensitive to exogenous pharmacological modulation. Heat shock preconditioning inhibits proliferation of superficially injured isolated gastric mucosa by a mechanism involving eicosanoid pathways and de novo protein synthesis.