SLAP/SLAP2 prevent excessive platelet (hem)ITAM signaling in thrombosis and ischemic stroke in mice

Glycoprotein VI and C-type lectin-like receptor 2 are essential platelet activating receptors in hemostasis and thrombo-inflammatory disease, which signal through a (hem)immunoreceptor tyrosine-based activation motif (ITAM)-dependent pathway. The adapter molecules Src-like adapter proteins (SLAP and SLAP2) are involved in the regulation of immune cell surface expression and signaling, but their function in platelets is unknown. In this study, we show that platelets expressed both SLAP isoforms and that overexpression of either protein in a heterologous cell line almost completely inhibited glycoprotein VI and C-type lectin-like receptor 2 signaling. In mice, single deficiency of SLAP or SLAP2 had only moderate effects on platelet function, whereas double deficiency of both adapters resulted in markedly increased signal transduction, integrin activation, granule release, aggregation, procoagulant activity, and thrombin generation in response to (hem)ITAM-coupled, but not G protein-coupled, receptor activation. In vivo, constitutive SLAP/SLAP2 knockout mice displayed accelerated occlusive arterial thrombus formation and a dramatically worsened outcome after focal cerebral ischemia. This was attributed to the absence of both adapter proteins in platelets, as demonstrated by adoptive transfer of Slap(-/-)/Slap2(-/-) platelets into wild-type mice. Our results establish SLAP and SLAP2 as critical inhibitors of platelet (hem)ITAM signaling in the setting of arterial thrombosis and ischemic stroke.

Chagas disease-related mortality trends, state of Sao Paulo, Brazil, 1985 to 2006: a study using multiple causes of death

Objectives. To study mortality trends related to Chagas disease taking into account all mentions of this cause listed on any line or part of the death certificate. Methods. Mortality data for 1985-2006 were obtained from the multiple cause-of-death database maintained by the Sao Paulo State Data Analysis System (SEADE). Chagas disease was classified as the underlying cause-of-death or as an associated cause-of-death (non-underlying). The total number of times Chagas disease was mentioned on the death certificates was also considered. Results. During this 22-year period, there were 40 002 deaths related to Chagas disease: 34 917 (87.29%) classified as the underlying cause-of-death and 5 085 (12.71%) as an associated cause-of-death. The results show a 56.07% decline in the death rate due to Chagas disease as the underlying cause and a stabilized rate as associated cause. The number of deaths was 44.5% higher among men. The fact that 83.5% of the deaths occurred after 45 years of age reflects a cohort effect. The main causes associated with Chagas disease as the underlying cause-of-death were direct complications due to cardiac involvement, such as conduction disorders, arrhythmias and heart failure. Ischemic heart disease, cerebrovascular disorders and neoplasms were the main underlying causes when Chagas was an associated cause-of-death. Conclusions. For the total mentions to Chagas disease, a 51.34% decline in the death rate was observed, whereas the decline in the number of deaths was only 5.91%, being lower among women and showing a shift of deaths to older age brackets. Using the multiple cause-of-death method contributed to the understanding of the natural history of Chagas disease.

Impact of chronic disease on quality of life among the elderly in the state of Sao Paulo, Brazil: a population-based study

Objectives. To assess the impact of chronic disease and the number of diseases on the various aspects of health-related quality of life (HRQOL) among the elderly in Sao Paulo, Brazil. Methods. The SF-36 (R) Health Survey was used to assess the impact of the most prevalent chronic diseases on HRQOL. A cross-sectional and population-based study was carried out with two-stage stratified cluster sampling. Data were obtained from a multicenter health survey administered through household interviews in several municipalities in the state of Sao Paulo. The study evaluated seven diseases-arthritis, back-pain, depression/anxiety, diabetes, hypertension, osteoporosis, and stroke-and their effects on quality of life. Results. Among the 1958 elderly individuals (60 years of age or older), 13.6% reported not having any of the illnesses, whereas 45.7% presented three or more chronic conditions. The presence of any of the seven chronic illnesses studied had a significant effect on the scores Of nearly all the SF-36 (R) scales. HRQOL achieved lower scores when related to depression/anxiety, osteoporosis, and stroke. The higher the number of diseases, the greater the negative effect on the SF-36 (R) dimensions. The presence of three or more diseases significantly affected HRQOL in all areas. The bodily pain, general health, and vitality scales were the most affected by diseases. Conclusions. The study detected a high prevalence of chronic diseases among the elderly population and found that the degree of impact on HRQOL depends on the type of disease. The results highlight the importance of preventing and controlling chronic diseases in order to reduce the number of comorbidities and lessen their impact on HRQOL among the elderly.

Multicenter Analysis of Glucocerebrosidase Mutations in Parkinson`s Disease

Background Recent studies indicate an increased frequency of mutations in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gaucher`s disease, among patients with Parkinson`s disease. We aimed to ascertain the frequency of GBA mutations in an ethnically diverse group of patients with Parkinson`s disease. Methods Sixteen centers participated in our international, collaborative study: five from the Americas, six from Europe, two from Israel, and three from Asia. Each center genotyped a standard DNA panel to permit comparison of the genotyping results across centers. Genotypes and phenotypic data from a total of 5691 patients with Parkinson`s disease (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews) were analyzed, with multivariate logistic-regression models and the Mantel-Haenszel procedure used to estimate odds ratios across centers. Results All 16 centers could detect two GBA mutations, L444P and N370S. Among Ashkenazi Jewish subjects, either mutation was found in 15% of patients and 3% of controls, and among non-Ashkenazi Jewish subjects, either mutation was found in 3% of patients and less than 1% of controls. GBA was fully sequenced for 1883 non-Ashkenazi Jewish patients, and mutations were identified in 7%, showing that limited mutation screening can miss half the mutant alleles. The odds ratio for any GBA mutation in patients versus controls was 5.43 across centers. As compared with patients who did not carry a GBA mutation, those with a GBA mutation presented earlier with the disease, were more likely to have affected relatives, and were more likely to have atypical clinical manifestations. Conclusions Data collected from 16 centers demonstrate that there is a strong association between GBA mutations and Parkinson`s disease.

Biomarkers of extracellular matrix metabolism (MMP-9 and TIMP-1) and risk of stroke, myocardial infarction and cause-specific mortality : cohort study

Objective: Turnover of the extracellular matrix in all solid organs is governed mainly by a balance between the degrading matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). An altered extracellular matrix metabolism has been implicated in a variety of diseases. We investigated relations of serum levels of MMP-9 and TIMP-1 to mortality risk from an etiological perspective. Design: The prospective Uppsala Longitudinal Study of Adult Men (ULSAM) cohort, followed from 1991–1995 for up to 18.1 years. A random population-based sample of 1,082 71-year-old men, no loss to follow-up. Endpoints were all-cause (n = 628), cardiovascular (n = 230), non-cardiovascular (n = 398) and cancer mortality (n = 178), and fatal or non-fatal myocardial infarction (n = 138) or stroke (n = 163). Results: Serum MMP-9 and TIMP-1 levels were associated with risk of all-cause mortality (Cox proportional hazard ratio [HR] per standard deviation 1.10, 95% confidence interval [CI] 1.03–1.19; and 1.11, 1.02–1.20; respectively). TIMP-1 levels were mainly related to risks of cardiovascular mortality and stroke (HR per standard deviation 1.22, 95% CI 1.09–1.37; and 1.18, 1.04–1.35; respectively). All relations except those of TIMP-1 to stroke risk were attenuated by adjustment for cardiovascular disease risk factors. Relations in a subsample without cardiovascular disease or cancer were similar to those in the total sample. Conclusion: In this community-based cohort of elderly men, serum MMP-9 and TIMP-1 levels were related to mortality risk. An altered extracellular matrix metabolism may be involved in several detrimental pathways, and circulating MMP-9 or TIMP-1 levels may be relevant markers thereof.

Risk of recurrent stroke and death after first stroke in long-distance ski race participants

Background: Physical activity is of benefit for primary prevention of cardiovascular diseases, but it appears to increase the risk for atrial fibrillation. We aimed to study a cohort of patients following a first stroke in individuals with previous high physical activity, compare them to the general population with respect to recurrent stroke and death, and relate these to atrial fibrillation. Methods and results: From the participants of the Vasaloppet, the world's largest ski-race, and matched individuals from the general population (n=708 604), we identified 5964 patients hospitalized with a first-time stroke between 1994 and 2010. Individuals with severe diseases were excluded. One half percent of skiers and 1% of nonskiers were hospitalized due to stroke. The incidence rate was 8.3 per 100 person-years among skiers and 11.1 among nonskiers. The hazard ratio (HR) for recurrent stroke or death between the 2 groups was 0.76 (95% CI 0.67 to 0.86). The result was consistent in subgroups. The HR for death was 0.66 (95% CI 0.56 to 0.78) and for recurrent stroke 0.82 (95% CI 0.70 to 0.96). After adjustment for smoking and socioeconomic factors, the HR for death was consistent at 0.70 (95% CI 0.56 to 0.87) while the HR for recurrent stroke was not statistically significant. Outcomes for skiers with atrial fibrillation tended to show a lower risk than for nonskiers. Conclusions: This large cohort study supports the hypothesis that patients with a stroke and with prior regular physical activity have a lower risk of death, while their risk for recurrent stroke is similar to that of nonskiers. The skiers had a higher incidence of atrial fibrillation, but still no increased risk of recurring stroke.

Frequency of coronary artery disease in patients with renal artery stenosis without clinical manifestations of coronary insufficiency

Atherosclerotic renal artery stenosis (RAS) and coronary artery disease (CAD) arise from the same multiple risk factors. The purpose of this study was to assess the frequency of previously undiagnosed CAD in patients with angiographically confirmed RAS, by conducting coronary arteriography in the same setting. of 57 consecutive patients referred for renal arteriography on clinical grounds during a 14-month period, 28 had no RAS and 6 had RAS, but previously documented CAD. of the remainder 23 patients. 17 (74%; CI 56%-92%) had both RAS and CAD (7 single vessel, 4 two-vessel, and 7 multivessel disease). The clinical characteristics, such as age, blood pressure (BP) levels, signs of heart failure, were no different between those with and without CAD, although the 4 diabetic patients, the 4 patients with fundoscopic findings of grade III retinopathy, 11 of 14 with peripheral arterial disease, and 7 of 8 patients with prior stroke belonged in the CAD group. None developed complications as a result of the two consecutive procedures. The data suggest that in patients with RAS the frequency of silent CAD is high and cannot be predicted on clinical grounds alone, therefore coronary angiography should be routinely recommended in the same setting.

Impact of chronic disease on quality of life among the elderly in the state of Sao Paulo, Brazil: A population-based study

Objectives. To assess the impact of chronic disease and the number of diseases on the various aspects of health-related quality of life (HROOL) among the elderly in Såo Paulo, Brazil. Methods. The SF-36® Health Survey was used to assess the impact of the most prevalent chronic diseases on HRQOL. A cross-sectional and population-based study was carried out with two-stage stratified cluster sampling. Data were obtained from a multicenter health survey administered through household interviews in several municipalities in the state of São Paulo. The study evaluated seven diseases - arthritis, back-pain, depression/anxiety, diabetes, hypertension, osteoporosis, and stroke - and their effects on quality of life. Results. Among the 1 958 elderly individuals (60 years of age or older), 13.6% reported not having any of the illnesses, whereas 45.7% presented three or more chronic conditions. The presence of any of the seven chronic illnesses studied had a significant effect on the scores of nearly all the SF-36® scales. HROOL achieved lower scores when related to depression/ anxiety, osteoporosis, and stroke. The higher the number of diseases, the greater the negative effect on the SF-36® dimensions. The presence of three or more diseases significantly affected HROOL in all areas. The bodily pain, general health, and vitality scales were the most affected by diseases. Conclusions. The study detected a high prevalence of chronic diseases among the elderly population and found that the degree of impact on HROOL depends on the type of disease. The results highlight the importance of preventing and controlling chronic diseases in order to reduce the number of comorbidities and lessen their impact on HROOL among the elderly.

Trochlear nerve palsy associated with claude bernard-horner syndrome after brainstem stroke

The association of unilateral trochlear nerve palsy with Claude Bernard-Horner syndrome represents a rare clinical condition. We present the case of a patient with this unusual presentation. The investigation performed implicated cerebrovascular disease as the underlying cause of the condition in this patient. © 2011 S. Karger AG, Basel.

Correlation Between Laryngeal Sensitivity and Penetration/Aspiration After Stroke

Stroke is the most common neurological disease in adults that is associated with deglutition disorders. The presence of laryngeal sensitivity is very important in developing safe swallowing without risk of pulmonary complications. The aim of this study was to correlate laryngeal sensitivity with laryngeal penetration and tracheal aspiration after swallows of three food consistencies (puree, thickened liquid, and liquid) in poststroke individuals in the late phase. A cross-sectional clinical study was performed with 91 post-ischemic stroke individuals, with oropharyngeal dysphagia, who were in rehabilitation center treatment from 2009 to 2011. They had a mean age of 68.1 years and average time since injury was 22.6 months; 39 had injury to the right hemisphere and 52 had injury to the left hemisphere. All underwent fiberoptic endoscopic evaluation of swallowing and evaluation of laryngeal sensitivity by touching the tip of the endoscope to the arytenoids and aryepiglottic folds. The linear correlation coefficient of Spearman was applied to evaluate the correlation between laryngeal penetration and tracheal aspiration and the presence/absence of laryngeal sensitivity. There was a negative correlation between the observation of penetration and tracheal aspiration and laryngeal sensitivity, with all bolus consistencies (p < 0.001 for aspiration and p a parts per thousand currency sign 0.01 for penetration). The absence of laryngeal sensitivity determines the more frequent findings of penetration and tracheal aspiration. This sensory stimulus in the mucosa of the pharynx and larynx is an essential element for safe swallowing and its deficiency associated with altered motor activity can cause laryngeal penetration and aspiration in poststroke individuals regardless of food consistency.

Perception and Attitude About Systemic Health and Periodontal Disease Among Dentistry Undergraduates

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Taste and Temperature in Swallowing Transit Time after Stroke

Background: Oropharyngeal dysphagia is common in individuals after stroke. Taste and temperature are used in dysphagia rehabilitation. The influence of stimuli, such as taste and temperature, on swallowing biomechanics has been investigated in both healthy individuals and in individuals with neurological disease. However, some questions still remain unanswered, such as how the sequence of offered stimuli influences the pharyngeal response. The goal of the present study was to determine the influence of the sequence of stimuli, sour taste and cold temperature, on pharyngeal transit time during deglutition in individuals after stroke. Methods: The study included 60 individuals with unilateral ischemic stroke, 29 males and 31 females, aged 41–88 years (mean age: 66.2 years) examined 0–50 days after ictus (median: 6 days), with mild to moderate oropharyngeal dysphagia. Exclusion criteria were hemorrhagic stroke patients, patients with decreased level of consciousness, and clinically unstable patients, as confirmed by medical evaluation. The individuals were divided into two groups of 30 individuals each. Group 1 received a nonrandomized sequence of stimuli (i.e. natural, cold, sour, and sour-cold) and group 2 received a randomized sequence of stimuli. A videofluoroscopic swallowing study was performed to analyze the pharyngeal transit time. Four different stimuli (natural, cold, sour, and sour-cold) were offered. The images were digitalized and specific software was used to measure the pharyngeal transit time. Since the values did not present regular distribution and uniform variances, nonparametric tests were performed. Results: Individuals in group 1 presented a significantly shorter pharyngeal transit time with the sour-cold stimulus than with the other stimuli. Individuals in group 2 did not show a significant difference in pharyngeal transit time between stimuli. Conclusions: The results showed that the sequence of offered stimuli influences the pharyngeal transit time in a different way in individuals after stroke and suggest that, when the sour-cold stimulus is offered in a randomized sequence, it can influence the response to the other stimuli in stroke patients. Hence, the sour-cold stimulus could be used as a therapeutic aid in dysphagic stroke patients.

Stroke as the First Clinical Manifestation of Takayasu's Arteritis

Takayasu's arteritis is a chronic inflammatory disease, and neurological symptoms occur in 50% of cases, most commonly including headache, dizziness, visual disturbances, convulsive crisis, transient ischemic attack, stroke and posterior reversible encephalopathy syndrome. The aim of this study was to report the case of a young Brazilian female with a focal neurological deficit. She presented with asymmetry of brachial and radial pulses, aphasia, dysarthria and right hemiplegia. Stroke was investigated extensively in this young patient. Only nonspecific inflammatory markers such as velocity of hemosedimentation and C-reactive protein were elevated. During hospitalization, clinical treatment was performed with pulse therapy showing improvement in neurological recuperation on subsequent days. In the chronic phase, the patient was submitted to medicated angioplasty of the brachiocephalic trunk with paclitaxel, with significant improvement of the stenosis. At the 6-month follow-up, the neurological exam presented mild dysarthria, faciobrachial predominant disproportionate hemiparesis, an NIHSS score of 4 and a modified Rankin Scale score of 3 (moderate incapacity). In conclusion, Takayasu's arteritis must be recognized as a potential cause of ischemic stroke in young females.

Using the National Institute of Health Stroke Scale to Predict Dysphagia in Acute Ischemic Stroke

Background and Purpose: Oropharyngeal dysphagia is a common manifestation in acute stroke. Aspiration resulting from difficulties in swallowing is a symptom that should be considered due to the frequent occurrence of aspiration pneumonia that could influence the patient's recovery as it causes clinical complications and could even lead to the patient's death. The early clinical evaluation of swallowing disorders can help define approaches and avoid oral feeding, which may be detrimental to the patient. This study aimed to create an algorithm to identify patients at risk of developing dysphagia following acute ischemic stroke in order to be able to decide on the safest way of feeding and minimize the complications of stroke using the National Institutes of Health Stroke Scale (NHISS). Methods: Clinical assessment of swallowing was performed in 50 patients admitted to the emergency unit of the University Hospital, Faculty of Medicine of Ribeirao Preto, Sao Paulo, Brazil, with a diagnosis of ischemic stroke, within 48 h after the beginning of symptoms. Patients, 25 females and 25 males with a mean age of 64.90 years (range 26-91 years), were evaluated consecutively. An anamnesis was taken before the patient's participation in the study in order to exclude a prior history of deglutition difficulties. For the functional assessment of swallowing, three food consistencies were used, i.e. pasty, liquid and solid. After clinical evaluation, we concluded whether there was dysphagia. For statistical analysis we used the Fisher exact test, verifying the association between the variables. To assess whether the NIHSS score characterizes a risk factor for dysphagia, a receiver operational characteristics curve was constructed to obtain characteristics for sensitivity and specificity. Results: Dysphagia was present in 32% of the patients. The clinical evaluation is a reliable method of detection of swallowing difficulties. However, the predictors of risk for the swallowing function must be balanced, and the level of consciousness and the presence of preexisting comorbidities should be considered. Gender, age and cerebral hemisphere involved were not significantly associated with the presence of dysphagia. NIHSS, Glasgow Coma Scale, and speech and language changes had a statistically significant predictive value for the presence of dysphagia. Conclusions: The NIHSS is highly sensitive (88%) and specific (85%) in detecting dysphagia; a score of 12 may be considered as the cutoff value. The creation of an algorithm to detect dysphagia in acute ischemic stroke appears to be useful in selecting the optimal feeding route while awaiting a specialized evaluation. Copyright (C) 2012 S. Karger AG, Basel

Antiphospholipid syndrome plus rheumatic fever: a higher risk factor for stroke?

To compare clinical and laboratory findings between patients with primary antiphospholipid syndrome (PAPS) versus secondary APS due to rheumatic fever (APS-RF) (according to Jones criteria). Seventy-three APS patients (Sapporo criteria) were enrolled, and demographic, clinical, and laboratory data were collected. Exclusion criteria were heart congenital abnormalities and previous infectious endocarditis. Patients were divided into two groups: PAPS (n = 68) and APS-RF (n = 5). The mean current age, disease duration, frequencies of female gender, and Caucasian race were similar in APS-RF and PAPS patients (P > 0.05). Remarkably, the frequency of stroke was significantly higher in APS-RF compared to PAPS patients (80% vs. 25%, P = 0.02). Of note, echocardiogram of these patients did not show intracardiac thrombus. No significant differences were found in peripheral thromboembolic events (P = 1.0), pulmonary thromboembolism (P = 1.0), miscarriage (P = 0.16), thrombocytopenia (P = 0.36), arterial events (P = 0.58), and thrombosis of small vessels (P = 1.0). There were no differences in the frequencies of comorbidities such as diabetes mellitus, hypertension, smoking, and hyperlipidemia in both groups (P > 0.05). The frequencies of lupus anticoagulant, IgG, and IgM anticardiolipin were similar in two groups. APS patients associated with rheumatic fever without infective endocarditis may imply a high stroke risk as compared with PAPS, and future studies are needed to confirm this finding.