Giuseppe Licata

Association Between Diabetes and Stroke Subtype on Survival and Functional Outcome 3 Months After Stroke Data From the European BIOMED Stroke Project

Background and Purpose— Although diabetes is a strong risk factor for stroke, it is still unclear whether stroke subtype, severity, and prognosis are different in diabetic and nondiabetic patients. We sought to evaluate stroke features, prognosis, and functional outcome in patients with diabetes compared with patients without diabetes. Methods— In a European Union Concerted Action involving 7 countries and 4537 patients hospitalized for a first-in-a-lifetime stroke, defined according to the Oxfordshire Community Stroke Project criteria, we collected data on demographics, risk factors, clinical presentation, and outcome. We used logistic regression to examine the relationship between diabetes and outcome at 3 months (disability, handicap, and death), controlling for risk factors, clinical presentation, and demographics. Results— Overall, diabetes was present in 937 patients (21%). Diabetic patients, compared with those without diabetes, were more likely to have limb weakness (P <0.02), dysarthria (P <0.001), ischemic stroke (P <0.001), and lacunar cerebral infarction (P =0.03). At 3 months, the case fatality rates were not higher in the diabetic groups (P =0.33). Handicap (Rankin Scale) and disability (Barthel Index) were significantly higher in diabetic patients (P =0.005 and P =0.016, respectively). Conclusions— Stroke in diabetic patients has a specific clinical pattern and a poor prognosis in terms of motor function, which emphasizes the need for early diagnosis and treatment of every case of diabetes.Background and Purpose— Although diabetes is a strong risk factor for stroke, it is still unclear whether stroke subtype, severity, and prognosis are different in diabetic and nondiabetic patients. We sought to evaluate stroke features, prognosis, and functional outcome in patients with diabetes compared with patients without diabetes. Methods— In a European Union Concerted Action involving 7 countries and 4537 patients hospitalized for a first-in-a-lifetime stroke, defined according to the Oxfordshire Community Stroke Project criteria, we collected data on demographics, risk factors, clinical presentation, and outcome. We used logistic regression to examine the relationship between diabetes and outcome at 3 months (disability, handicap, and death), controlling for risk factors, clinical presentation, and demographics. Results— Overall, diabetes was present in 937 patients (21%). Diabetic patients, compared with those without diabetes, were more likely to have limb weakness (P<0.02), dysarthria (P<0.001),...

Inflammatory Cytokines in Acute Ischemic Stroke

Three major cytokines, namely, tumor necrosis factor (TNF-alpha), interleukin (IL)-1, and IL-6 are produced by cultured brain cells after various stimuli such as ischemia. Neurones, astrocytes, microglia and oligodendrocytes can produce inflammatory mediators, and cytokine receptors are expressed constitutionally throughout the Central Nervous System (CNS), albeit at low levels. Cytokines are involved in virtually every facet of stroke and they have numerous pro-inflammatory and pro-coagulant effects on endothelium. TNF-alpha expression after stroke stimulates expression of tissue factor and adhesion molecules for leukocytes, release of interleukin-1 (IL-1), nitric oxide, factor VIII/von Willebrand factor, platelet-activating factor and endothelin, suppression of the thrombomodulin-protein C-protein S system, reduction of tissue-plasminogen activator and release of plasminogen activator inhibitor-1. Research into the actions of IL-1beta in the brain initially focused on its role in host defence responses to systemic disease. IL-1beta can also elicit an array of responses which could either inhibit, exacerbate or induce neuronal damage and death. IL-6 can be induced by a variety of molecules including IL-1, TNF-alpha, transforming growth factor-beta and prostaglandins (PGs), and many other mediators such as b-amyloid, interferon-g (IFNg) and IL-4 can potentiate these primary inducers, highlighting the complex nature of IL-6 modulation. Several studies reported that plasma levels of TNF-alpha and IL-6 are associated with prognosis after ischemic stroke and our group showed that plasma levels of cytokines such as TNF-alpha, IL-1beta are different in every diagnostic subtype of ischemic stroke, and how plasma levels of some immunoinflammatory markers and thrombotic-phybrinolitic markers are predictive of acute ischemic stroke diagnosis in the acute setting.

Twenty-four hour ambulatory blood pressure monitoring to evaluate effects on blood pressure of physical activity in hypertensive patients.

ObjectiveElevated blood pressure is an important risk factor for cardiovascular disease and stroke. Several studies have demonstrated that physical exercise reduces blood pressure levels in hypertensive subjects and improves control of several well-known risk factors for atherosclerosis such as diabetes mellitus, blood lipid profile and obesity. Our group attempted to evaluate if an exercise program based on periodic controlled fast walking sessions would reduce blood pressure levels in hypertensive subjects. DesignWe enrolled hypertensive subjects not suffering from obesity (Body Mass Index <30) already under pharmacological therapy; in these subjects we performed a six-week program of mobility exercise based on fast walking. SettingSecondary care. PatientsWe enrolled 189 subjects; 168 subjects completed the training period. Entry criteria were Stage I WHO hypertension in pharmacological treatment, BMI <30, and absence of any pathological condition resulting in reduced mobility. InterventionsA six-week mobility program centered on fast walking. Main Outcome MeasurementsSystolic and diastolic blood pressure levels before and after the walking program. ResultsMean 24 h systolic blood pressure changed from 143.1 to 135.5 mmHg. Mean 24 h diastolic blood pressure changed from 91.1 to 84.8 mmHg. ConclusionsThis reduction, evaluated with Ambulatory Blood Pressure Monitoring (ABPM), confirms that physical exercise should be a part of lifestyle changes for the management of hypertension both in untreated hypertensive patients or high-risk subjects for hypertension, and also for hypertensive patients in association with pharmacological therapy.

Angiotensin-Converting Enzyme Gene Deletion Polymorphism Determines an Increase in Frequency of Migraine Attacks in Patients Suffering from Migraine without Aura

Many authors have reported an association between the angiotensin-converting enzyme (ACE)-D allele and coronary heart disease and other cardiovascular diseases. The mechanism underlying the positive associations between the ACE-D alleles and diseases are not yet clear. Previous reports showed an association between migraine without aura and ACE-D allele polymorphism. The study is aimed to evaluate if the DD genotype could also be associated with the frequency and duration of migraine without aura. In 302 patients suffering from migraine without aura (at least for 1 year), with no history of cardiovascular diseases and major risk factors for ischemic events, the genotypes of the ACE gene, plasma ACE activity, and the frequency (weekly) and duration of migraine attacks were evaluated. No drugs were given before (4 weeks) and during the study. The same evaluations were performed in 201 subjects without migraine. The molecular biologist and the physician evaluating the patient data were blinded to the clinical history and ACE-DD gene determination. Genotypes were determined by polymerase chain reaction amplification. Plasma ACE activity was performed by the HPLC method. The groups were similar for sex, age and smoking habit (migraines: 302 patients (200 F/102 M), mean age 37.8 ± 8.2 years; control: 201 subjects (127 F/74 M), mean age 37.5 ± 9.3 years). Patients with migraine without aura showed higher incidence of the ACE-DD gene (48.34%) than control subjects (37.32%), p < 0.05. The frequency of migraine (average attacks per week) was higher in patients with DD (2.11 ± 1.9) than in patients with ID (1.54 ± 1.44), p < 0.05. No difference in duration of migraine attacks (hours per week) was observed. Plasma ACE activity was increased in patients with the ACE-DD gene. Our data suggest that ACE-DD gene polymorphism could have an important role in determining migraine attacks and the frequency of these attacks. Further data are needed through further studies, especially on the biomolecular level.

Atherosclerosis as an Inflammatory Disease

In many ways, atherosclerosis is a chronic inflammatory disorder and this issue is confirmed by recent investigations of that have focused on inflammation, providing new insight into mechanisms of disease. Several recent studies have addressed the role of chemokines in leukocyte accumulation in atherosclerosis, extending our knowledge and understanding of the complex and cell type-specific functions of chemokines in atherosclerosis. Activated T-lymphocytes within the atherosclerotic vessel wall express the CD40 ligand surface molecule, known to play a major role in several immunological pathways. In addition to activated T-lymphocytes, functional CD40 and CD40L are coexpressed by human vascular endothelial cells, smooth muscle cells and human macrophages in vitro as well as in situ in human atherosclerotic lesions. Recent studies indicate that CD40L activates atheroma-associated cells by promoting the expression of molecules thought to be involved in atherosclerosis, such as adhesion molecules, cytokines, matrix metalloproteinases, and tissue factor. Atherosclerosis starts with an innate immune response involving the recruitment and activation of monocytes macrophages that respond to an excessive accumulation of modified lipids within the arterial wall, followed by an adaptive immune response involving antigen-specific T lymphocytes. Effector T cells recognize modified auto-antigens such as oxidized LDL and heat shock proteins (i.e. HSP-60) that are presented by antigen-presenting cells such as macrophages or dendritic cells. The accumulation of inflammatory cells within the arterial wall leads to local production of chemokines, interleukins and proteases that enhance the influx of monocytes and lymphocytes, thereby promoting the progression of atherosclerotic lesions Recent reports have helped explain some of these questions by pointing to a role of contact dependent interaction between CD40 and CD40 ligand (CD40L, renamed CD154) as a stimulus for atheroma-associated cells. Also Macrophages play important roles in the progression of atherosclerosis by exhibiting unique characteristics under the various stimuli, evolving the plaque instability, thrombus formation and remodeling. Macrophage recruitment by abnormal endothelium over developing atherosclerotic plaques, is aided by endothelial expression of adhesion molecules (ICAM-1, VCAM, ELAM). The knowledge of atherosclerosis as an inflammatory disease offers the opportunity to develop novel therapeutic strategies targeting the inflammatory component of the disease.

Vascular Effects of Progesterone: Role of Cellular Calcium Regulation

Vascular actions of progesterone have been reported, independently of estrogen, affecting both blood pressure and other aspects of the cardiovascular system. To study possible mechanisms underlying these effects, we examined the effects of P in vivo in intact rats and in vitro in isolated artery and vascular smooth muscle cell preparations. In anesthetized Sprague-Dawley rats , bolus intravenous injections of P (100 &mgr;g/kg) significantly decreased pressor responses to norepinephrine (0.3 &mgr;g/kg). In vitro, progesterone (10−8 to 10−5 mmol/L) produced a significant, dose-dependent relaxation of isolated helical strips, both of rat tail artery precontracted with KCl (60 mmol/L) or arginine vasopressin (3 nmol/L), and of rat aorta precontracted with KCl (60 mmol/L) or norepinephrine (0.1 &mgr;mol/L). In isolated vascular smooth muscle cells, progesterone (5×10−7 mol/L) reversibly inhibited KCl (30 mmol/L) -induced elevation of cytosolic-free calcium by 64.1±5.5% (P <0.05), and in whole-cell patch-clamp experiments, progesterone (5×10−6 mol/L) reversibly and significantly blunted L-type calcium channel inward current, decreasing peak inward current to 65.7±4.3% of the control value (P <0.05). Our results provide evidence that progesterone is a vasoactive hormone, inhibiting agonist-induced vasoconstriction. The data further suggest that progesterone effects on vascular tissue may, at least in part, be mediated by modulation of the L-type calcium channel current activity and, consequently, of cytosolic-free calcium content.

Effects of high-dose furosemide and small-volume hypertonic saline solution infusion in comparison with a high dose of furosemide as a bolus, in refractory congestive heart failure.

Diuretics, have been accepted as first‐line treatment in refractory heart failure, but a lack of response is a frequent event. A randomised single blind study was performed to evaluate the effects of the combination of high‐dose furosemide and small‐volume hypertonic saline solution (HSS) infusion in the treatment of refractory NYHA class IV congestive heart failure (CHF).

Carotid atherosclerosis and chronic hepatitis C: A prospective study of risk associations

There are contrasting results in studies of cardiovascular risk in patients with genotype 1 chronic hepatitis C (G1 CHC). We evaluated the prevalence of carotid atherosclerosis compared with a control population in order to assess the potential association between atherosclerosis, host and viral factors, and liver histological features. In all, 174 consecutive biopsy‐proven G1 CHC patients were evaluated by anthropometric and metabolic measurements and 174 patients attending an outpatient cardiology unit were used as controls. Intima‐media thickness (IMT) and carotid plaques, defined as focal thickening of >1.3 mm at the level of common carotid, were evaluated using ultrasonography. All G1 CHC biopsies were scored by one pathologist for staging and grading, and graded for steatosis. Carotid plaques were found in 73 (41.9%) G1 CHC patients compared with 40 (22.9%) control patients (P < 0.001). Similarly, G1 CHC patients had a greater IMT compared with control patients (1.04 ± 0.21 versus 0.90 ± 0.16; P < 0.001). Multivariate logistic regression analysis showed that older age (odds ratio [OR] 1.047, 95% confidence interval [CI]: 1.014‐1.082, P = 0.005), and severe hepatic fibrosis (OR 2.177, 95% CI: 1.043‐4.542, P = 0.03), were independently linked to the presence of carotid plaques. In patients ≤55 years, 15/67 cases with F0‐F2 fibrosis (22.3%) had carotid plaques, compared with 11/21 (52.3%) with F3‐F4 fibrosis (P = 0.008). By contrast, in patients >55 years the prevalence of carotid plaques was similar in those with or without severe fibrosis (25/43, 58.1% versus 22/43, 51.1%; P = 0.51). Conclusion: Severe hepatic fibrosis is associated with a high risk of early carotid atherosclerosis in G1 CHC patients. (HEPATOLOGY 2012)

Inflammation in Ischemic Stroke Subtypes

Determining the cause of stroke does influence choices for management. categorization of subtypes of ischemic stroke has had considerable study, but definitions are hard to formulate and their application for diagnosis in an individual patient is often problematic. Cerebral ischemia initiates a complex cascade of events at genomic, molecular, and cellular levels, and inflammation is important in this cascade. In 1993 for For the Trial of Org 10172 in Acute Stroke Treatment (TOAST), Adams et al] conducted a placebo-controlled, randomized, blinded study of the low-molecular-weight heparinoid given to patients within 24 hours after stroke and developed a system for diagnosis of subtype of ischemic stroke that uses components of existing diagnostic schemes. The type of acute ischemic stroke was classified according to the TOAST classification: 1) Large Artery AtheroSclerosis (LAAS); 2) CardioEmbolic Infarct (CEI); 3) LACunar infarct (LAC); 4) stroke of Other Determined Etiology (ODE); 5) stroke of UnDetermined Etiology (UDE) (see Fig. (1)). On the basis of pathophysiologic differences of each stroke subtype its possible to hypothesize a different pattern of immuno-inflammatory activation in relation of ischemic stroke subtype. A nonspecific systemic inflammatory response occurs after both ischemic and hemorrhagic stroke, either as part of the process of brain damage or in response to complications such as deep venous thrombosis. Several studies have reported that higher levels of inflammatory markers such as C-reactive protein (CRP) and interleukin-6 (IL-6) are associated with worse outcome after ischemic stroke. Our group reported that patients with cardioembolic subtype showed significantly higher median plasma levels of TNF-α, IL-6, IL-1β whereas the lacunar subtype showed significantly lower median plasma levels of TNF-α, IL-6 and IL-1β. Our findings underlined the significant association was noted between the severity of neurological deficit at admission, the diagnostic subtype and some inflammatory variables.

Neuron Protection as a Therapeutic Target in Acute Ischemic Stroke

Involvement of various neurotransmitters and neuromodulators have been shown to contribute to the ischemic injury and neuronal death associated with stroke Role of excitatory amino acid receptor activation, calcium overload, nitric oxide, and oxidative stress in the pathogenesis of ischemic brain damage is well established. Several new strategies are currently emerging, based on recent advances in our understanding of molecular pathways that could be considered as potential therapeutic targets. For example reactive oxygen species (ROS) are important contributors to the secondary injury cascade following traumatic brain injury (TBI), and ROS inhibition has consistently been shown to be neuroprotective following experimental TBI and brain ischemia. Furthermore, more recently, some authors concluded that nonanticoagulant 3K3A-APC exhibits greater neuroprotective efficacy with no risk for bleeding compared with drotrecogin-alfa activated, a hyperanticoagulant form of APC. Excessive calcium entry into depolarized neurons contributes significantly to cerebral tissue damage after ischemia. Included in the sequence of events leading to neuronal death in ischemic tissue following stroke is an excessive and toxic rise in the intracellular Ca(2+)-concentration, predominantly due to an influx of Ca2+ through nonselective cation-channels as well as Ca(2+)-channels.. Some authros conducted a study to investigate whether the enhancement of GABA receptor activity could inhibit NMDA receptor-mediated nitric oxide (NO) production by neuronal NO synthase (nNOS) in brain ischemic injury. The results showed that both the GABA(A) receptor agonist muscimol and the GABA(B) receptor agonist baclofen had neuroprotective effect, and the combination of two agonists could significantly protect neurons against death induced by ischemia/reperfusion. On this basis we conclude that neuroprotection for ischemic stroke refers to strategies, applied singly or in combination, that antagonize the injurious biochemical and molecular events that eventuate in irreversible ischemic injury. There has been a recent explosion of interest in this field, with over 1000 experimental papers and over 400 clinical articles appearing within the past 6 years. These studies, in turn, are the outgrowth of three decades of investigative work to define the multiple mechanisms and mediators of ischemic brain injury, which constitute potential targets of neuroprotection.