Long-term antithrombotic treatment in intracranial hemorrhage survivors with atrial fibrillation.

OBJECTIVE: To perform a systematic review and meta-analysis of studies reporting recurrent intracranial hemorrhage (ICH) and ischemic stroke (IS) in ICH survivors with atrial fibrillation (AF) during long-term follow-up. METHODS: A comprehensive literature search including MEDLINE, EMBASE, Cochrane library, clinical trials registry was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We considered studies capturing outcome events (ICH recurrence and IS) for ≥3 months and treatment exposure to vitamin K antagonists (VKAs), antiplatelet agents (APAs), or no antithrombotic medication (no-ATM). Corresponding authors provided aggregate data for IS and ICH recurrence rate between 6 weeks after the event and 1 year of follow-up for each treatment exposure. Meta-analyses of pooled rate ratios (RRs) were conducted with the inverse variance method. RESULTS: Seventeen articles met inclusion criteria. Seven observational studies enrolling 2,452 patients were included in the meta-analysis. Pooled RR estimates for IS were lower for VKAs compared to APAs (RR = 0.45, 95% confidence interval [CI] 0.27-0.74, p = 0.002) and no-ATM (RR = 0.47, 95% CI 0.29-0.77, p = 0.002). Pooled RR estimates for ICH recurrence were not significantly increased across treatment groups (VKA vs APA: RR = 1.34, 95% CI 0.79-2.30, p = 0.28; VKA vs no-ATM: RR = 0.93, 95% CI 0.45-1.90, p = 0.84). CONCLUSIONS: In observational studies, anticoagulation with VKA is associated with a lower rate of IS than APA or no-ATM without increasing ICH recurrence significantly. A randomized controlled trial is needed to determine the net clinical benefit of anticoagulation in ICH survivors with AF.

Cardiac monitoring for detection of atrial fibrillation after TIA: A systematic review and meta-analysis.

Background and purpose The detection rate of atrial fibrillation has not been studied specifically in transient ischemic attack (TIA) patients although extrapolation from ischemic stroke may be inadequate. We conducted a systematic review and meta-analysis to determine the rate of newly diagnosed atrial fibrillation using different methods of ECG monitoring in TIA. Methods A comprehensive literature search was performed following a pre-specified protocol the PRISMA statement. Prospective observational studies and randomized controlled trials were considered that included TIA patients who underwent cardiac monitoring for >12 h. Primary outcome was frequency of detection of atrial fibrillation ≥30 s. Analyses of subgroups and of duration and type of monitoring were performed. Results Seventeen studies enrolling 1163 patients were included. The pooled atrial fibrillation detection rate for all methods was 4% (95% CI: 2-7%). Yield of monitoring was higher in selected (higher age, more extensive testing for arrhythmias before enrolment, or presumed cardioembolic/cryptogenic cause) than in unselected cohorts (7% vs 3%). Pooled mean atrial fibrillation detection rates rose with duration of monitoring: 4% (24 h), 5% (24 h to 7 days) and 6% (>7 days), respectively. Yield of non-invasive was significantly lower than that of invasive monitoring (4% vs. 11%). Significant heterogeneity was observed among studies (I2=60.61%). Conclusion This first meta-analysis of atrial fibrillation detection in TIA patients finds a lower atrial fibrillation detection rate in TIA than reported for IS and TIA cohorts in previous meta-analyses. Prospective studies are needed to determine actual prevalence of atrial fibrillation and optimal diagnostic procedure for atrial fibrillation detection in TIA.

Characterization of Neutrophil Function in Human Cutaneous Leishmaniasis Caused by Leishmania braziliensis.

Infection with different Leishmania spp. protozoa can lead to a variety of clinical syndromes associated in many cases with inflammatory responses in the skin. Although macrophages harbor the majority of parasites throughout chronic infection, neutrophils are the first inflammatory cells to migrate to the site of infection. Whether neutrophils promote parasite clearance or exacerbate disease in murine models varies depending on the susceptible or resistant status of the host. Based on the hypothesis that neutrophils contribute to a systemic inflammatory state in humans with symptomatic L. braziliensis infection, we evaluated the phenotype of neutrophils from patients with cutaneous leishmaniasis (CL) during the course of L. braziliensis infection. After in vitro infection with L. braziliensis, CL patient neutrophils produced more reactive oxygen species (ROS) and higher levels of CXCL8 and CXCL9, chemokines associated with recruitment of neutrophils and Th1-type cells, than neutrophils from control healthy subjects (HS). Despite this, CL patient and HS neutrophils were equally capable of phagocytosis of L. braziliensis. There was no difference between the degree of activation of neutrophils from CL versus healthy subjects, assessed by CD66b and CD62L expression using flow cytometry. Of interest, these studies revealed that both parasite-infected and bystander neutrophils became activated during incubation with L. braziliensis. The enhanced ROS and chemokine production in neutrophils from CL patients reverted to baseline after treatment of disease. These data suggest that the circulating neutrophils during CL are not necessarily more microbicidal, but they have a more pro-inflammatory profile after parasite restimulation than neutrophils from healthy subjects.

Accuracy of the spot sign on computed tomography angiography as a predictor of haematoma enlargement after acute spontaneous intracerebral haemorrhage: a systematic review.

BACKGROUND: A common early complication of intracerebral haemorrhage (ICH) is haematoma enlargement (HE), a strong independent predictor of a poor outcome. Therapeutic options to limit haematoma progression are currently scarce. Haemostatic therapy may be effective in patients with ICH, but it carries the risk of thromboembolic events in unselected patients. Accurate patient selection would, therefore, be of key importance for delivering potentially successful therapeutic strategies. Currently, there is no gold standard to accurately predict HE. The presence of contrast extravasation within the haematoma on computed tomography angiography (CTA), the 'spot sign', has been reported in several studies and seems a particularly promising marker but lacks a standardised evaluation so far. SUMMARY: We conducted a systematic review of published data to address the research question: In adults with acute spontaneous ICH, how accurately does the spot sign predict HE on follow-up imaging and thus poor functional outcome or mortality? We searched PubMed and Embase databases (from 1980 to May 2012), using a highly sensitive search strategy and including all studies involving adult patients with spontaneous ICH evaluated with CTA and follow-up CT scans, reporting any measure of clinical outcome, and reporting or allowing calculation of accuracy measures of the spot sign in predicting HE and clinical outcome. Baseline characteristics, accuracy measures and effect measures, as well as bias assessment, were reported according to PRISMA recommendations. The quality of the studies was appraised using an adapted version of the REMARK reporting recommendations. From 259 potentially relevant studies, we finally selected 6 studies (1 of them was a multicentre cohort study) covering a total of 709 patients. Studies varied substantially in terms of size, methodological quality, definitions of terms, outcomes selected and results. In particular, definition of the spot sign was not consistent in all studies. Furthermore, the only outcome measure consistently available was HE, while definitions and analyses of clinical outcomes seemed not adequate. Lastly, the choice of candidate variables for univariate and multivariate analyses did not include all determinants of HE and poor functional outcome. High heterogeneity was demonstrated (I(2): 94% for HE) with substantial potential of bias. KEY MESSAGES: Studies of the spot sign are diverse and therefore complex to interpret. Our research question could not be answered due to heterogeneity and potential of bias in the selected studies. Further appropriately powered studies using standardised definitions and taking all predictors of HE and poor clinical outcome into account are required for a proper clinical implementation.

Macrophages participate in host protection and the disease pathology associated with Leishmania braziliensis infection.

BACKGROUND: Leishmania preferentially infects macrophages, which allow the parasite to multiply but can also kill the parasite. Although the T cell response in human leishmaniasis is well-characterized, little is known about the concomitant macrophage behavior. The aim of this study was to characterize the macrophage immune response after Leishmania braziliensis infection in cells derived from cutaneous leishmaniasis (CL) or mucosal leishmaniasis (ML) patients, subclinical individuals (SC) and healthy control subjects (HS). METHODS: Peripheral blood mononuclear cell-derived macrophages from the different groups were exposed to L. braziliensis in vitro and were evaluated for susceptibility to Leishmania infection, ability to kill Leishmania and chemokine/cytokine production. Nitric Oxide (NO) and superoxide (O2-) levels in the supernatant of infected macrophage cultures were monitored. RESULTS: After exposure to L. braziliensis, peripheral blood mononuclear cell-derived macrophages from SC individuals showed a lower infection rate and a smaller number of intracellular amastigotes compared to cells from CL and ML patients. Macrophages from CL and ML patients produced more chemokines and TNF-α than those from the SC group. Production of NO and O2- were detected but did not vary significantly among the different groups. CONCLUSIONS: Our data indicate that macrophages play a pivotal role in controlling L. braziliensis infection and in leishmaniasis pathology by secreting pro-inflammatory chemokines/cytokines that activate and recruit T cells, overwhelming the inflammatory response.

Evaluation of the microbicidal activity and cytokines/chemokines profile released by neutrophils from HTLV-1-infected individuals.

Human T cell lymphotropic virus type-1 (HTLV-1) induces activation and spontaneous proliferation of T cells with production of type-1 pro-inflammatory cytokines. It modifies the immune response to other antigens and increases susceptibility to infectious diseases. However, little is known about innate immunity in HTLV-1 infection. HTLV-1-infected individuals have higher spontaneous neutrophil activation than HTLV-1-seronegative individuals, as shown by the nitroblue tetrazolium (NBT) assay. This study was conducted to evaluate neutrophil function in HTLV-1-infected individuals. Participants in the study included 18 HTLV-1-infected individuals and 14 HTLV-1-seronegative controls. We evaluated the ability of neutrophils (PMNs) to control a parasite infection, to produce peroxynitrite, cytokines and chemokines and to express activation markers in cultures when stimulated with LPS or infected with Leishmania. When compared with the control group, there was no difference in the percentage of PMNs infected with Leishmania or in the number of amastigotes/100 PMNs in HTLV-1-infected individuals. The microbicidal activity of the PMNs and the levels of CXCL8 and CCL4 released by these cells did not show a difference between HTLV-1-infected individuals and the control group. In both the HTLV-1 group and the control group, infection with Leishmania or stimulation of PMNs led to cellular activation. These observations suggest that neutrophils from HTLV-1-infected individuals have preserved their ability to become activated and to produce chemokines and peroxynitrite after stimulation and that the susceptibility to infection by intracellular Leishmania amazonensis in HTLV-1-infected individuals does not depend on impairment of neutrophil function.

BALB/c mice infected with antimony treatment refractory isolate of Leishmania braziliensis present severe lesions due to IL-4 production.

BACKGROUND: Leishmania braziliensis is the main causative agent of cutaneous leishmaniasis in Brazil. Protection against infection is related to development of Th1 responses, but the mechanisms that mediate susceptibility are still poorly understood. Murine models have been the most important tools in understanding the immunopathogenesis of L. major infection and have shown that Th2 responses favor parasite survival. In contrast, L. braziliensis-infected mice develop strong Th1 responses and easily resolve the infection, thus making the study of factors affecting susceptibility to this parasite difficult. METHODOLOGY/PRINCIPAL FINDINGS: Here, we describe an experimental model for the evaluation of the mechanisms mediating susceptibility to L. braziliensis infection. BALB/c mice were inoculated with stationary phase promastigotes of L. braziliensis, isolates LTCP393(R) and LTCP15171(S), which are resistant and susceptible to antimony and nitric oxide (NO), respectively. Mice inoculated with LTCP393(R) presented larger lesions that healed more slowly and contained higher parasite loads than lesions caused by LTCP15171(S). Inflammatory infiltrates in the lesions and production of IFN-γ, TNF-α, IL-10 and TGF-ß were similar in mice inoculated with either isolate, indicating that these factors did not contribute to the different disease manifestations observed. In contrast, IL-4 production was strongly increased in LTCP393(R)-inoculated animals and also arginase I (Arg I) expression. Moreover, anti-IL-4 monoclonal antibody (mAb) treatment resulted in decreased lesion thickness and parasite burden in animals inoculated with LTCP393(R), but not in those inoculated with LTCP15171(S). CONCLUSION/SIGNIFICANCE: We conclude that the ability of L. braziliensis isolates to induce Th2 responses affects the susceptibility to infection with these isolates and contributes to the increased virulence and severity of disease associated with them. Since these data reflect what happens in human infection, this model could be useful to study the pathogenesis of the L. braziliensis infection, as well as to design new strategies of therapeutic intervention.

Resistance of Leishmania (Viannia) braziliensis to nitric oxide: correlation with antimony therapy and TNF-alpha production.

BACKGROUND: Nitric oxide (NO) produced in macrophages plays a pivotal role as a leishmanicidal agent. A previous study has demonstrated that 20% of the L. (V.) braziliensis isolated from initial cutaneous lesions of patients from the endemic area of Corte de Pedra, Bahia, Brazil, were NO resistant. Additionally, 5 to 11% of the patients did not respond to three or more antimony treatments" (refractory patients). The aim of this study is to investigate if there is an association between the resistance of L. (V.) braziliensis to NO and nonresponsiveness to antimony therapy and cytokine production. METHODS: We evaluated the in vitro toxicity of NO against the promastigotes stages of L. (V.) braziliensis isolated from responsive and refractory patients, and the infectivity of the amastigote forms of these isolates against human macrophages. The supernatants from Leishmania infected macrophage were used to measure TNF-alpha and IL-10 levels. RESULTS: Using NaNO2 (pH 5.0) as the NO source, L. (V.) braziliensis isolated from refractory patients were more NO resistant (IC50 = 5.8 +/- 4.8) than L. (V.) braziliensis isolated from responsive patients (IC50 = 2.0 +/- 1.4). Four isolates were selected to infect human macrophages: NO-susceptible and NO-resistant L. (V.) braziliensis isolated from responsive and refractory patients. NO-resistant L. (V.) braziliensis isolated from refractory patients infected more macrophages stimulated with LPS and IFN-gamma at 120 hours than NO-susceptible L. (V.) braziliensis isolated from refractory patients. Also, lower levels of TNF-alpha were detected in supernatants of macrophages infected with NO-resistant L. (V.) braziliensis as compared to macrophages infected with NO-susceptible L. (V.) braziliensis (p < 0.05 at 2, 24 and 120 hours), while no differences were detected in IL-10 levels. CONCLUSION: These data suggest that NO resistance could be related to the nonresponsiveness to antimony therapy seen in American Tegumentary Leishmaniasis.

Effects of restless legs syndrome on quality of life and psychological status in patients with type 2 diabetes.

PURPOSE: The purpose of this study was to evaluate the effects of restless legs syndrome (RLS) on quality of life (QoL), anxiety, and depression in people with type 2 diabetes. METHODS: One hundred twenty-four patients with type 2 diabetes were enrolled in this study. RLS was diagnosed by a neurologist masked on psychological evaluation. Data on severity, frequency, and duration of the sleep disorder were collected. The Italian version of the SF-36 was used to assess QoL. Psychological status was investigated by a neuropsychologist masked on RLS diagnosis. Patients with a diagnosis of generalized anxiety disorder (GAD) and major depressive disorder (MDD) were considered affected by anxiety and depression, respectively. A modified version of the Hamilton Anxiety and Depression Rating Scales (HARS and HDRS) was also administered. RESULTS: RLS was an independent predictor for several mental domains of the SF-36 and for the mental component summary. Multivariate analysis showed that RLS was an independent predictor of anxiety and depression. RLS severity correlated with HARS and HDRS scores, whereas frequency per week of RLS had a significant correlation only with HARS score. CONCLUSIONS: Among individuals with diabetes, RLS can impair mental health, increasing the risk for anxiety and depression. Since RLS consequences on nocturnal rest and psychological status may impair glycemic control in this population, diabetologists and diabetes educators should investigate for the presence of RLS in their patients and treat them.

Who will consent to emergency treatment trials for subarachnoid hemorrhage?

OBJECTIVES: Aneurysmal subarachnoid hemorrhage (SAH) is a devastating disorder that still requires much clinical study. However, the decision to participate in a randomized clinical trial, particularly a neuroemergency trial, is a complex one. The purposes of this survey were to determine who would participate in a randomized clinical trial that intended to examine transfusion practices after SAH, to identify who could serve as potential proxy decision-makers, and to find which patient characteristics were associated with the decision to participate. METHODS: This was a cross-sectional study using a self-administered questionnaire, composed of a brief description of the proposed trial followed by questions about participation using a 5-point Likert scale. Information sought included potential decision-maker, demographic data, setting and reason for current health care access, and personal or family history of neurologic injury. RESULTS: Nine-hundred five subjects were enrolled during emergency department (ED) visits, office visits, hospital admissions, or online, during a 1-month period: 63% were women and 46% were white. Nonneurologic problems were the leading reason (90%) for health care access, but 45% had a personal or family history of neurologic injury. Overall, 54% (95% confidence interval [CI] = 51% to 57%) of subjects stated they would definitely or probably consent to participate. No subject characteristics were associated with this decision: age (p = 0.28), sex (p = 0.16), race/ethnicity (p = 0.07), education (p = 0.44), religion (p = 0.42), clinical setting (p = 0.14), reason for visit (p = 0.58), and/or history of neurologic injury (p = 0.33). The vast majority (88%) identified a family member as the proxy decision-maker, again without differences among groups. CONCLUSIONS: Greater than half of respondents stated they would participate in a proposed emergency treatment trial for SAH. Our survey suggests that the decision to participate is highly individualized, because no demographic, pathologic, historical, or access-related predictors of choice were found. Educational materials designed for this type of trial would need to be broad-based. Family members should be considered as proxy decision-makers where permitted by federal and local regulations.

B-type natriuretic peptide as a marker of asymptomatic re-stenosis after coronary implantation of a paclitaxel-eluting stent.

BACKGROUND: The aim of the present study was the detection of asymptomatic coronary re-stenosis after percutaneous coronary intervention (PCI). METHODS: We studied 26 subjects who had been recently implanted with a paclitaxel-eluting coronary stent by both a conventional exercise test and the determination of plasma B-type natriuretic peptide (BNP) levels. RESULTS: At control coronary angiography, nine months after initial PCI, six patients had re-stenosis and 20 were re-stenosis free. We found that re-stenosis was best predicted by the combination of a basal plasma BNP level > or = 50 pg/ml and a positive or uncertain conventional exercise test (positive likelihood ratio of the combination = 10). The best predictor of absence of re-stenosis was a low (< 50 pg/ml) plasma BNP level (negative likelihood ratio = 0.26). CONCLUSIONS: Accordingly, basal BNP level testing can be recommended in the follow-up evaluation of coronary patients after PCI, to improve both the detection and the exclusion of asymptomatic re-stenosis.

Association of restless legs syndrome in type 2 diabetes: a case-control study.

STUDY OBJECTIVE: To look for an association between restless legs syndrome (RLS) and type 2 diabetes in a case-control study; to analyze the characteristics of RLS in diabetic patients; and to identify possible risk factors for the development of RLS in diabetic patients. DESIGN: A case-control study. SETTING: Diabetic outpatient clinic of a major university hospital. PARTICIPANTS: One hundred twenty-four consecutive outpatients with diabetes and 87 consecutive controls with a previous diagnosis of other endocrine disease. INTERVENTIONS: RLS was diagnosed using the criteria of the International RLS Study Group, and severity of RLS was assessed using the International RLS Study Group Rating Scale. Characteristics of RLS and several laboratory parameters were investigated in diabetic patients and controls affected by the sleep disorder. A clinical diagnosis of polyneuropathy was assessed to evaluate its role as a risk factor for RLS in diabetic patients. MEASUREMENT AND RESULTS: RLS was diagnosed in 22 diabetic patients (17.7%) and in only 5 controls (5.5%), 3 of whom had pituitary and 2 had adrenal gland disorders, and RLS was independently associated with type 2 diabetes (P < 0.04). Even if a clinical diagnosis of polyneuropathy was made in only 27% of diabetic patients affected by RLS, after multivariate logistic regression, the presence of polyneuropathy was the only variable associated with RLS in diabetics (odds ratio, 7.88; 95% confidence interval, 1.34-46.28; P < 0.02). RLS in diabetics showed a frequency of positive family history lower than that known for primary RLS, showed a late age of onset, and manifested itself after the diagnosis of diabetes was made. CONCLUSIONS: This is the first controlled study confirming a significant association between RLS and type 2 diabetes. In diabetic patients, polyneuropathy represents the main risk factor for RLS. However, polyneuropathy only partially explains the increased prevalence of RLS in type 2 diabetics. Clinical characteristics of RLS in diabetic patients are those of a secondary form.

Resistance of Leishmania (Leishmania) amazonensis and Leishmania (Viannia) braziliensis to nitric oxide correlates with disease severity in Tegumentary Leishmaniasis.

BACKGROUND: Nitric oxide (NO*) plays a pivotal role as a leishmanicidal agent in mouse macrophages. NO* resistant Escherichia coli and Mycobacterium tuberculosis have been associated with a severe outcome of these diseases. METHODS: In this study we evaluated the in vitro toxicity of nitric oxide for the promastigote stages of Leishmania (Viannia) braziliensis and Leishmania (Leishmania) amazonensis parasites, and the infectivity of the amastigote stage for human macrophages. Parasites were isolated from patients with cutaneous, mucosal or disseminated leishmaniasis, and NO* resistance was correlated with clinical presentation. RESULTS: Seventeen isolates of L. (L.) amazonensis or L. (V.) braziliensis promastigotes were killed by up to 8 mM of more of NaNO2 (pH 5.0) and therefore were defined as nitric oxide-susceptible. In contrast, eleven isolates that survived exposure to 16 mM NaNO2 were defined as nitric oxide-resistant. Patients infected with nitric oxide-resistant Leishmania had significantly larger lesions than patients infected with nitric oxide-susceptible isolates. Furthermore, nitric oxide-resistant L. (L.) amazonensis and L. (V.) braziliensis multiplied significantly better in human macrophages than nitric oxide-susceptible isolates. CONCLUSION: These data suggest that nitric oxide-resistance of Leishmania isolates confers a survival benefit for the parasites inside the macrophage, and possibly exacerbates the clinical course of human leishmaniasis.

Differential effects of antigens from L. braziliensis isolates from disseminated and cutaneous leishmaniasis on in vitro cytokine production.

BACKGROUND: Disseminated leishmaniasis is an emerging infectious disease, mostly due to L. braziliensis, which has clinical and histopathological features distinct from cutaneous leishmaniasis. METHODS: In the current study we evaluated the in vitro production of the cytokines IFN-gamma, TNF-alpha, IL-5 and IL-10 by peripheral blood mononuclear cells (PBMC) from 15 disseminated leishmaniasis and 24 cutaneous leishmaniasis patients upon stimulation with L. braziliensis antigens genotyped as disseminated leishmaniasis or cutaneous leishmaniasis isolates. RESULTS: Regardless of the source of L. braziliensis antigens, PBMC from cutaneous leishmaniasis patients produced significantly higher IFN-gamma than PBMC from disseminated leishmaniasis patients. Levels of TNF-alpha by PBMC from cutaneous leishmaniasis patients were significantly higher than disseminated leishmaniasis patients only when stimulated by genotyped cutaneous leishmaniasis antigens. The levels of IL-5 and IL-10 production by PBMC were very low and similar in PBMCs from both disseminated leishmaniasis and cutaneous leishmaniasis patients. The immune response of each patient evaluated by the two L. braziliensis antigens was assessed in a paired analysis in which we showed that L. braziliensis genotyped as disseminated leishmaniasis isolate was more potent than L. braziliensis genotyped as cutaneous leishmaniasis isolate in triggering IFN-gamma and TNF-alpha production in both diseases and IL-5 only in cutaneous leishmaniasis patients. CONCLUSION: This study provides evidence that antigens prepared from genotypically distinct strains of L. braziliensis induce different degrees of immune response. It also indicates that both parasite and host play a role in the outcome of L. braziliensis infection.