Secondary prevention after acute myocardial infarction: drug adherence, treatment goals, and predictors of health lifestyle habits. The BLITZ-4 Registry.

BACKGROUND: To describe drug adherence and treatment goals, and to identify the independent predictors of smoking persistence and unsatisfactory lifestyle habits six months after an acute myocardial infarction (AMI). METHODS AND RESULTS: 11,706 patients with AMI (30% female, mean age 68 years) were enrolled in 163 large-volume coronary care units (CCUs). At six months, drug adherence was ≥90%, while blood pressure (BP) <140/90 mmHg, low density lipoprotein (LDL) <100 mg/dl (in patients on statins), HbA1c <7% (in treated diabetics), and smoking persistence were observed in 74%, 76%, 45%, and 27% of patients, respectively. Inadequate fish intake decreased from 73% to 55%, inadequate intake of fruit and vegetables from 32% to 23%, and insufficient exercise in eligible patients from 74% to 59% (p < 0.0001). At multivariable analysis, a post-discharge cardiac visit and referral to cardiac rehabilitation at follow-up were independently associated with a lower risk of insufficient physical exercise (odds ratio (OR) 0.71 and 0.70, respectively) and persistent smoking (OR 0.68 and 0.60), whereas only referral to cardiac rehabilitation was associated with a lower risk of inadequate fish and fruit/vegetable intake (OR 0.70 and 0.65). CONCLUSIONS: Six months after an AMI, despite a high adherence to drug treatments, BP, LDL, and diabetic goals are inadequately achieved. Subjects with healthy lifestyles improved after discharge, but the rate of those with regular exercise habits and adequate fish intake could be further improved. Access to post-discharge cardiac visit and referral to cardiac rehabilitation were associated with better adherence to healthy lifestyles. Knowledge of the variables associated with specific lifestyle changes may help in tailoring secondary prevention programmes.

Radial artery access for above the knee angioplasty: a feasibility study.

AIMS: Lower limb angioplasty is usually performed by transfemoral access despite the risk of local complications. Transradial access (TRA) has gained acceptance for coronary interventions. The aim of this study was to evaluate the feasibility and safety of TRA for above the knee (ATK) angioplasty. METHODS AND RESULTS: Twenty-five consecutive patients (eight females; mean age 72, range 55-85 years; seven symptomatic for critical limb ischaemia, 18 for claudication) underwent ATK angioplasty by left (19) or right (6) TRA. A total of 32 lesions were addressed; 16 stents were positioned in 12 patients with an overall success rate of 81%, and a success rate of 38% on occlusions and of 96% on stenoses. The overall success rate on the 16 supra-inguinal lesions was 81%, (success rate 60% on occlusions and 91% on stenoses). The overall success rate on the 16 infra-inguinal lesions was 81%, (success rate 0% on occlusions and 100% on stenoses). Any haemorrhagic complications or local complications needing surgery were observed in the cohort of patients. CONCLUSIONS: TRA can represent a feasible and safe alternative for ATK angioplasty in case of difficult femoral access.

Aspectos do tratamento odontológico de pacientes hemofílicos: revisão de literatura / . Aspects of the dental treatment of hemophilic patients: review of literature

A hemofilia representa uma condição sistêmica que ainda gera insegurança no seu atendimento por parte dos cirurgiões-dentistas. No entanto, os procedimentos preventivos e restauradores em indivíduos hemofílicos, pouco diferem do tratamento de individuos normorreativos. Como em qualquer paciente, uma anamnese completa e detalhada é necessária: antes do tratamento odontológico de pacientes hemofílicos, deve-se conhecer o tipo e o grau do distúrbio de sangramento...

Hemophilia poses as a systemic condition that still raises in some general dentists lack of confidence on its dental management. However, preventive and restorative procedures in hemophilic subjects are not too diferent of the treatment in healthy ones. A full detailed medical questionnaire in necessary as in any patient: before the dental treatment of hemophilic patients, it must be know the type and severity of the bleeding disorder...

Prevalência de cárie e aspectos periodontais em crianças e adolescentes portadores de hemofilia tipo A e B / Dental carie prevalence and periodontal aspects in children and adolescents with hemophilia A and B

A hemofilia é um distúrbio hematológico que pode comprometer a cavidade oral, e necessita de cuidados adicionais durante um tratamento odontológico pela possibilidade de haver sangramento persistente. No entanto, é necessário reconhecer qual a extensão dos efeitos desta condição hereditária e sua influência na cárie e na doença periodontal...

Effectiveness of the transradial approach to reduce bleedings in patients undergoing urgent coronary angioplasty with GPIIb/IIIa inhibitors for acute coronary syndromes.

OBJECTIVES: To analyze the effectiveness of the transradial approach in reducing bleeding rates following urgent percutaneous coronary intervention (PCI) in patients with acute coronary syndromes treated with glycoprotein IIb/IIIa inhibitors (GPIs). BACKGROUND: PCI and use of GPIs are recommended in acute coronary syndromes, but are strong predictors of severe hemorrhagic complications, which, in turn, are associated with reduced survival. The transradial approach represents a simple and effective solution to reduce vascular access site bleedings, particularly with GPIs. METHODS: All consecutive patients undergoing urgent transradial PCI under GPI treatment were enrolled in the registry. No patients were excluded. In addition, we performed a case-matched comparison of the transradial versus transfemoral approach using propensity analysis to adjust for known risk factors for bleeding. The primary end point was the rate of bleedings, graded according to the Thrombolysis in Myocardial Infarction (TIMI) classification. RESULTS: Five hundred thirty-one consecutive patients were prospectively enrolled in the registry. TIMI major, minor, and minimal bleedings were 0.2%, 1.7%, and 6.4%, respectively. Transfusion rate was 0.8%. After propensity-matched analysis, the transradial approach was associated with significantly lower rates of all types of bleedings, while the transfemoral approach was the strongest predictor of TIMI major/minor bleedings (odds ratio 6.67; 95% confidence interval 1.72-25; P = 0.006). CONCLUSIONS: The transradial approach dramatically reduces access site bleedings, including TIMI major and minor bleedings, and transfusion rate, while preserving procedural success and clinical outcome. The transradial approach is an attractive solution to reduce bleeding complications in patients treated with GPIs.

Dendritic cell modulation by mast cells controls the Th1/Th2 balance in responding T cells.

The cytokines secreted by pathogen-activated human dendritic cells (DC) are strongly regulated in vitro by histamine, a major component of mast cell granules, ultimately modulating the capacity of the DC to polarize naive T cells. Because DC and mast cells are located in close proximity in peripheral compartments, we hypothesized that mast cell products would influence the maturation of DC and hence the Th balance of an immune response in vivo. In this study, we show that specific mast cell degranulation stimuli, given s.c. in mice with Ag and adjuvant, produce effector T cells that proliferate to Ag but secrete dramatically reduced levels of IFN-gamma and increased amounts of IL-4 compared with control T cells primed in the absence of a mast cell stimulus. Immunization with Ag and adjuvant in the presence of a degranulation stimulus also resulted in the accumulation of DC in the draining lymph nodes that had reduced capacity to induce Ag-specific Th1 cells, in comparison with DC from mice lacking a degranulation stimulus. Therefore, by acting upon DC at sites of inflammation, mast cells play a critical role in determining the polarity of Ag-specific T cell responses in vivo.

Cytoplasmic targeting motifs control localization of toll-like receptor 9.

Toll-like receptors (TLRs) are essential for host defense. Although several TLRs reside on the cell surface, nucleic acid recognition of TLRs occurs intracellularly. For example, the receptor for CpG containing bacterial and viral DNA, TLR9, is retained in the endoplasmic reticulum. Recent evidence suggests that the localization of TLR9 is critical for appropriate ligand recognition. Here we have defined which structural features of the TLR9 molecule control its intracellular localization. Both the cytoplasmic and ectodomains of TLR9 contain sufficient information, whereas the transmembrane domain plays no role in intracellular localization. We identify a 14-amino acid stretch that directs TLR9 intracellularly and confers intracellular localization to the normally cell surface-expressed TLR4. Truncation or mutation of the cytoplasmic tail of TLR9 reveals a vesicle localization motif that targets early endosomes. We propose a model whereby modification of the cytoplasmic tail of TLR9 results in trafficking to early endosomes where it encounters CpG DNA.

Uso do laser na esfoliação de dentes decíduos em pacientes hemofílicos / Use of laser in the exfoliation of deciduous teeth in hemophilic patients

Os autores descrevem um novo método de utilização do laser para esfoliação de dentes decíduos em pacientes hemofílicos, no qual se evita o sangramento e, portanto, terapia de reposição sanguínea e de fatores de coagulação.

A computer protocol to evaluate subjects with chest pain in the emergency department: a multicenter study.

OBJECTIVE: Chest pain is a frequent cause of medical admission to the emergency department and the main differential diagnosis is between coronary and non-coronary chest pain. We elaborated a computer protocol for the management of patients with chest pain. METHODS: The computer protocol was made of three sections according to clinical, electrocardiographic and biochemical data. Each section was coded by a letter indicating the probability of coronary chest pain for each section. The combination of the three letters formed a score string used to assign patients to four subgroups of overall probability of coronary chest pain (low, medium-low, medium-high, and high). Low-probability patients were discharged from the emergency department, whereas high-probability patients were admitted to the coronary care unit. The medium-probability patients underwent further evaluation by means of a stress test and were re-classified as having a final low probability (negative test) or high probability (positive test). RESULTS: We evaluated 472 patients (mean age 64 years, range 18-97 years; 47% female). The incidence of coronary events in patients with low, medium-low, medium-high and high overall probability was 1.9, 12.8,13.5 and 68.0%, respectively (P < 0.05). The positive and negative predictive values of the protocol were 64.7 and 97.1%, respectively. CONCLUSIONS: Our computer protocol represents a reliable method for the management of patients with chest pain and a non-diagnostic electrocardiogram.

Osteomas exofíticos múltiplos de ossos craniofaciais não associados à Síndrome de Gardner: relato de caso / Multiple exophytic osteomas of craniofacial bones non-associated with Gardner's Syndrome: a case report

Osteomas exofíticos são protuberâncias de osso maduro que necessitam ser cuidadosamente diferenciados de outras lesões. Os autores apresentam relato de paciente do sexo masculino, com 44 anos de idade, apresentando osteomas exofíticos múltiplos localizados na região vestíbulo-maxilar em ambos os lados, região de pré-molares e molares não associados à Síndrome de Gardner.

CD95-mediated apoptosis is impaired at receptor level by cellular FLICE-inhibitory protein (long form) in wild-type p53 human ovarian carcinoma.

PURPOSE: Ovarian carcinoma is a highly lethal malignancy that often becomes resistant to chemotherapy. Alterations in apoptotic signals and p53 status contribute to drug resistance, and CD95-mediated apoptosis is also deficient in resistant cells. We analyzed the mechanism of resistance to CD95-mediated apoptosis in ovarian carcinoma cell lines differing in p53 status. EXPERIMENTAL DESIGN: CD95-mediated apoptosis was induced by agonistic anti-CD95 antibody, and the apoptotic cascade was monitored with biochemical and functional assays. RESULTS: CD95-mediated apoptosis was blocked in human ovarian cancer cells. In cell lines with wild-type p53, treatment with the protein synthesis inhibitor cycloheximide (CHX) together with anti-CD95 overcame the resistance, suggesting the presence of a labile inhibiting protein. Indeed, the labile protein cellular FLICE-inhibitory protein long form (c-FLIP(L)) was found to block caspase-8 recruitment to the death-inducing signaling complex (DISC), and sensitization of cells by CHX was due to c-FLIP(L) down-modulation at the DISC level. Down-regulation of c-FLIP(L) with antisense oligonucleotides increased CD95-mediated apoptosis as in cells sensitized by CHX, demonstrating the direct involvement of c-FLIP(L) in apoptosis resistance. Removal of c-FLIP(L) block at DISC level allowed full activation of the mitochondrial pathway and, eventually, apoptosis in wild-type p53 cells, whereas in cells with mutated p53, c-FLIP(L) involvement in CD95-mediated apoptosis resistance appeared to be irrelevant. Immunohistochemical analysis of an ovarian tumor tissue array revealed c-FLIP(L) expression in samples with no p53 accumulation (P = 0.034), and a significant (P = 0.037) inverse relationship between c-FLIP(L) and p53 expression levels was also observed in 27 epithelial ovarian cancer specimens with known p53 status. CONCLUSION: The inhibitory protein c-FLIP(L) is involved in resistance to CD95-mediated apoptosis in ovarian carcinoma cells with wild-type p53.

TLR9 is localized in the endoplasmic reticulum prior to stimulation.

In mammals, 10 TLRs recognize conserved pathogen-associated molecular patterns, resulting in the induction of inflammatory innate immune responses. One of these, TLR9, is activated intracellularly by bacterial DNA and synthetic oligodeoxynucleotides (ODN), containing unmethylated CpG dinucleotides. Following treatment with CpG ODN, TLR9 is found in lysosome-associated membrane protein type 1-positive lysosomes, and we asked which intracellular compartment contains TLR9 before CpG exposure. Surprisingly, we found by microscopy and supporting biochemical evidence that both transfected and endogenously expressed human TLR9 is retained in the endoplasmic reticulum. By contrast, human TLR4 trafficked to the cell surface, indicating that endoplasmic reticulum retention is not a property common to all TLRs. Because TLR9 is observed in endocytic vesicles following exposure to CpG ODN, our data indicate that a special mechanism must exist for translocating TLR9 to the signaling compartments that contain the CpG DNA.

A complex of soluble MD-2 and lipopolysaccharide serves as an activating ligand for Toll-like receptor 4.

MD-2, a glycoprotein that is essential for the innate response to lipopolysaccharide (LPS), binds to both LPS and the extracellular domain of Toll-like receptor 4 (TLR4). Following synthesis, MD-2 is either secreted directly into the medium as a soluble, active protein, or binds directly to TLR4 in the endoplasmic reticulum before migrating to the cell surface. Here we investigate the function of the secreted form of MD-2. We show that secreted MD-2 irreversibly loses activity over a 24-h period at physiological temperature. LPS, but not lipid A, prevents this loss in activity by forming a stable complex with MD-2, in a CD14-dependent process. Once formed, the stable MD-2.LPS complex activates TLR4 in the absence of CD14 or free LPS indicating that the activating ligand of TLR4 is the MD-2.LPS complex. Finally we show that the MD-2.LPS complex, but not LPS alone, induces epithelial cells, which express TLR4 but not MD-2, to secrete interleukin-6 and interleukin-8. We propose that the soluble MD-2.LPS complex plays a crucial role in the LPS response by activating epithelial and other TLR4(+)/MD-2(-) cells in the inflammatory microenvironment.

Controlling the Toll road to dendritic cell polarization.

The activation of dendritic cells (DC) via Toll-like receptors (TLRs) plays a decisive role in shaping the outcome of primary immune responses. Following TLR engagement by microbial products, DC migrate from peripheral tissues to lymphoid organs and up-regulate major histocompatibility complex and costimulatory molecules, acquiring the unique capacity to prime pathogen-specific, naïve T cells. In addition, DC determine the character of the ensuing immune response by secreting cytokines that drive the development of T cells into T helper cell type 1 (Th1), Th2, or T regulatory effector cells. Three major factors influence the pattern of cytokines released by DC and accordingly, the Th balance: the lineage to which DC belong; the maturation stimulus; and inflammatory mediators present at the site of infection. A major focus of this review is the capacity of DC to integrate these factors and elicit distinct classes of immune responses.

Leucine-rich repeats and pathogen recognition in Toll-like receptors.

Toll-like receptors (TLRs) are the major cell-surface initiators of inflammatory responses to pathogens. They bind a wide variety of pathogenic substances through their ectodomains (ECDs). Here, we ask: what is the structural basis for this interaction? Toll-like receptor ECDs comprise 19-25 tandem copies of a motif known as the leucine-rich repeat (LRR). No X-ray structure of a TLR-ECD is currently available but there are several high-resolution LRR-containing proteins that can be used to model TLRs. We suggest that the basic framework of TLRs is a horseshoe-shaped solenoid that contains an extensive beta-sheet on its concave surface, and numerous ligand-binding insertions. Together, these insertions and the beta-sheet could provide a binding surface that is 10-fold greater in area than binding surfaces in antibodies and T-cell receptors.

L-arginine metabolism in myeloid cells controls T-lymphocyte functions.

Although current attention has focused on regulatory T lymphocytes as suppressors of autoimmune responses, powerful immunosuppression is also mediated by a subset of myeloid cells that enter the lymphoid organs and peripheral tissues during times of immune stress. If these myeloid suppressor cells (MSCs) receive signals from activated T lymphocytes in the lymphoid organs, they block T-cell proliferation. MSCs use two enzymes involved in arginine metabolism to control T-cell responses: inducible nitric oxide synthase (NOS2), which generates nitric oxide (NO) and arginase 1 (Arg1), which depletes the milieu of arginine. Th1 cytokines induce NOS2, whereas Th2 cytokines upregulate Arg1. Induction of either enzyme alone results in a reversible block in T-cell proliferation. When both enzymes are induced together, peroxynitrites, generated by NOS2 under conditions of limiting arginine, cause activated T lymphocytes to undergo apoptosis. Thus, NOS2 and Arg1 might act separately or synergistically in vivo to control specific types of T-cell responses, and selective antagonists of these enzymes might prove beneficial in fighting diseases in which T-cell responses are inappropriately suppressed. This Opinion is the second in a series on the regulation of the immune system by metabolic pathways.

The role of disulfide bonds in the assembly and function of MD-2.

MD-2 is a secreted glycoprotein that binds to the extracellular domain of Toll-like receptor 4 (TLR4) and is required for the activation of TLR4 by lipopolysaccharide (LPS). The protein contains seven Cys residues and consists of a heterogeneous collection of disulfide-linked oligomers. To investigate the role of sulfhydryls in MD-2 structure and function, we created 17 single and multiple Cys substitution mutants. All of the MD-2 mutant proteins, including one totally lacking Cys residues, were secreted and stable. SDSPAGE analyses indicated that most Cys residues could participate in oligomer formation and that no single Cys residue was required for oligomerization. Of the single Cys substitutions, only C95S and C105S failed to confer LPS responsiveness on TLR4 when mutant and TLR4 were cotransfected into cells expressing an NF-kappaB reporter plasmid. Surprisingly, substitution of both C95 and C105 partially restored activity. Structural analyses revealed that C95 and C105 formed an intrachain disulfide bond, whereas C95 by itself produced an inactive dimer. In contrast to the cotransfection experiments, only WT MD-2 conferred responsiveness to LPS when secreted proteins were added directly to TLR4 reporter cells. Our data are consistent with a model in which most, possibly all sulfhydryls lie on the surface of a stable MD-2 core structure where they form both intra- and interchain disulfide bridges. These disulfide bonds produce a heterogeneous array of oligomers, including some species that can form an active complex with TLR4.

Cutting edge: histamine inhibits IFN-alpha release from plasmacytoid dendritic cells.

Plasmacytoid dendritic cells (DC) are professional APC and a major source of type I IFN following viral infection. We previously showed that histamine alters the cytokine profiles of maturing monocyte-derived DC resulting in a change from Th1 to Th2 in their T cell polarizing function. In this study, we show that human plasmacytoid DC, activated by either CpG oligodeoxynucleotides or viral infection, also respond to histamine through H2 receptors, leading to a marked down-regulation of IFN-alpha and TNF-alpha and a moderate switch in their capacity to polarize naive T cells. Our findings provide an explanation for low levels of type I IFN frequently observed in atopic individuals.

IL-4-induced arginase 1 suppresses alloreactive T cells in tumor-bearing mice.

We previously demonstrated that a specialized subset of immature myeloid cells migrate to lymphoid organs as a result of tumor growth or immune stress, where they suppress B and T cell responses to Ags. Although NO was required for suppression of mitogen activation of T cells by myeloid suppressor cells (MSC), it was not required for suppression of allogenic responses. In this study, we describe a novel mechanism used by MSC to block T cell proliferation and CTL generation in response to alloantigen, which is mediated by the enzyme arginase 1 (Arg1). We show that Arg1 increases superoxide production in myeloid cells through a pathway that likely utilizes the reductase domain of inducible NO synthase (iNOS), and that superoxide is required for Arg1-dependent suppression of T cell function. Arg1 is induced by IL-4 in freshly isolated MSC or cloned MSC lines, and is therefore up-regulated by activated Th2, but not Th1, cells. In contrast, iNOS is induced by IFN-gamma and Th1 cells. Because Arg1 and iNOS share L-arginine as a common substrate, our results indicate that L-arginine metabolism in myeloid cells is a potential target for selective intervention in reversing myeloid-induced dysfunction in tumor-bearing hosts.