Comparative study of the expression of cholinergic system components in the CNS of experimental autoimmune encephalomyelitis mice: Acute vs remitting phase.

Acetylcholine (ACh) is involved in the modulation of the inflammatory response. ACh levels are regulated by its synthesizing enzyme, choline acetyltransferase (ChAT), and by its hydrolyzing enzymes, mainly acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). A more comprehensive understanding of the cholinergic system in experimental autoimmune encephalomyelitis (EAE) disease progression could pave the path for the development of therapies to ameliorate multiple sclerosis (MS). In this work, we analyzed possible alterations of the CNS cholinergic system in the neuroinflammation process by using a MOG-induced EAE mice model. MOG- and vehicle-treated animals were studied at acute and remitting phases. We examined neuropathology and analyzed mRNA expression of ChAT, AChE and the α7 subunit of the nicotinic acetylcholine receptor (α7nAChR), as well as AChE and BuChE enzyme activities, in brain and spinal cord sections during disease progression. The mRNA expression and enzyme activities of these cholinergic markers were up- or down-regulated in many cholinergic areas and other brain areas of EAE mice in the acute and remitting phases of the disease. BuChE was present in a higher proportion of astroglia and microglia/macrophage cells in the EAE remitting group. The observed changes in cholinergic markers expression and cellular localization in the CNS during EAE disease progression suggests their potential involvement in the development of the neuroinflammatory process and may lay the ground to consider cholinergic system components as putative anti-inflammatory therapeutic targets for MS.

Quimioterapia e cardiotoxicidade / Chemotherapy and cardiotoxicity

A evolução do tratamento oncológico resultou no desenvolvimento de fármacos altamente eficazes. No entanto, os efeitos colaterais da terapia antitumoral ainda são frequentes e, muitas vezes, limitantes. Entre os efeitos adversos possíveis, a cardiotoxicidade representa um grupo importante de manifestações, com impacto negativo a curto e longo prazo na evolução desses pacientes. Esses eventos podem ocorrer na ausência de fatores de risco de doença cardiovascular e sua evolução ainda não está totalmente esclarecida. Curiosamente, podem ser desencadeadas tanto por terapias sistêmicas convencionais quanto por novas terapias relacionadas com alvos moleculares específicos. As definições de cardiotoxicidade ainda são diversas e não há um consenso universal. Em linhas gerais, pode ser entendida como qualquer alteração da homeostase do sistema cardiovascular induzida pelo tratamento do câncer. O dano cardíaco pode apresentar-se por vasta gama de condições clínicas, como por exemplo, alterações metabólicas, hipertensão arterial sistêmica, síndromes coronarianas agudas, tromboembolismo arterial e venoso, arritmias, entre outros. Muitos destes eventos têm prognóstico pior que muitas neoplasias. Assim, o conhecimento dos efeitos adversos cardíacos do tratamento antineoplásico é de suma importância, e a avaliação cardiovascular do paciente com câncer é fundamental. O intuito desta revisão é apresentar de forma prática as drogas oncológicas com maior potencial cardiotóxico e discutir de forma resumida seus principais efeitos cardiovasculares. Serão discutidas brevemente as definições, os mecanismos de agressão cardíaca e as manifestações clínicas principais, além da evolução e manejo inicial

The evolution of oncological treatment has resulted in the development of highly effective drugs. However, the side effects of antineoplastic therapy are still frequent, and often limiting. Among the possible adverse effects, cardiotoxicity represents an important group of manifestations, with negative impact on the clinical development of these patients in the short and long terms. These events can occur in the absence of risk factors for cardiovascular disease, and their clinical course is still not fully clarified. Interestingly, they can be triggered by both conventional systemic therapies and by new therapies with specific molecular targets. There are several definitions of cardiotoxicity, and there is no universal consensus. In general terms, it can be understood as any modification of cardiovascular system homeostasis induced by cancer treatment. Cardiac damage can present as a wide range of clinical conditions, such as metabolic changes, systemic arterial hypertension, acute coronary syndromes, arterial and venous thromboembolism, and arrhythmias, among others. Many of these events have a worse prognosis than many neoplasms. Thus, the knowledge of the adverse cardiac effects of antineoplastic treatment is of paramount importance, and the cardiovascular evaluation of the cancer patient is essential. The purpose of this review is to offer a practical presentation of oncological drugs with greater cardiotoxic potential, and to summarize its main cardiovascular effects. The definitions, mechanisms of cardiac aggression, and main clinical manifestations will be briefly discussed, as well as the clinical course and initial management

miRNAs in B-cell lymphoma: Molecular mechanisms and biomarker potential.

MicroRNAs (miRNAs) are small non-coding RNAs that regulate many human genes including those involved in normal B-cell development. When these miRNAs are aberrantly expressed in B-cells they play key pathogenetic roles in the development and maintenance of B-cell lymphomas and by association may serve as useful biomarkers. In this review, we provide an overview of the importance of miRNAs to B-cell lymphomagenesis, as well as considering their use as biomarkers, and their potential usefulness for the clinic.

Cholinergic System and Neuroinflammation: Implication in Multiple Sclerosis.

BACKGROUND: Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system (CNS) characterized by leucocytes infiltration, demyelination, axonal degeneration and neuronal death. Although the etiology of MS is still unkwon, inflammation and autoimmunity are considered to be key players of the disease. Nervous System: The severe alterations affecting the nervous system contribute to the motor and cognitive disabilities and are in large part dependent on severe inflammatory processes active in both central nervous system and immune system. Acetylcholine (ACh) appears to be involved in the modulation of central and peripheral inflammation. Immune cells as well as astrocytes and microglia respond to ACh stimuli by activation of cholinergic receptors. Muscarinic and nicotinic receptors differently contribute to the modulation of immunological and inflammatory processes stimulating pro- and anti-inflammatory cytokines respectively. The role played by ACh in MS is not yet fully understood, although some results point to its involvement in different neurological disorders such as Alzheimer's disease and schizophrenia. CONCLUSION: In the present review we summarize the evidence indicating the correlation between nervous system dysfunction in MS, with inflammation and cholinergic system alterations. Experiments performed in MS animal models and analyses on biological fluids from MS patients such as blood, serum and cerebrospinal fluid suggest that cholinergic alterations may contribute to the dysregulated inflammatory processes of MS. Many current therapeutic approaches in MS are based on anti-inflammatory drugs. We also discuss how the use of cholinesterase inhibitors or ACh mimetics may represent a new interesting therapeutic approach in MS.

Side effects and complication of Port-A-Cath.

Central venous catheter techniques find at present use for administering of NPT, for the drug injection ( especially chemiotherapeutic drugs) because of the possible damage of a few substances when perfused in a peripheral way. At present port-a-cath find their most extensive use: these are systems which can be set up and tolerated for many months. For the access to subclavian vein must be necessary put in supine decubitus, with light Trendelenburg position, with the opposite arm along the body and the head turned on the opposite side. In this way the clavicle is in perpendicular position with regard to the sternal handlebar, except for patient affected with bpco, kypho-scoliosis, scapular-homeral arthrosis. In these patients the clavicle can put on a particular course, oblique and upper as to the sternal articular face. So there is a serious obstacle to the passage to the metal needle under the clavicle. KEY WORDS: Chemiotherapy, CVC, NPT, Port-a-Cath.

Critical pneumonia complicating early-stage pregnancy.

We present a case of community-acquired methicillin-resistant Staphylococcus aureus necrotizing pneumonia, Panton-Valentine leukocidin positive, in a woman at 14 weeks of pregnancy. To our knowledge, this is the first case reporting this critical lung infection occurring during an early phase of pregnancy. This case study alerts physicians to the increasing worldwide spread of these uncommon yet virulent and potentially lethal infections. In our patient, antibiotic therapy with linezolid plus rifampin started at 14 weeks of pregnancy had a successful outcome without inducing toxicity or teratogenesis in the fetus.

Intraoperative strategy in patients with extended involvement of mediastinal structures.

The mediastinum is a virtual space containing several vital organs and structures. Biopsy and resection of lesions located within this region often require several considerations that bear on intraoperative strategy. To optimize outcome, clinicians must be able to predict which patients are at highest risk of anesthetic complications. Superior vena cava involvement, extensive compression of the airway, and pericardial effusion have a clear impact on the decision-making of the anesthetist and surgeon, who should plan together when forming the surgical strategy.

Association study of an epidermal growth factor gene functional polymorphism with the risk and prognosis of gliomas in Brazil.

Epidermal growth factor (EGF) plays an important role in cancer. A functional single nucleotide polymorphism (SNP) in the 5'-untranslated region of the EGF gene (+61 A>G) may influence its expression and contribute to cancer predisposition and aggressiveness. Aiming to investigate the role of EGF +61 A>G in the susceptibility to glioma and its prognosis, we performed a case-control study with 165 patients and 200 healthy controls from Brazil. Comparisons of genotype distributions and allele frequencies did not reveal any significant differences between the groups. The mean overall survival was 9.2 months for A/A, 8.2 months for A/G, and 7.7 months for G/G. When survival curves were plotted we found that the +61G allele is associated with poor overall survival (p=0.023) but not with disease-free survival (p=0.527). Our data suggest that, although there is no association between the EGF +61 A>G genotype and glioma susceptibility, this SNP is associated with shorter overall survival of glioma patients in the Brazilian population. Nevertheless, future studies utilizing a larger series are essential for a definitive conclusion.

Intrapleural intercostal nerve block associated with mini-thoracotomy improves pain control after major lung resection.

OBJECTIVE: To prospectively assess the impact of intrapleural intercostal nerve block (IINB) associated with mini-thoracotomy on postoperative pain and surgical outcome after major lung resections. METHODS: Between January 2004 and February 2005, we randomly assigned 120 consecutive patients undergoing mini-thoracotomy (10-13 cm) for major lung resections, to receive or not IINB from the 4th to the 8th space at the moment of thoracotomy using 20 ml (7.5 mg/ml) ropivacain injection at the dose of 4 ml for each space. Postoperative analgesia consisted of continuous intravenous infusion of tramadol (10 mg/h) and ketoralac tromethamine (3 mg/h) for 48 h for all patients. RESULTS: The two groups (60 patients each) were comparable for age, sex, pulmonary function, type and duration of the procedure. Mortality and morbidity were 0% and 10%, respectively, for the IINB group and 3.3% and 15%, respectively, for the non-IINB group (p>0.05, NS). Mean postoperative pain measured by the 'Visual Analogue Scale' were as follows: 2.3+/-1 at 1 h, 2.2+/-0.8 at 12 h, 1.8+/-0.7 at 24 h, and 1.6+/-0.6 at 48 h for the IINB group; and 3.6+/-1.4 at 1 h, 3.4+/-2 at 12 h, 2.9+/-1.2 at 24 h, and 2.0+/-1 at 48 h for the non-IINB group. Differences were significant at 1 h, 12 h, 24 h, and 48 h (p<0.05). Mean postoperative hospital stay was 5.7 days in the IINB group and 6.5 days in the non-IINB group (p<0.05). CONCLUSION: IINB associated with mini-thoracotomy reduces postoperative pain and contributes to improve postoperative outcome after major pulmonary resections.

Microvascular dysfunction and skeletal muscle oxygenation assessed by phase-modulation near-infrared spectroscopy in patients with septic shock.

OBJECTIVE: Sepsis is now considered a disease of the microcirculation. Little is known about the various sepsis-induced changes responsible for microvascular dysfunction. We investigated human microvascular function, regulation, oxygenation, and cellular metabolism during subacute septic shock. DESIGN AND SETTING: Prospective case-control study in a nine-bed polyvalent surgical ICU of a university hospital. PATIENTS AND PARTICIPANTS: A prospectively enrolled group of 26 patients (13 with septic shock, 13 nonseptic postsurgical patients) and 15 healthy volunteer controls. MEASUREMENTS AND RESULTS: The absolute tissue hemoglobin concentrations (oxygenated hemoglobin and deoxyhemoglobin) were measured noninvasively in arterioles, capillaries, and venules by phase-modulation near-infrared spectroscopy in the human brachioradial muscle during a series of venous occlusions and an arterial occlusion (ischemia) induced by applying a pneumatic cuff. These measurements were used to calculate tissue blood volume, postischemic hemoglobin resaturation time, microvascular compliance, and O2 consumption. Patients with sepsis had significantly higher tissue blood volume values and lower compliance than healthy controls. They also had longer postischemic hemoglobin resaturation times than the other two groups and blunted resaturation curves. O2 consumption was lower in patients with sepsis than in healthy controls. In patients with septic shock cuff-induced ischemia left O2 consumption unchanged, whereas in healthy volunteers it reduced O2 consumption to values almost matching those of patients with septic shock. CONCLUSIONS: These findings show that septic shock alters microvascular muscle function and regulation. Diminished local VO2 presumably reflects maldistribution and faulty autoregulation of local blood flow.

Hypotensive anesthesia and recovery of cognitive function in long-term craniofacial surgery.

The aim of our study was to compare three different anesthesiological techniques with regard to hemodynamics, recovery, and postoperative morbidity, for craniofacial surgery. One hundred twenty patients with American Society of Anesthesiologists (ASA) classification of I or II patients, 18 to 32 years old, and undergoing maxillary and mandibular osteotomies were randomly assigned to receive anesthesia with propofol-remifentanil (group P), desflurane-remifentanil (group D), or sevoflurane-remifentanil (group S). All patients were given premedication: midazolam 0.03 mg/kg, atropine 0.007 mg/kg, desametasone 0.1 mg/kg, NaCl 0.9% 100 mL + 2 mg/kg ketoprofene + 1.5 mg/kg ranitidine + 1 microg/kg clonidine. Anesthesia was induced by O2/air (FiO2 0.5), remifentanil 0.5 microg/kg/min, propofol 2 mg/kg, rocuronium 0.6 mg/kg. Maintenance group P received O2/air (FiO2 0.5), remifentanil 0.25 to 1.5 microg/kg/min, propofol 6 to 10 mg/kg/h; groups D and S received O2/air (FiO2 0.5), remifentanil 0.25 to 1.5 microg/kg/min, and respectively, sevoflurane or desflurane 0.5 minimum alveolar anesthetic concentration. The dosage of propofol, desflurane, and sevoflurane, obtained with a value of bispectral index (BIS) 40, was kept unchanged throughout the course, and remifentanil was titrated to maintain controlled hypotension: systolic arterial blood pressure 70 to 90 mmHg and mean arterial blood pressure 50 to 65 mmHg. A 24-hour elastomeric infusion system (ketoprofene 320 mg) was started 60 minutes before induction and cloridrat ondansetron 0.1 mg/kg was administered 30 minutes before the end of surgery. Hypotension was successfully obtained in all three groups with a bloodless surgical field, and there was no need for additional use of a potent hypotensive agent. Early and late recovery were faster and more complete in the D group; P < 0.05. Postoperative morbidity (nausea, vomiting, shivering, pain, and edema) was slight and did not significantly differ among the groups.

Atypical squamous cells of undetermined significance-favour reactive compared to atypical squamous cells of undetermined significance-favour dysplasia: association with cervical intraepithelial lesions and human papillomavirus infection.

BACKGROUND AND OBJECTIVES: The current study compared the cervical cytological sub-category "atypical squamous cells of undetermined significance-favour reactive (AFR)", recently recommended to be eliminated by the Bethesda system, to the sub-category "atypical squamous cells of undetermined significance-favour dysplasia (ASC-US)", in terms of prevalence of coexistent squamous intraepithelial lesions of either low-grade (LSIL) or high-grade (HSIL) and rate of human papillomavirus (HPV) infection. STUDY DESIGN: One hundred women with AFR and 100 with ASC-US were consecutively included in the study. All patients underwent colposcopy, followed by biopsy when necessary, and were screened for HPV infection by the combined use of Hybrid Capture II (DIGENE) and PCR with MY09/11 primers, the latter followed by direct sequencing of the amplifications products for HPV genotyping. RESULTS: LSIL were detected in 5.6% of AFR and 18.5% of ASC-US (p=0.00812), HSIL only in 4.3% of ASC-US. HPV infection was diagnosed in 11.2% of AFR and 38.0% of ASC-US (p=0.00003); high-risk HPV types (namely, HPV-16, -18, -31, -66, -67 and -70) were found in 6.7% of AFR and 22.8% of ASC-US (p=0.00239). Evidence of HPV infection in absence of SIL was proven in 7.1% of AFR and in 22.5% of ASC-US (p=0.00622). CONCLUSION: The association of AFR with SIL and high-risk HPV infection is low but not inexistent. Thus, to avoid the risk of leaving some high-risk AFR patients untreated or without follow-up, it could be proposed to keep AFR as a cytological category and to triage it by HPV testing, similarly to what has been already recommended for ASC-US.

Pulmonary transit of echocontrast agents during mechanical ventilation: a clinical transthoracic echocardiographic study.

In this study, we investigated whether the ultrasound contrast agents Levovist or Sono Vue injected intravenously during mechanical ventilation effectively pass through the pulmonary circulation. With echocardiography, we measured the time for the contrast to pass through the lungs; and the intensity of right and left ventricular cavity opacification at four time points: during spontaneous breathing (baseline), 5 minutes after the beginning of mechanical ventilation, and 5 minutes and 30 minutes after extubation. Forty patients undergoing elective peripheral neurosurgical procedures were prospectively and randomly enrolled: 20 patients received intravenous Levovist 1 g and 20 patients received intravenous Sono Vue 1 mL, at the four predefined time points. After intravenous injection, both Levovist and Sono Vue effectively passed through the lungs and opacified the right and left ventricular cavities, at the four time points. Pulmonary transit times were similar and constant for the two contrast agents tested: 6 +/- 2 seconds at baseline, 5 +/- 2 seconds during mechanical ventilation, 7 +/- 2 seconds at 5 minutes and 6 +/- 2 seconds at 30 minutes after extubation with Levovist; and 6 +/- 4 seconds at baseline, 6 +/- 3 seconds during mechanical ventilation, 6 +/- 2 seconds at 5 minutes and 7 +/- 3 seconds at 30 minutes after extubation with Sono Vue. In all patients, each of the four contrast injections achieved high-grade right and left ventricular chamber opacification. In conclusion, both the ultrasound contrast agents tested in this study, Levovist and Sono Vue, after intravenous injection pass through the pulmonary circulation during mechanical ventilation. Ultrasound contrast agents with these characteristics are suitable for intraoperative organ perfusion studies, with intravenous injection.