ABNORMAL EXPRESSION OF VOLTAGE-GATED SODIUM CHANNELS Nav1.7, Nav1.3 AND Nav1.8 IN TRIGEMINAL NEURALGIA

Voltage-gated sodium channels have been implicated in acute and chronic neuropathic pain. Among subtypes, Nav1.7 single mutations can cause congenital indifference to pain or chronic neuropathic pain syndromes, including paroxysmal ones. This channel is co-expressed with Nav1.8, which sustains the initial action potential; Nav1.3 is an embrionary channel which is expressed in neurons after injury, as in neuropathic conditions. Few studies are focused on the expression of these molecules in human tissues having chronic pain. Trigeminal neuralgia (TN) is an idiopathic paroxysmal pain treated with sodium channel blockers. The aim of this study was to investigate the expression of Nav1.3, Nav1.7 and Nav1.8 by RT-PCR in patients with TN, compared to controls. The gingival tissue was removed from the correspondent trigeminal area affected. We found that Nav1.7 was downregulated in TN (P=0.017) and Nav1.3 was upregulated in these patients (P=0.043). We propose a physiopathological mechanism for these findings. Besides vascular compression of TN, this disease might be also a channelopathy. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved.

Facial sensibility of patients with trigeminal neuralgias

Objectives: Idiopathic trigeminal neuralgia (ITN) is an excruciating shock-like paroxysmal pain restricted to the trigeminal area of innervation, with discrete loss of sensibility (thermal, tactile and painful). Trigeminal postherpetic neuralgia (PHN) is a neuropathic pain at the trigeminal territory that persists after Herpes zoster infection, which also is associated to sensorial compromise. The objective of this study was to evaluate the somesthetic facial sensibility (pain, thermal and tactile) and to compare the findings between PHN and ITN. Methods: 18 patients with PHN and 26 patients with ITN were diagnosed by the IASP criteria. They were evaluated with a systematic approach, which included mechanical, thermal (cold and warm) and painful stimuli. Results: We found statistical significance at the ophthalmic branch of PHN in pain (p=0.001), tactile (p=0.002), cold (p=0.016) and warm (p=0.013); in ITN, the maxillary branch had higher threshold with pinpricks (p=0.016) and the mandibular branch had higher tactile threshold. Conclusions: The trigeminal area affected by the disease had the higher sensorial losses (ophthalmic branch in PHN and maxillary/mandibular branches in ITN). PHN patients had losses in large and small fibers; therefore, ITN patients had the losses mostly in large fibers, which support different peripheral neural mechanisms for these neuropathic diseases. (C) 2010 Elsevier B.V. All rights reserved.

Kallikrein-Kinin System Mediated Inflammation in Alzheimer`s Disease In Vivo

The Kallikrein-Kinin System (KKS) has been associated to inflammatory and immunogenic responses in the peripheral and central nervous system by the activation of two receptors, namely B1 receptor and B2 receptor. The B1 receptor is absent or under-expressed in physiological conditions, being up-regulated during tissue injury or in the presence of cytokines. The B2 receptor is constitutive and mediates most of the biological effects of kinins. Some authors suggest a link between the KKS and the neuroinflammation in Alzheimer`s disease (AD). We have recently described an increase in bradykinin (BK) in the cerebrospinal fluid and in densities of B1 and B2 receptors in brain areas related to memory, after chronic infusion of amyloid-beta (A beta) peptide in rats, which was accompanied by memory disruption and neuronal loss. Mice lacking B1 or B2 receptors presented reduced cognitive deficits related to the learning process, after acute intracerebroventricular (i.c.v). administration of A. Nevertheless, our group showed an early disruption of cognitive function by i.c.v. chronic infusion of A beta after a learned task, in the knock-out B2 mice. This suggests a neuroprotective role for B2 receptors. In knock-out B1 mice the memory disruption was absent, implying the participation of this receptor in neurodegenerative processes. The acute or chronic infusion of A beta can lead to different responses of the brain tissue. In this way, the proper involvement of KKS on neuroinflammation in AD probably depends on the amount of A beta injected. Though, BK applied to neurons can exert inflammatory effects, whereas in glial cells, BK can have a potential protective role for neurons, by inhibiting proinflammatory cytokines. This review discusses this duality concerning the KKS and neuroinflammation in AD in vivo.

Cardiac and peripheral adjustments induced by early exercise training intervention were associated with autonomic improvement in infarcted rats: role in functional capacity and mortality

Aims To test the effects of early exercise training (ET) on left ventricular (LV) and autonomic functions, haemodynamics, tissues blood flows (BFs), maximal oxygen consumption (VO(2) max), and mortality after myocardial infarction (MI) in rats. Methods and results Male Wistar rats were divided into: control (C), sedentary-infarcted (SI), and trained-infarcted (TI). One week after MI, TI group underwent an ET protocol (90 days, 50-70% VO2 max). Left ventricular function was evaluated noninvasively and invasively. Baroreflex sensitivity, heart rate variability, and pulse interval were measured. Cardiac output (CO) and regional BFs were determined using coloured microspheres. Infarcted area was reduced in TI (19 +/- 6%) compared with SI (34 +/- 5%) after ET. Exercise training improved the LV and autonomic functions, the CO and regional BF changes induced by MI, as well as increased SERCA2 expression and mRNA vascular endothelial growth factor levels. These changes brought about by ET resulted in mortality rate reduction in the TI (13%) group compared with the SI (54%) group. Conclusion Early aerobic ET reduced cardiac and peripheral dysfunctions and preserved cardiovascular autonomic control after MI in trained rats. Consequently, these ET-induced changes resulted in improved functional capacity and survival after MI.

Adaptations in autonomic function during exercise training in heart failure

Although neurohumoral excitation is the hallmark of heart failure (HF), the mechanisms underlying this alteration are not entirely known. Abnormalities in several systems contribute to neurohumoral excitation in HF, including arterial and cardiopulmonary baroreceptors, central and peripheral chemoreceptors, cardiac chemoreceptors, and central nervous system abnormalities. Exercise intolerance is characteristic of chronic HF, and growing evidence strongly suggests that exercise limitation in patients with chronic HF is not due to elevated filling pressures or inadequate cardiac output during exercise, but instead due to skeletal myopathy. Several lines of evidence suggest that sympathetic excitation contributes to the skeletal myopathy of HF, since sympathetic activity mediates vasoconstriction at rest and during exercise likely restrains muscle blood flow, arteriolar dilatation, and capillary recruitment, leading to underperfused areas of working muscle, and areas of muscle ischemia, release of reactive oxygen species (ROS), and inflammation. Although controversial, either unmyelinated, metabolite-sensitive afferent fibers, and/or myelinated, mechanosensitive afferent fibers in skeletal muscle underlie the exaggerated sympathetic activity in HF. Exercise training has emerged as a unique non-pharmacological strategy for the treatment of HF. Regular exercise improves functional capacity and quality of life, and perhaps prognosis in chronic HF patients. Recent studies have provided convincing evidence that these benefits in chronic HF patients are mediated by significant reduction in central sympathetic outflow as a consequence of improvement in arterial and chemoreflex controls, and correction of central nervous system abnormalities, and increase in peripheral blood flow with reduction in cytokines and increase in mass muscle.

The influence of peripheral afferent signals on the rating of perceived exertion and time to exhaustion during exercise at different intensities

This study determined which peripheral variables would better predict the rating of perceived exertion (RPE) and time to exhaustion (TE) during exercise at different intensities. Ten men performed exercises at first lactate threshold (LT1), second lactate threshold (LT2), 50% of the distance from LT1 to LT2 (TT(50%)), and 25% of the distance from LT2 to maximal power output (TW(25%)). Lactate, catecholamines, potassium, pH, glucose, (V) over dotO(2), VE, HR, respiratory rate (RR) and RPE were measured and plotted against the exercise duration for the slope calculation. Glucose, dopamine, and noradrenaline predicted RPE in TT(50%) (88%), LT2 (64%), and TW(25%) (77%), but no variable predicted RPE in LT1. RPE (55%), RPE+HR (86%), and RPE+RR (92% and 55%) predicted TE in LT1, TT(50%), LT2, and TW(25%), respectively. At intensities from TT(50%) to TW(25%), variables associated with brain activity seem to explain most of the RPE slope, and RPE (+HR and+RR) seems to predict the TE.

Use of peripheral vision in the interception of moving targets

Use of peripheral vision to organize and reorganize an interceptive action was investigated in young adults. Temporal errors and kinematic variables were evaluated in the interception of a virtual moving target, in situations in which its initial velocity was kept unchanged or was unexpectedly decreased. Observation of target approach was made through continuous visual pursuit (focal vision) or keeping visual focus at the origin of the trajectory or at the contact spot (peripheral vision). Results showed that visual focus at the contact spot led to temporal errors similar to focal vision, although showing a distinct kinematic profile, while focus at the origin led to an impoverished performance

Adverse drug events in an intensive care unit of a university hospital

Purpose Adverse drug events (ADEs) are harmful and occur with alarming frequency in critically ill patients. Complex pharmacotherapy with multiple medications increases the probability of a drug interaction (DI) and ADEs in patients in intensive care units (ICUs). The objective of the study is to determine the frequency of ADEs among patients in the ICU of a university hospital and the drugs implicated. Also, factors associated with ADEs are investigated. Methods This cross-sectional study investigated 299 medical records of patients hospitalized for 5 or more days in an ICU. ADEs were identified through intensive monitoring adopted in hospital pharmacovigilance and also ADE triggers. Adverse drug reactions (ADR) causality was classified using the Naranjo algorithm. Data were analyzed through descriptive analysis, and through univariate and multiple logistic regression. Results The most frequent ADEs were ADRs type A, of possible causality and moderate severity. The most frequent ADR was drug-induced acute kidney injury. Patients with ADEs related to DIs corresponded to 7% of the sample. The multiple logistic regression showed that length of hospitalization (OR = 1.06) and administration of cardiovascular drugs (OR = 2.2) were associated with the occurrence of ADEs. Conclusion Adverse drug reactions of clinical significance were the most frequent ADEs in the ICU studied, which reduces patient safety. The number of ADEs related to drug interactions was small, suggesting that clinical manifestations of drug interactions that harm patients are not frequent in ICUs.

Utility of Quantitative Ultrasound of the Calcaneus in Diagnosing Osteoporosis in Spinal Cord Injury Patients

Bittar CK, Cliquet A Jr, dos Santos Floter M: Utility of quantitative ultrasound of the calcaneus in diagnosing osteoporosis in spinal cord injury patients. Am J Phys Med Rehabil 2011;90:477-481. Objective: The aim of this study was to assess the utility of quantitative ultrasound of the calcaneus in diagnosing osteoporosis in spinal cord injury patients in a Brazilian Teaching Hospital. Design: This is a diagnostic test criterion standard comparison study. Between January 2008 and October 2009, the bone density of 15 spinal cord injury patients was assessed for analysis before beginning rehabilitation using muscle stimulation. The bone density was assessed using bone densitometry examination (DEXA) and ultrasound examination of the calcaneus (QUS). The measurements acquired using QUS and DEXA were compared between patients with spinal cord injury and a control group of ten healthy individuals. Results: The T-score values for femoral neck using DEXA (P < 0.0022) and those using QUS of the calcaneus (P < 0.0005) differed significantly between the groups, and the means in the normal subjects were higher than those in spinal cord injury patients who would receive electrical stimulation. In spinal cord injury patients, the significant differences were found between the QUS T-score for calcaneus and the DEXA scores for the lumbar spine and femoral neck. Conclusions: Because of the low level of mechanical stress on the calcaneus, the results of the QUS could not be correlated with the DEXA results for diagnosing osteoporosis. Therefore, QUS seems to be not a good choice for diagnosis and follow-up.

Altered left ventricular diastolic function in subjects with spinal cord injury

Study design: This is cross-sectional study. Objectives: The aim of this study is to investigate the cardiac structure and function of subjects with spinal cord injury (SCI) and the impact of metabolic, hemodynamic and inflammatory factors on these parameters. Setting: Sao Paulo, Brazil. Methods: Sixty-five nondiabetic, nonhypertensive, sedentary, nonsmoker men (34 with SCI and 31 healthy subjects) were evaluated by medical history, anthropometry, laboratory tests, analysis of hemodynamic and inflammatory parameters and echocardiography. Results: Subjects with SCI had lower systolic blood pressure and higher levels of C-reactive protein and tumor necrosis factor receptors than the healthy ones. Echocardiography data showed that the SCI group presented similar left ventricular (LV) structural and systolic parameters, but lower initial diastolic velocity (Em) (9.2 +/- 0.5 vs 12.3 +/- 0.5 cm s(-1); P<0.001) and higher peak early inflow velocity (E)/Em ratio (7.7 +/- 0.5 vs 6.1 +/- 0.3; P = 0.009) compared with the able-bodied group, even after adjustment for systolic blood pressure and C-reactive protein levels. Furthermore, injured subjects with E/Em >8 had lower peak spectral longitudinal contraction (Sm) (9.0 +/- 0.7 vs 11.6 +/- 0.4cm s(-1); P<0.001) and cardiac output (4.2 +/- 0.2 vs 5.0 +/- 0.21 min(-1); P = 0.029), as well as higher relative wall thickness (0.38 +/- 0.01 vs 0.35 +/- 0.01; P = 0.005), than individuals with SCI with E/Em<8, but similar age, body mass index, blood pressure, injury level, metabolic parameters and inflammatory marker levels. Conclusion: Subjects with SCI presented impaired LV diastolic function in comparison with able-bodied ones. Moreover, worse LV diastolic function was associated with a pattern of LV concentric remodeling and subclinical decreases in systolic function among injured subjects. Overall, these findings might contribute to explain the increased cardiovascular risk reported for individuals with SCI. Spinal Cord (2011) 49, 65-69; doi: 10.1038/sc.2010.88; published online 27 July 2010

ABCA1 expression and statins: inhibitory effect in peripheral blood mononuclear cells

The ATP-binding cassette transporter A1 (ABCA1) has an essential role in the formation of nascent high-density lipoprotein particles and also participates in the cholesterol efflux from macrophages in the artery wall. Several substances, such as statins, or even gene variants are able to modulate ABCA1 expression. There is strong evidence that statin treatment downregulates the ABCA1 expression in nonloaded macrophages. Interestingly, in cholesterol-loaded macrophages, which are more relevant to atherogenesis, this effect is lost. We observed an inhibitory effect of atorvastatin in peripheral blood mononuclear cells of hypercholesterolemic individuals. Moreover, in these individuals, the ABCA1 -14C > T polymorphism was associated with high baseline gene-expression levels. Other studies are needed to evaluate how relevant these findings are to the formation of arterial foam cells in vivo.

Transcriptional responses of host peripheral blood cells to tuberculosis infection

Host responses following exposure to Mycobacterium tuberculosis (TB) are complex and can significantly affect clinical outcome. These responses, which are largely mediated by complex immune mechanisms involving peripheral blood cells (PBCs) such as T-lymphocytes, NK cells and monocyte-derived macrophages, have not been fully characterized. We hypothesize that different clinical outcome following TB exposure will be uniquely reflected in host gene expression profiles, and expression profiling of PBCs can be used to discriminate between different TB infectious outcomes. In this study, microarray analysis was performed on PBCs from three TB groups (BCG-vaccinated, latent TB infection, and active TB infection) and a control healthy group. Supervised learning algorithms were used to identify signature genomic responses that differentiate among group samples. Gene Set Enrichment Analysis was used to determine sets of genes that were co-regulated. Multivariate permutation analysis (p < 0.01) gave 645 genes differentially expressed among the four groups, with both distinct and common patterns of gene expression observed for each group. A 127-probeset, representing 77 known genes, capable of accurately classifying samples into their respective groups was identified. In addition, 13 insulin-sensitive genes were found to be differentially regulated in all three TB infected groups, underscoring the functional association between insulin signaling pathway and TB infection. Published by Elsevier Ltd.

Free Phenolic Acids from the Seaweed Halimeda monile with Antioxidant Effect Protecting against Liver Injury

Phenolic compounds are found in seaweed species together with other Substances presenting antioxidant activity. The objective of this work was to evaluate the antioxidant activity of the free phenolic acids (FPA) fraction from the seaweed Halimeda monile, and its activity to protect the expression of hepatic enzymes in rats, under experimental CCI(4) injury. The antioxidant activity was measured by the DPPH method. The FPA fraction (80 mg/kg, p.o.) was administered during 20 consecutive days to rats. The peroxidation was performed by thiobarbituric acid reactive substances (TBARS). The SOD and CAT enzymatic expressions were measured by RT/PCR. The histology technique was used to evaluate liver injuries. The expression of both, CAT and SOD genes, was more preserved by FPA. Only partial injury could be observed by histology in the liver of rats receiving FPA as compared with the control group; and CCI(4) administration induced 60% more peroxidation as compared with the rats receiving FPA. These data suggest that FPA could modulate the antioxidant enzymes and oxidative status in the liver through protection against adverse effects induced by chemical agents.

ABCB1 and ABCC1 expression in peripheral mononuclear cells is influenced by gene polymorphisms and atorvastatin treatment

This study investigated the effects of atorvastatin on ABCB1 and ABCC1 mRNA expression on peripheral blood mononuclear cells (PBMC) and their relationship with gene polymorphisms and lowering-cholesterol response. one hundred and thirty-six individuals with hypercholesterolemia were selected and treated with atorvastatin (10 mg/day/4 weeks). Blood samples were collected for serum lipids and apolipoproteins measurements and DNA and RNA extraction. ABCB1 (C3435T and G2677T/A) and ABCC1 (G2012T) gene polymorphisms were identified by polymerase chain reaction-restriction (PCR)-RFLP and mRNA expression was measured in peripheral blood mononuclear cells by singleplex real-time PCR. ABCB1 polymorphisms were associated with risk for coronary artery disease (CAD) (p < 0.05). After atorvastatin treatment, both ABCB1 and ABCC1 genes showed 50% reduction of the mRNA expression (p < 0.05). Reduction of ABCB1 expression was associated with ABCB1 G2677T/A polymorphism (p = 0.039). Basal ABCB1 mRNA in the lower quartile (<0.024) was associated with lower reduction rate of serum low-density lipoprotein (LDL) cholesterol (33.4 +/- 12.4%) and apolipoprotein B (apoB) (17.0 +/- 31.3%) when compared with the higher quartile (>0.085: LDL-c = 40.3 +/- 14.3%; apoB = 32.5 +/- 10.7%; p < 0.05). ABCB1 substrates or inhibitors did not affect the baseline expression, while ABCB1 inhibitors reversed the effects of atorvastatin on both ABCB1 and ABCC1 transporters. In conclusion, ABCB1 and ABCC1 mRNA levels in PBMC are modulated by atorvastatin and ABCB1 G2677T/A polymorphism. and ABCB1 baseline expression is related to differences in serum LDL cholesterol and apoB in response to atorvastatin. (C) 2008 Elsevier Inc. All rights reserved.

Balloon catheter injury abolishes phenylephrine-induced relaxation in the rat contralateral carotid

BACKGROUND AND PURPOSE The consequences of compensatory responses to balloon catheter injury in rat carotid artery, on phenylephrine-induced relaxation and contraction in the contralateral carotid artery were studied. EXPERIMENTAL APPROACH Relaxation and contraction concentration-response curves for phenylephrine were obtained for contralateral carotid arteries in the presence of indomethacin (COX inhibitor), SC560 (COX-1 inhibitor), SC236 (COX-2 inhibitor) or 4-hydroxytetramethyl-L-piperidine-1-oxyl (tempol; superoxide dismutase mimetic). Reactive oxygen species were measured in carotid artery endothelial cells fluorimetrically with dihydroethidium. KEY RESULTS Phenylephrine-induced relaxation was abolished in contralateral carotid arteries from operated rats (E(max) = 0.01 +/- 0.004 g) in relation to control (E(max) = 0.18 +/- 0.005 g). Phenylephrine-induced contractions were increased in contralateral arteries (E(max) = 0.54 +/- 0.009 g) in relation to control (E(max) = 0.38 +/- 0.014 g). SC236 restored phenylephrine-induced relaxation (E(max) = 0.17 +/- 0.004 g) and contraction (E(max) = 0.34 +/- 0.018 g) in contralateral arteries. Tempol restored phenylephrine-induced relaxation (E(max) = 0.19 +/- 0.012 g) and contraction (E(max) = 0.42 +/- 0.014 g) in contralateral arteries, while apocynin did not alter either relaxation (E(max) = 0.01 +/- 0.004 g) or contraction (E(max) = 0.54 +/- 0.009 g). Dihydroethidium fluorescence was increased in contralateral samples (18 882 +/- 435 U) in relation to control (10 455 +/- 303 U). SC236 reduced the fluorescence in contralateral samples (8250 +/- 365 U). CONCLUSIONS AND IMPLICATIONS Balloon catheter injury abolished phenylephrine-induced relaxation and increased phenylephrine-induced contraction in contralateral carotid arteries, through O(2)(-) derived from COX-2.