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Unlabelled: Sarcopenia is an aging syndrome that can be characterized by many criteria adjusted or not by fat mass. This study suggested that the optimal criteria should be selected according to body mass index (BMI) in older men and identified age, BMI, race, smoking, physical activity, hip bone mineral density (BMD) as risk factors for this syndrome., Introduction: This study aims to analyze the prevalence of sarcopenia and associated risk factors using appendicular skeletal mass (ASM)/height(2) and ASM adjusted for total fat mass criteria in older men from community., Methods: Three hundred ninety-nine men were included and answered a questionnaire about lifestyle and medical history. Individuals were classified by their BMI using the classification adjusted by age. Body composition and bone mineral density were measured by dual X-ray absorptiometry. Sarcopenia was classified according to both criteria. Logistic regression models were used to analyze risk factors associated with sarcopenia., Results: The mean BMI was 26.46 kg/m(2): 12.5 % underweight, 43.6 % normal, and 43.9 % overweight/obese. Fifty-four (13.5 %) were considered sarcopenic by ASM/height(2) and 79 (19.8 %) by ASM adjusted for fat (p = 0.001). Fifty-one (12.8 %) individuals had discordant sarcopenia classification: 13 were classified only by ASM/height(2) and 38 only by ASM adjusted for fat. Of the 13 subjects classified as sarcopenic only by ASM/height(2), 84.6 % (11/13) were underweight and solely one (7.7 %) was considered overweight/obese. In contrast, of those 38 older men classified as sarcopenic only by ASM adjusted for fat, none were underweight and 53 % (20/38) were overweight/obese. Subjects classified as sarcopenic according to both criteria had the same risk factors in the final model analyses (age, BMI, race, smoking, physical activity, hip BMD; p < 0.05)., Conclusion: This study suggested that the optimal criteria for sarcopenia should be selected according to BMI in community-dwelling older men.

Brain accumulation of soluble amyloid-β oligomers (AβOs) has been implicated in synapse failure and cognitive impairment in Alzheimer's disease (AD). However, whether and how oligomers of different sizes induce synapse dysfunction is a matter of controversy. Here, we report that low-molecular-weight (LMW) and high-molecular-weight (HMW) Aβ oligomers differentially impact synapses and memory. A single intracerebroventricular injection of LMW AβOs (10 pmol) induced rapid and persistent cognitive impairment in mice. On the other hand, memory deficit induced by HMW AβOs (10 pmol) was found to be reversible. While memory impairment in LMW oligomer-injected mice was associated with decreased hippocampal synaptophysin and GluN2B immunoreactivities, synaptic pathology was not detected in the hippocampi of HMW oligomer-injected mice. On the other hand, HMW oligomers, but not LMW oligomers, induced oxidative stress in hippocampal neurons. Memantine rescued both neuronal oxidative stress and the transient memory impairment caused by HMW oligomers, but did not prevent the persistent cognitive deficit induced by LMW oligomers. Results establish that different Aβ oligomer assemblies act in an orchestrated manner, inducing different pathologies and leading to synapse dysfunction. Furthermore, results suggest a mechanistic explanation for the limited efficacy of memantine in preventing memory loss in AD.

Objective: Vertebral fractures are associated with higher morbidity and mortality. Since 70% of vertebral fractures are clinically silent, a radiologic image of the spine has to be acquired for the diagnosis. The aim of this study was to compare the performance of Vertebral Fracture Assessment (VFA) by dual x-ray absorptiometry (DXA) with radiographs to identify vertebral fractures in community-dwelling older adults., Methods: A total of 429 older adults (ages ≥65 years) were enrolled in this cohort. VFA by DXA measurements were evaluated by 2 expert rheumatologists by consensus, and spine radiographs were analyzed according to the semiquantitative method by an expert radiologist. The correlation between VFA and spine radiographs to identify vertebral fractures was analyzed by kappa scores., Results: The prevalence of vertebral fractures in VFA and radiographs was 29.1% and 29.4%, respectively (P = 0.99). The frequency of unavailable vertebrae was significantly lower in spinal radiographs than in VFA (0.9% and 5.6%, respectively; P < 0.001), particularly in T4-T6. According to VFA, 5,013 vertebrae (96%) were identified as normal and 144 (2.7%) had grade 1, 58 (1.1%) had grade 2, and 12 (0.2%) had grade 3 fractures. The sensitivity of VFA was 72.9% and the specificity was 99.1% to identify vertebral fractures. The sensitivity increased to 92% and the specificity increased to 99.9% when excluding grade 1 deformities. A good correlation between VFA and radiographs (κ = 0.74) was observed, and the exclusion of grade 1 resulted in even better agreement (κ = 0.84)., Conclusion: In community-dwelling older adults, VFA and radiographs had comparable performances in identifying vertebral fractures, particularly if mild deformities are excluded. Therefore, this methodology is a feasible and promising alternative to improve the management of patients with a high risk of osteoporotic fractures., (Copyright © 2013 by the American College of Rheumatology.)

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the degeneration of dopaminergic nigrostriatal neurons. Although the etiology of the majority of human PD cases is unknown, experimental evidence points to oxidative stress as an early and causal event. Probucol is a lipid-lowering phenolic compound with anti-inflammatory and antioxidant properties that has been recently reported as protective in neurotoxicity and neurodegeneration models. This study was designed to investigate the effects of probucol on the vulnerability of striatal dopaminergic neurons to oxidative stress in a PD in vivo model. Swiss mice were treated with probucol during 21 days (11.8 mg/kg; oral route). Two weeks after the beginning of treatment, mice received a single intracerebroventricular (i.c.v.) infusion of 6-hydroxydopamine (6-OHDA). On the 21st day, locomotor performance, striatal oxidative stress-related parameters, and striatal tyrosine hydroxylase and synaptophysin levels, were measured as outcomes of toxicity. 6-OHDA-infused mice showed hyperlocomotion and a significant decrease in striatal tyrosine hydroxylase (TH) and synaptophysin levels. In addition, 6-OHDA-infused mice showed reduced superoxide dismutase activity and increased lipid peroxidation and catalase activity in the striatum. Notably, probucol protected against 6-OHDA-induced hyperlocomotion and striatal lipid peroxidation, catalase upregulation and decrease of TH levels. Overall, the present results show that probucol protects against 6-OHDA-induced toxicity in mice. These findings may render probucol as a promising molecule for further pharmacological studies on the search for disease-modifying treatment in PD.

Summary: The criteria most used for the definition of sarcopenia, those based on the ratio between the appendicular skeletal muscle mass (ASM) and the square of the height (h(2)) underestimate prevalence in overweight/obese people whereas another criteria consider ASM adjusted for total fat mass. We have shown that ASM adjusted for fat seems to be more appropriate for sarcopenia diagnosis., Introduction: Since the prevalence of overweight and obesity is a growing public health issue, the aim of this study was to evaluate the prevalence and risk factors associated with sarcopenia, based on these two criteria, among older women., Methods: Six hundred eleven community-dwelling women were evaluated by specific questionnaire including clinical data. Body composition and bone mineral density were evaluated by dual X-ray absorptiometry. Logistic regression models were used to identify factors independently related to sarcopenia by ASM/h(2) and ASM adjusted for total fat mass criteria., Results: The prevalence of overweight/obesity was high (74.3 %). The frequency of sarcopenia was lower using the criteria of ASM/h(2) (3.7 %) than ASM adjusted for fat (19.9 %) (P < 0.0001). We also note that less than 5 %(1/23) of sarcopenic women, according to ASM/h(2), had overweight/obesity, whereas 60 % (74/122) of sarcopenic women by ASM adjusted for fat had this complication. Using ASM/h(2), the associated factors observed in regression models were femoral neck T-score (OR = 1.90; 95 % CI 1.06-3.41; P = 0.03) and current alcohol intake (OR = 4.13, 95 % CI 1.18-14.45, P = 0.03). In contrast, we have identified that creatinine (OR = 0.21; 95 % CI 0.07-0.63; P = 0.005) and the White race (OR = 1.81; 95 % CI 1.15-2.84; P = 0.01) showed a significant association with sarcopenia using ASM adjusted for fat., Conclusions: In women with overweight/obesity, ASM adjusted for fat seems to be the more appropriate criteria for sarcopenia diagnosis. This finding has relevant public health implications, considering the high prevalence of overweight/obesity in older women.

Objective: To analyze the association between abdominal aortic calcification scores (AACS) and bone metabolism parameters in a well-characterized general population of older adults., Background: Several studies suggest a link between bone mineral metabolism disorders and vascular calcification; although only few of them analyze bone mineral density(BMD), laboratory bone markers and cardiovascular parameters at the same time and none were done in a miscegenated population., Methods: This cross-sectional study included 815 subjects ≥ 65 years old. The risk factors for osteoporosis and cardiovascular disease as well as a wide array of demographic and lifestyle characteristics were collected using a standardized questionnaire. BMD was measured by DXA. Kauppila's method was used to quantify the AAC score (AACS) by spine X-rays. Laboratory analyses were also performed., Results: AAC was observed in 63.2% of subjects with a median AACS of 2 (IQR: 0-7). AACS were categorized in quartiles and the highest quartile of AACS (>7) were compared with the three lower quartiles of AACS (≤ 7). Logistic regression analysis was performed using parameters with statistical significance in the univariate analysis. The best logistic regression model revealed that AACS>7 was negatively associated with femoral neck BMD and positively associated with phosphorus, adjusted by age, current smoking, LDL, and arterial hypertension in the elderly community-dwelling population., Conclusions: We identified that higher serum phosphate levels and lower hip BMD are independent bone variables that are associated with elevated vascular calcification scores, supporting the search for effective prevention and treatment strategies that may simultaneously reduce these modifiable risk factors in older subjects., (Copyright © 2012 Elsevier Inc. All rights reserved.)

We have recently demonstrated that rodents treated intranasally with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) suffered impairments in olfactory, cognitive, emotional and motor functions associated with time-dependent disruption of dopaminergic neurotransmission in different brain structures conceivably analogous to those observed during different stages of Parkinson's disease (PD). Agmatine, an endogenous arginine metabolite, has been proposed as a novel neuromodulator that plays protective roles in several models of neuronal cellular damage. In the present study we demonstrated that repeated treatment with agmatine (30 mg/kg, i.p.) during 5 consecutive days increased the survival rate (from 40% to 80%) of 15-month-old C57BL/6 female mice infused with a single intranasal (i.n.) administration of MPTP (1 mg/nostril), improving the general neurological status of the surviving animals. Moreover, pretreatment with agmatine was found to attenuate short-term social memory and locomotor activity impairments observed at different periods after i.n. MPTP administration. These behavioral benefits of exogenous agmatine administration were accompanied by a protection against the MPTP-induced decrease of hippocampal glutamate uptake and loss of dopaminergic neurons in the substantia nigra pars compacta of aging mice, without altering brain monoamine oxidase B (MAO-B) activity. These results provide new insights in experimental models of PD, indicating that agmatine represents a potential therapeutic tool for the management of cognitive and motor symptoms of PD, together with its neuroprotective effects., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objectives: The aim of this study was to investigate the impact of asymptomatic vertebral fractures on the quality of life in older women as part of the Sao Paulo Ageing & Health Study., Methods: This study was a cross-sectional study with a random sample of 180 women 65 years of age or older with or without vertebral fractures. The Quality of Life Questionnaire of the European Foundation for Osteoporosis was administered to all subjects. Anthropometric data were obtained by physical examination, and the body mass index was calculated. Lateral thoracic and lumbar spine X-ray scans were obtained to identify asymptomatic vertebral fractures using a semi-quantitative method., Results: Women with asymptomatic vertebral fractures had lower total scores [61.4(15.3) vs. 67.1(14.2), p = 0.03] and worse physical function domain scores [69.5(20.1) vs. 77.3(17.1), p = 0.02] for the Quality of Life Questionnaire of the European Foundation for Osteoporosis compared with women without fractures. The total score of this questionnaire was also worse in women classified as obese than in women classified as overweight or normal. High physical activity was related to a better total score for this questionnaire (p = 0.01). Likewise, lower physical function scores were observed in women with higher body mass index values (p<0.05) and lower physical activity levels (p<0.05). Generalized linear models with gamma distributions and logarithmic link functions, adjusted for age, showed that lower total scores and physical function domain scores for the Quality of Life Questionnaire of the European Foundation for Osteoporosis were related to a high body mass index, lower physical activity, and the presence of vertebral fractures (p<0.05)., Conclusion: Vertebral fractures are associated with decreased quality of life mainly physical functioning in older community-dwelling women regardless of age, body mass index, and physical activity. Therefore, the results highlight the importance of preventing and controlling asymptomatic vertebral fractures to reduce their impact on quality of life among older women.

Endothelial dysfunction has been implicated in portal vein obstruction, a condition responsible for major complications in chronic portal hypertension. Increased vascular tone due to disruption of endothelial function has been associated with an imbalance in the equilibrium between endothelium-derived relaxing and contracting factors. Herein, we assessed underlying mechanisms by which expression of bradykinin B(1) receptor (B(1)R) is induced in the endothelium and how its stimulation triggers vasoconstriction in the rat portal vein. Prolonged in vitro incubation of portal vein resulted in time- and endothelium-dependent expression of B(1)R and cyclooxygenase-2 (COX-2). Inhibition of protein kinase C (PKC) or phosphatidylinositol 3-kinase (PI3K) significantly reduced expression of B(1)R through the regulation of transcription factors, activator protein-1 (AP-1) and cAMP response element-binding protein (CREB). Moreover, pharmacological studies showed that B(1)R-mediated portal vein contraction was reduced by COX-2, but not COX-1, inhibitors. Notably, activation of endothelial B(1)R increased phospholipase A(2)/COX-2-derived thromboxane A(2) (TXA(2)) levels, which in turn mediated portal vein contraction through binding to TXA(2) receptors expressed in vascular smooth muscle cells. These results provide novel molecular mechanisms involved in the regulation of B(1)R expression and identify a critical role for the endothelial B(1)R in the modulation of portal vein vascular tone. Our study suggests a potential role for B(1)R antagonists as therapeutic tools for diseases where portal hypertension may be involved., (Copyright © 2012 Elsevier Inc. All rights reserved.)

This study evaluated the relevance of CXCR2 chemokine receptors in oral squamous cell carcinoma, by means of in vitro and in vivo approaches. The in vitro incubation of the selective and non-peptide CXCR2 receptor antagonist N-(2-hydroxy-4-nitrophenyl)-N9-(2-bromophenyl) Urea (SB225002; 25 to 800 nM) produced a time- and concentration-dependent inhibition of SCC158 (rat) and HN30 (human) cell lines viability. Conversely, this antagonist did not significantly affect the viability of the immortalized keratinocyte lineage, HaCaT. Additionally, the incubation of human IL-8 and rat CINC-1 CXCR2 agonists produced a concentration-related increase on HN30 and SCC158 proliferation. The submucosal injection of SCC158 cells (5 × 10(6) cells) into the tongue of Fischer 344 rats induced tumor development, which displayed typical clinical features. Immunohistochemical analysis of rat tongue biopsies revealed a marked increase of CXCR2 receptor immunoreactivity, which was accompanied by augumented expression of VEGF and caspase-3. Our data suggests an important role for CXCR2 receptors in oral squamous cell carcinoma.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by synaptic loss and cognitive impairments. The presence of extracellular senile plaques (mainly composed of amyloid-β (Aβ) peptide) is an important molecular hallmark in AD and neuronal damage has been attributed, at least in part, to Aβ-mediated toxicity. Although the molecular mechanisms involved in the pathogenesis of AD are not yet completely understood, several lines of evidence indicate that oxidative stress and cholesterol dyshomeostasis play crucial roles in mediating the synaptic loss and cognitive deficits observed in AD patients. This study evaluated the effects of Probucol, a phenolic lipid-lowering agent with anti-inflammatory and antioxidant properties, on biochemical parameters related to oxidative stress and synaptic function (hippocampal glutathione and synaptophysin levels; glutathione peroxidase, glutathione reductase and acetylcholinesterase activities; lipid peroxidation), as well as on behavioral parameters related to the cognitive function (displaced and new object recognition tasks) in Aβ-exposed mice. Animals were treated with a single intracerebroventricular (i.c.v.) injection of aggregated Aβ(1-40) (400 pmol/site) and, subsequently, received Probucol (10 mg/kg, i.p.) once a day, during the following 2 weeks. At the end of treatments, Aβ(1-40)-exposed animals showed a significant impairment on learning-memory ability, which was paralleled by a significant decrease in hippocampal synaptophysin levels, as well as by an increase in hippocampal acetylcholinesterase activity. Importantly, Probucol treatment blunted the deleterious effects of Aβ(1-40) on learning-memory ability and hippocampal biochemistry. Although Aβ(1-40) treatment did not change hippocampal glutathione levels and glutathione peroxidase (GPx) and glutathione reductase (GR) activities, Aβ(1-40)-exposed animals showed increased hippocampal lipid peroxidation and this event was completely blunted by Probucol treatment. These findings reinforce and extend the notion of the hazardous effects of Aβ(1-40) toward hippocampal synaptic homeostasis and cognitive functions. In addition, the present results indicate that Probucol is able to counteract the cognitive and biochemical impairments induced by i.c.v. Aβ(1-40) administration in mice. The study is the first to report the protective effects of Probucol (a "non-statin cholesterol-lowering drug") against Aβ(1-40)-induced synaptic and behavioral impairments, rendering this compound a promising molecule for further pharmacological studies on the search for therapeutic strategies to treat or prevent AD., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The toxicity of amyloid β (Aβ) is highly associated with Alzheimer's disease (AD), which has a high incidence in elderly people worldwide. While the current treatment for moderate and severe AD includes blockage of the N-methyl-d-aspartate receptor (NMDAR), the molecular mechanisms of its effect are still poorly understood. Herein, we report that a single i.p. administration of the selective and competitive (NMDAR) antagonist LY235959 reduced Aβ neurotoxicity by preventing the down-regulation of glial glutamate transporters (glutamate-aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1)), the decrease in glutamate uptake, and the production of reactive oxygen species (ROS) induced by Aβ(1-40). Importantly, the blockage of NMDAR restored the Aβ(1-40)-induced synaptic dysfunction and cognitive impairment. However, LY235959 failed to prevent the inflammatory response associated with Aβ(1-40) treatment. Altogether, our data indicate that the acute administration of Aβ promotes oxidative stress, a decrease in glutamate transporter expression, and neurotoxicity. Our results reinforce the idea that NMDAR plays a critical regulatory action in Aβ toxicity and they provide further pre-clinical evidence for the potential role of the selective and competitive NMDAR antagonists in the treatment of AD., (Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: Physiological root resorption differentiates primary from permanent teeth. The understanding of what protects and regulates root resorption might help to develop therapies to its control., Aim: To verify the presence and distribution of ECRM and the expression of CK14, OPG, TRAP and COX-2 in the periodontal ligament (PDL) of human primary and permanent teeth. Design.  Eight primary teeth undergoing physiological or pathological root resorption and 4 permanent teeth were immunohistochemically processed for CK14, TRAP, COX-2 and OPG expression., Results: PDL from primary and permanent teeth showed similar morphological features; however, fewer ECRM clusters and higher immunoreactivity to CK14 were found in primary PDL. In permanent teeth, ECRM were distributed along the entire PDL tissue. Howship's lacunae were found only in primary teeth, associated with the presence of TRAP-positive cells and increase in COX-2 expression. OPG expression in primary PDL was detected in nonresorptive cervical areas and in lacunae showing reparative tissue. It was observed higher expression of OPG in all permanent teeth when compared to primary specimens., Conclusions: It may be concluded that PDL from primary teeth shows less ECRM clusters and lower expression of OPG. These features may be associated with lower protection against root resorption in primary teeth., (2011 The Authors. International Journal of Paediatric Dentistry © 2011 BSPD, IAPD and Blackwell Publishing Ltd.)

Introduction: Mineral trioxide aggregate (MTA) and calcium hydroxide [Ca(OH)(2)] are promising biomaterials for stimulating dentinogenesis and cementogenesis. This research was undertaken to understand how MTA and CA(OH)(2) participate in the inflammatory, healing, and biomineralization processes. In this part of the study, we evaluated inflammatory signaling molecules promoted by in vivo host interaction with MTA and Ca(OH)(2)., Methods: Human dentin tubes were filled with ProRoot MTA (Dentsply Tulsa Dental, Tulsa, OK), Ca(OH)(2), or kept empty. After 12 hours and 1, 3, 7, 15, 30, and 60 days of implantation in subcutaneous tissues in the backs of mice, the tubes and surrounding tissues were retrieved for cytokine level quantification and histological and immunohistochemical analysis., Results: MTA and Ca(OH)(2) induced proinflammatory cytokine up-regulation for up to 3 days. Moreover, interleukin-10 overexpression was noted on the tissue in contact with the biomaterials during the acute phase of the inflammatory reaction. Immunohistochemical analyses showed an increased expression of myeloperoxidase, nuclear factor kappa B (NF-κB), cyclooxygenase-2, inducible nitric oxide synthase enzymes, and vascular endothelial growth factor on day 1 for all groups., Conclusions: MTA and Ca(OH)(2) increased the activation of the NF-κB signaling system on day 1 for all groups. This finding can be associated with a proinflammatory and pro-wound healing environment, which was promoted earlier by MTA., (Copyright © 2011 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Cells are endowed with several overlapping peroxide-degrading systems whose relative importance is a matter of debate. In this study, three different sources of neural cells (rat hippocampal slices, rat C6 glioma cells, and mouse N2a neuroblastoma cells) were used as models to understand the relative contributions of individual peroxide-degrading systems. After a pretreatment (30 min) with specific inhibitors, each system was challenged with either H₂O₂ or cumene hydroperoxide (CuOOH), both at 100 μM. Hippocampal slices, C6 cells, and N2a cells showed a decrease in the H₂O₂ decomposition rate (23-28%) by a pretreatment with the catalase inhibitor aminotriazole. The inhibition of glutathione reductase (GR) by BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea) significantly decreased H₂O₂ and CuOOH decomposition rates (31-77%). Inhibition of catalase was not as effective as BCNU at decreasing cell viability (MTT assay) and cell permeability or at increasing DNA damage (comet test). Impairing the thioredoxin (Trx)-dependent peroxiredoxin (Prx) recycling by thioredoxin reductase (TrxR) inhibition with auranofin neither potentiated peroxide toxicity nor decreased the peroxide-decomposition rate. The results indicate that neural peroxidatic systems depending on Trx/TrxR for recycling are not as important as those depending on GSH/GR. Dimer formation, which leads to Prx2 inactivation, was observed in hippocampal slices and N2a cells treated with H₂O₂, but not in C6 cells. However, Prx-SO₃ formation, another form of Prx inactivation, was observed in all neural cell types tested, indicating that redox-mediated signaling pathways can be modulated in neural cells. These differences in Prx2 dimerization suggest specific redox regulation mechanisms in glia-derived (C6) compared to neuron-derived (N2a) cells and hippocampal slices., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The risk of osteoporotic fractures is known to vary among populations. There are no studies analyzing concomitantly clinical, densitometric, and lab risk factors in miscigenated community-dwelling population of Brazil. A total of 1007 elderly subjects (600 women and 407 men) from São Paulo, were evaluated using a questionnaire that included risk factors for osteoporotic fractures. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry at the hip and lumbar spine. Laboratory blood tests were also obtained. The prevalence of osteoporotic fractures was 13.2% (133 subjects), and the main fracture sites were distal forearm (6.0%), humerus (2.3%), femur (1.3%), and ribs (1.1%). Women had a higher prevalence (17.5%; 95% confidence interval [CI]: 14.6-20.6) than men (6.9%; 95% CI: 4.4-9.3) (p<0.001). After adjusting for significant variables, logistic regression revealed that female gender (odds ratio [OR]=2.7; 95% CI; 1.6-4.5; p<0.001), current smoking (OR=1.9; 95% CI: 1.2-3.3; p=0.013), and the femoral neck T-score (OR=0.7; 95% CI: 0.5-0.9; p=0.001) remain significant risk factors for osteoporotic fractures in the community-dwelling elderly. Our findings identified that female gender, current smoking, and low hip BMD are independent risk factors for osteoporotic fractures., (Copyright © 2011 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

The glucose-dependent insulinotropic peptide receptor (GIPR) has been implicated with neuroplasticity and may be related to epilepsy. GIPR expression was analyzed by immunohistochemistry in the hippocampus (HIP) and neocortex (Cx) of rats undergoing pilocarpine induced status epilepticus (Pilo-SE), and in three young male patients with left mesial temporal lobe epilepsy related to hippocampal sclerosis (MTLE-HS) treated surgically. A combined GIPR immunohistochemistry and Fluoro-Jade staining was carried out to investigate the association between the GIPR expression and neuronal degeneration induced by Pilo-SE. GIPR was expressed in the cytoplasm of neurons from the HIP CA subfields, dentate gyrus (DG) and Cx of animals and human samples. The GIPR expression after the Pilo-SE induction increases significantly in the HIP after 1h and 5 days, but not after 12h or 50 days. In the Cx, the GIPR expression increases after 1h, 12h and 5 days, but not 50 days after the Pilo-SE. The expression of GIPR 12h after Pilo-SE was inversely proportional to the Fluoro-Jade staining intensity. In the human tissue, GIPR expression patterns were similar to those observed in chronic Pilo-SE animals. No Fluoro-Jade stained cells were observed in the human sample. GIPR is expressed in human HIP and Cx. There was a time and region dependent increase of GIPR expression in the HIP and Cx after Pilo-SE that was inversely associated to neuronal degeneration., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Early symptoms of Alzheimer's disease (AD) have been attributed to amyloid-β (Aβ) toxicity. The pathophysiology of AD is complex and involves several different biochemical pathways, including defective Aβ protein metabolism, neuroinflammation, oxidative processes, and mitochondrial dysfunction. In the current study, we assessed the molecular mechanisms, mainly the modifications in the activity of mitochondrial complexes, whereby the association of folic acid and α-tocopherol protects mice against the Aβ-induced neurotoxicity. Oral treatment with folic acid (50 mg/kg) plus α-tocopherol (500 mg/kg), once a day during 14 consecutive days, protected mice against the Aβ₁₋₄₀-induced cognitive decline, synaptic loss, and neuronal death. However, chronic treatment comprising folic acid plus α-tocopherol was ineffective on Aβ-induced glial cell activation, suggesting that the effect of this treatment is independent of anti-inflammatory features. Interestingly, the results obtained in our study suggest that mitochondrial energy metabolism is impaired by the Aβ peptide, and upregulation of mitochondrial genes may be a compensatory response, as demonstrated by the increase in mitochondrial complexes I, II, and IV activity, in the hippocampus of mice, after Aβ₁₋₄₀ injection. Of note, the chronic treatment comprising folic acid plus α-tocopherol prevented the increase in the activity of mitochondrial complexes I and IV induced by Aβ₁₋₄₀. Together, these results show the antioxidant effect of the combination of folic acid and α-tocopherol, as observed by the decrease in NO generation from iNOS and nNOS, preventing an increase in the activity of mitochondrial complexes, mainly I and IV, and the neuronal death induced by the Aβ₁₋₄₀ peptide.

Introduction: This study proposed to investigate aspects of cell proliferation and death in the epithelium of radicular (RCs) and dentigerous (DCs) cysts., Methods: Serial sections of 17 RCs and 9 DCs were prepared for immunohistochemical detection of caspase-3, Bcl-2, and Ki-67 antigens., Results: Caspase-3 was detected mainly in the suprabasal and superficial epithelial cells of RCs and DCs, whereas Ki-67 was detected predominantly in the basal layer. Both markers had significant expression in hyperplastic epithelium related to an intense inflammation in the capsule. Immunoreactivity for Bcl-2 was restricted to the basal layer and was significantly higher in atrophic epithelium of DCs than that of RCs., Conclusions: These results suggest that epithelial proliferation is balanced by apoptosis and that the presence of inflammation inhibits the Bcl-2 expression. DCs and RCs have different formation mechanisms but have similar biological behavior in the presence of intense inflammatory infiltrate., (Copyright © 2011 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Background: Multiple sclerosis (MS) is a demyelinating and neuroinflammatory disease of the human central nervous system (CNS). The expression of kinins is increased in MS patients, but the underlying mechanisms by which the kinin receptor regulates MS development have not been elucidated., Methodology/principal Findings: Experimental autoimmune encephalomyelitis (EAE) was induced in female C57BL/6 mice by immunization with MOG(35-55) peptide emulsified in complete Freund's adjuvant and injected with pertussis toxin on day 0 and day 2. Here, we report that blockade of the B(1)R in the induction phase of EAE markedly suppressed its progression by interfering with the onset of the immune response. Furthermore, B(1)R antagonist suppressed the production/expression of antigen-specific T(H)1 and T(H)17 cytokines and transcription factors, both in the periphery and in the CNS. In the chronic phase of EAE, the blockade of B(1)R consistently impaired the clinical progression of EAE. Conversely, administration of the B(1)R agonist in the acute phase of EAE suppressed disease progression and inhibited the increase in permeability of the blood-brain barrier (BBB) and any further CNS inflammation. Of note, blockade of the B(2)R only showed a moderate impact on all of the studied parameters of EAE progression., Conclusions/significance: Our results strongly suggest that kinin receptors, mainly the B(1)R subtype, play a dual role in EAE progression depending on the phase of treatment through the lymphocytes and glial cell-dependent pathways.

Background: Kinin B1 receptors are inducible molecules up-regulated after inflammatory stimuli. This study evaluated the relevance of kinin B1 receptors in a mouse depression behavior model., Methods: Mice were exposed to a 5-min swimming session, and 30 min later they were injected with E. coli lipopolysaccharide (LPS). Depression-like behavior was assessed by determining immobility time in a tail suspension test. Different brain structures were collected for molecular and immunohistochemical studies. Anhedonia was assessed by means of a sucrose intake test., Results: Our protocol elicited an increase in depression-like behavior in CF1 mice, as assessed by the tail-suspension test, at 24 h. This behavior was significantly reduced by treatment with the selective B1 receptor antagonists R-715 and SSR240612. Administration of SSR240612 also prevented an increase in number of activated microglial cells in mouse hippocampus, but did not affect a reduction in expression of mRNA for brain-derived neurotrophic factor. The increased immobility time following LPS treatment was preceded by an enhancement of hippocampal and cortical B1 receptor mRNA expression (which were maximal at 1 h), and a marked production of TNFα in serum, brain and cerebrospinal fluid (between 1 and 6 h). The depression-like behavior was virtually abolished in TNFα p55 receptor-knockout mice, and increased B1 receptor mRNA expression was completely absent in this mouse strain. Furthermore, treatment with SSR240612 was also effective in preventing anhedonia in LPS-treated mice, as assessed using a sucrose preference test., Conclusion: Our data show, for the first time, involvement of kinin B1 receptors in depressive behavioral responses, in a process likely associated with microglial activation and TNFα production. Thus, selective and orally active B1 receptor antagonists might well represent promising pharmacological tools for depression therapy.

We have recently demonstrated that rodents treated intranasally with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) suffered impairments in olfactory, cognitive and motor functions associated with time-dependent disruption of dopaminergic neurotransmission in different brain structures conceivably analogous to those observed during different stages of Parkinson's disease (PD). On the other hand, the proanthocyanidin-rich fraction (PRF) obtained from the bark of Croton celtidifolius Baill (Euphorbiaceae), a tree frequently found in the Atlantic forest in south Brazil, has been described to have several neurobiological activities including antioxidant and anti-inflammatory properties, which may be of interest in the treatment of PD. The present data indicated that the pretreatment with PRF (10 mg/kg, i.p.) during five consecutive days was able to prevent mitochondrial complex-I inhibition in the striatum and olfactory bulb, as well as a decrease of the enzyme tyrosine hydroxylase expression in the olfactory bulb and substantia nigra of rats infused with a single intranasal administration of MPTP (1 mg/nostril). Moreover, pretreatment with PRF was found to attenuate the short-term social memory deficits, depressive-like behavior and reduction of locomotor activity observed at different periods after intranasal MPTP administration in rats. Altogether, the present findings provide strong evidence that PRF from C. celtidifolius may represent a promising therapeutic tool in PD, thus being able to prevent both motor and non-motor early symptoms of PD, together with its neuroprotective potential.

Background: Capsular contracture is one of the most common complications associated with silicone breast implants. The surface of the implant is one of the factors often associated with the occurrence of capsular contracture. In this study, the authors evaluated the differences in morphologic and molecular characteristics of the capsule formed around polyurethane-coated versus textured-surface silicone implants in rats, mainly the modifications in angiogenesis and the expression of vascular endothelial growth factor (VEGF)., Methods: A pocket was performed on the animal's back, where the silicone implants were introduced. Two groups of animals received a polyurethane-coated silicone implant and the other groups received a textured-surface silicone implant, and the capsules around the prostheses were submitted to histologic and immunohistochemistry analysis, 30 or 90 days after surgery., Results: The capsules around the polyurethane-coated silicone prostheses were significantly thicker than the textured-surface silicone implants. Furthermore, the layer adjacent to the polyurethane-coated silicone implants was more cellular and irregular than the layer around the textured-surface silicone implants. Textured implant periprosthetic capsules presented fewer inflammatory cells and less vascularization than the polyurethane-coated silicone implants. The collagen layer of periprosthetic tissue of textured implants appears to be more continuous and aligned in parallel fashion than polyurethane-coated implants. Immunohistochemical analysis revealed high levels of transforming growth factor-β and VEGF in the capsules around the polyurethane-coated silicone implants when compared with the textured-surface silicone implants., Conclusion: These findings suggest that the intense VEGF expression in capsules around the polyurethane-coated silicone implant is able to improve the tissue vascularization, resulting in a softer capsule compared with the textured-surface silicone implant.

The accumulation of amyloid-beta (Aβ) peptides in the brain of human and rodents has been associated with the activation of glial cells, neuroinflammatory and oxidative responses, and cognitive deficits. These oxidative changes leave glutamate transporters more vulnerable and may result in reduction of their functions, resulting in excitotoxic damage. Herein, we evaluated the effects of atorvastatin, a HMG-CoA reductase inhibitor, in molecular and behavioral alterations induced by a single intracerebroventricular injection of aggregated Aβ(1-40) (400 pmol) in mice. An increased glial fibrillar acidic protein (GFAP) expression and cyclooxygenase-2 (COX-2) levels, as well as increased lipid peroxidation and impairment in the glutathione antioxidant system and cell degeneration was found in the hippocampus of Aβ(1-40)-treated mice. Aβ(1-40) also induced a marked decrease in glutamatergic transporters (GLAST and GLT-1) expression and in l-[³H] glutamate uptake in mice hippocampus, in addition to spatial learning and memory deficits. Atorvastatin (10 mg/kg/day v.o.) was administered after Aβ(1-40) injection and through seven consecutive days. Atorvastatin treatment was neuroprotective against cell degeneration induced by Aβ(1-40), reducing inflammatory and oxidative responses and increasing the expression of glutamatergic transporters. On the other hand, atorvastatin did not reverse the cognitive impairments and failed to alter the hippocampal glutamate uptake in Aβ(1-40)-treated mice. These results reinforce and extend the notion of the potential neuroprotective action of atorvastatin against the neuronal toxicity induced by Aβ(1-40). In addition, the present findings suggest that the spatial learning and memory deficits induced by Aβ peptides in rodents may not be entirely related to neuronal damage., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Cognitive deficits and psychiatric disorders are significant sequelae of traumatic brain injury (TBI). Animal models have been widely employed in TBI research, but few studies have addressed the effects of experimental TBI of different severities on emotional and cognitive parameters. In this study, mice were subjected to weight-drop TBI to induce mild, intermediate, or severe TBI. After neurological assessment, the mice recovered for 10 days, and were then subjected to a battery of behavioral tests, which included open-field, elevated plus-maze, forced swimming, tail suspension, and step-down inhibitory avoidance tests. Oxidative stress-related parameters (nonprotein thiols [NPSH], glutathione peroxidase [GPx], glutathione reductase [GR], and thiobarbituric acid reactive species [TBARS]) were quantified in the cortex and hippocampus at 2 and 24 h and 14 days after TBI, and histopathological analysis was performed 15 days after TBI. Mice subjected to mild TBI showed increased anxiety and depressive-like behaviors, while intermediate and severe TBI induced robust memory deficits. The severe TBI group also displayed increased locomotor activity. Intermediate and severe TBI caused extensive macroscopic and microscopic brain damage, while mild TBI typically had no histological abnormalities. Moreover, a significant increase in TBARS in the ipsilateral cortex and GPx in the ipsilateral hippocampus was observed at 24 h and 14 days, respectively, following intermediate TBI. The current experimental TBI model induced emotional and cognitive changes comparable to sequelae seen in human TBI, and it might therefore represent a useful approach to the study of mechanisms of and new treatments for TBI and related disorders.

Glucose-dependent insulinotropic polypeptide (GIP) is a 42-amino acid hormone, secreted from the enteroendocrine K cells, which has insulin-releasing and extra-pancreatic actions. GIP and its receptor present a widespread distribution in the mammalian brain where they have been implicated with synaptic plasticity, neurogenesis, neuroprotection and behavioral alterations. This review attempts to provide a comprehensive picture of the role of GIP in the central nervous system and to highlight recent findings from our group showing its potential involvement in neurological illnesses including epilepsies, Parkinson's disease and Alzheimer's disease.

Introduction: The biological processes underlying the ability of mineral trioxide aggregate (MTA) to promote hard-tissue deposition and wound healing remain unclear. To further study these processes, specific signaling molecules related to the inflammatory response and the biomineralization process were analyzed to assess host-MTA interactions in vivo., Methods: For cytokine level quantification and immunohistochemical analysis, human dentin tubes were filled with ProRoot MTA (Dentsply, Tulsa Dental, OK) or kept empty and were implanted in subcutaneous tissues in the backs of mice. Dentin tubes were retrieved and subsequently observed using a scanning electron microscope., Results: MTA induced a time-dependent proinflammatory cytokine up-regulation up to 3 days. Immunohistochemical analyses showed an up-regulated expression of myeloperoxidase, nuclear factor-kappa B, activating protein-1, cyclooxygenase-2, inducible nitric oxide synthase, and vascular endothelial growth factor on day 1. Scanning electron microscopic examination revealed the presence of apatite-like clusters on collagen fibrils over the surface of tubes containing MTA. With the increase in time after implantation, a more extensive mineralization showing a compact layer of apatite was observed., Conclusion: MTA induced a proinflammatory and pro-wound healing environment. The biomineralization process occurred simultaneously at the biomaterial-dentin-tissue interface, with the acute inflammatory response. This promoted the integration of the biomaterial into the environment., (Copyright 2010 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Background: Breast cancer is the most common cause of death in women by neoplasia. The mechanisms related to recurrence are unclear, specially the hemostatic alterations that occur during the development of the disease. Plasma D-dimer is a hypercoagulability and fibrinolytic system marker and is increased in patients with various solid tumors. The purpose of this study was to evaluate the hemostatic status assessed by plasma D-dimer in operable breast cancer patients and to investigate its value as a prognostic marker., Materials and Methods: The study comprised 32 patients with operable hormone receptor-negative breast cancer and a control group with 43 healthy women. Variables included presence and absence of breast cancer, clinical and histopathology findings, and overall survival., Results: Plasma D-dimer level was normal in the control group and significantly higher in breast cancer patients (P = 0.001), as well as in nonsurvivors compared with survivors (P = 0.025). The results showed that plasma D-dimer levels were not correlated with clinical and histopathology findings (P > 0.213)., Conclusions: The results taken together indicate the presence of a hypercoagulability state in women with operable hormone receptor-negative breast cancer given the increased levels of D-dimer in this group. Therefore, considering higher levels of D-dimer in patients with a poor outcome, its evaluation may be a promising tool for prognosis in women with operable hormone receptor-negative breast cancer.

Alzheimer's disease (AD), a chronic degenerative and inflammatory brain disorder characterized by neuronal dysfunction and loss, is linked to accumulation of beta-amyloid (Abeta) peptide. Tumor necrosis factor-alpha (TNF-alpha) and cyclooxygenase-2 (COX-2) are proteins that have key roles in immune cell activation, inflammation and cognitive function in the brain. Here, we evaluated the link between TNF-alpha and COX-2 on the acute responses elicited by Abeta. Behavioral and molecular analyses were performed in mice after an intracerebroventricular (i.c.v.) injection of Abeta(1-40). Genetic and/or pharmacological approaches were used to inhibit TNF-alpha and COX-2. I.c.v. Abeta(1-40) injection in mice activates TNF-alpha signaling pathway resulting in COX-2 upregulation, synaptic loss and cognitive decline. Pharmacological studies revealed that COX-2 is involved in the cognitive impairment mediated by TNF-alpha. However, COX-2 inhibition failed in reducing the synaptophysin loss induced by Abeta(1-40). The COX-2 upregulation induced by Abeta(1-40) was attributed to activation of different protein kinases and transcriptional factors that are greatly regulated by TNF-alpha. Together, these results indicate that Abeta(1-40) induces the activation of several TNF-alpha-dependent intracellular signaling pathways that play a key role in the control of COX-2 upregulation and activation, synaptic loss and cognitive decline in mice. Therefore, selective TNF-alpha inhibitors may be potentially interesting tools for AD drug development.

In this study, we have identified a secreted 13 kDa lectin from Mtb (Mtb, Mycobacterium tuberculosis; sMTL-13) by homology search of a non-redundant lectin database. Bioinformatic analysis revealed that sMTL-13 belongs to the ricin-type beta-trefoil family of proteins containing a Sec-type signal peptide present in Mtb complex species, but not in non-tuberculous mycobacteria. Following heterologous expression of sMTL-13 and generation of an mAb (clone 276.B7/IgG1kappa), we confirmed that this lectin is present in culture filtrate proteins from Mtb H37Rv, but not in non-tuberculous mycobacteria-derived culture filtrate proteins. In addition, sMTL-13 leads to an increased IFN-gamma production by PBMC from active tuberculosis (ATB) patients. Furthermore, sera from ATB patients displayed high titers of IgG Ab against sMTL-13, a response found to be decreased following successful anti-tuberculosis therapy. Together, our findings reveal a secreted 13 kDa ricin-like lectin from Mtb, which is immunologically recognized during ATB and could serve as a biomarker of disease treatment.

Purpose: To compare the lamellar body number density (LBND) count in amniotic fluid using the fluorescent polarization (FP) test as a diagnostic parameter for the assessment of fetal pulmonary maturity., Method: This was an analytical, controlled cross-sectional study conducted on 60 pregnant women from March 2002 to December 2007. Amniotic fluid specimens were obtained by amniocentesis or at the time of caesarean section, and submitted to the LBND and FP tests (TDxFLM, Abbott Laboratories), the latter considered to be a reference test, and compared in terms of the presence or absence of respiratory distress syndrome (RDS). Cut-off values for maturity were established at 30,000 lamellar bodies/microL for the LBND test and 55 mg/g albumin for the FP test. Maternal and perinatal characteristics and neonatal evolution were evaluated, and the performance of the diagnostic tests regarding fetal pulmonary maturity was determined. In the statistical analysis, descriptive measures were used and the sensitivity, specificity and positive and predictive values of the tests were determined with the level of significance set at p<0.05., Results: Maternal age ranged from 15 to 34 years (mean: 26.6 years) and gestational age ranged from 24.3 to 41.6 weeks (mean: 35.1 weeks). RDS was diagnosed in 35.1% of neonates. Perinatal characteristics such as weight, Apgar score, and RDS incidence were compared to the results of the LBND and FP tests and a significant correspondence (p<0.05) was observed between the groups of neonates clinically classified as mature and immature in both tests. The tests were concordant in 68.3% of the cases. Comparison of the PF and LBND tests revealed 100% specificity for both and a higher specificity for the LBND test (73.1% as opposed to 51.9% for the PF test). The gold standard for the determination of fetal maturity is the occurrence of RDS. The positive predictive value of the LBND test was higher (36.4%) than that of the FP test (24.2%) (p<0.05) and the negative predictive value was 100% for both tests., Conclusions: The present study demonstrated that the LBND test has 100% sensitivity and higher specificity than the reference test (FP). In addition, the LBND test is considered to be rapid, accessible, inexpensive and feasible for the Brazilian reality, and it can be used as a reliable test for the prediction of fetal pulmonary maturity.

Alzheimer disease (AD) is the most common form of dementia in the elderly, and the neuro-pathological hallmarks of AD include neurofibrillary tangles (NFT), and deposition of beta-amyloid (Abeta) in extracellular plaques. In addition, chronic inflammation due to recruitment of activated glial cells to amyloid plaques are an invariant component in AD, and several studies have reported that the use of non-steroidal anti-inflammatory drugs (NSAIDs) may provide a measure of protection against AD. In this report we have investigated whether phosphoinositide 3-kinase gamma (PI3Kgamma), which is important in inflammatory cell migration, plays a critical role in the neuro-inflammation, synaptic dysfunction, and cognitive deficits induced by intracerebroventricular injection of Abeta(1-40) in mice. We found that the selective inhibitor of PI3Kgamma, AS605240, was able to attenuate the Abeta(1-40)-induced accumulation of activated astrocytes and microglia in the hippocampus, and decrease immuno-staining for p-Akt and cyclooxygenase-2 (COX-2). Interestingly, Abeta(1-40) activated macrophages treated with AS605240 or another PI3Kgamma inhibitor, AS252424, displayed impaired chemotaxis in vitro, but their expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) was unaffected. Finally, AS605240 prevented Abeta(1-40)-induced cognitive deficits and synaptic dysfunction, but failed to modify scopolamine-induced amnesia. Our data suggests that inhibition of PI3Kgamma may represent a novel therapeutic target for treating AD patients., (2009 Elsevier Inc. All rights reserved.)

Many studies have shown that deficits in olfactory and cognitive functions precede the classical motor symptoms seen in Parkinson's disease (PD) and that olfactory testing may contribute to the early diagnosis of this disorder. Although the primary cause of PD is still unknown, epidemiological studies have revealed that its incidence is increased in consequence of exposure to certain environmental toxins. In this study, most of the impairments presented by C57BL/6 mice infused with a single intranasal (i.n.) administration of the proneurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (1 mg/nostril) were similar to those observed during the early phase of PD, when a moderate loss of nigral dopamine neurons results in olfactory and memory deficits with no major motor impairments. Such infusion decreased the levels of the enzyme tyrosine hydroxylase in the olfactory bulb, striatum, and substantia nigra by means of apoptotic mechanisms, reducing dopamine concentration in different brain structures such as olfactory bulb, striatum, and prefrontal cortex, but not in the hippocampus. These findings reinforce the notion that the olfactory system represents a particularly sensitive route for the transport of neurotoxins into the central nervous system that may be related to the etiology of PD. These results also provide new insights in experimental models of PD, indicating that the i.n. administration of MPTP represents a valuable mouse model for the study of the early stages of PD and for testing new therapeutic strategies to restore sensorial and cognitive processes in PD.

This paper describes the design and realization of a wireless sensor gateway (WSG) within a wireless sensor network (WSN) for health monitoring. The WSN allows recording and wireless transmission of biosignals, namely the electrocardiogram, pulse wave and body weight, which are important parameters for cardiovascular monitoring. These can be displayed, analysed, and saved on the WSG through a user interface based on a touch screen. The proposed WSG has the distinctive feature of using two different radio transceivers, exploiting the advantages of each device. Currently, most personal computers and handhelds have standardized Bluetooth interfaces (IEEE 802.15.1) but not ZigBee interfaces (IEEE 802.15.4). Hence, the proposed gateway is designed to receive data from wireless sensors through its ZigBee interface and to forward them to a personal computer via its Bluetooth interface. This feature, combined with simple touch screen menu navigation will reach increased patient compliance and consequently increased benefit for patient in terms of healthcare and safety.

This paper presents a low power wireless acquisition module for use within wearable health monitoring systems and Ambient Assisted Living applications. The acquisition module provides continuous monitoring of the user's electrocardiogram (ECG) and activity, as well as the local temperature at the module. The module is placed on the chest of the user, and its wearability is achieved due to its fabrication based on a flexible PCB, and by the complete absence of connecting wires, as a result of the integration of flexible and dry ECG monitoring electrodes on the acquisition module, which do not require preparation with electrolyte gel. The design of the acquisition module also aimed for the minimization of power consumption to enable long-term continuous monitoring, namely concerning the wireless link, for which a proprietary low power solution was adopted. A low power analog frontend was custom designed for single-lead ECG monitoring, achieving a current consumption of 220 εA. The wireless acquisition module has a current consumption down to 1.3 mA while processing the acquisition of sensor data, and 4 mA when the wireless transceiver is active.

The cellular prion protein (PrP(C)) is a neuronal-anchored glycoprotein that has been associated with various functions in the CNS such as synaptic plasticity, cognitive processes and neuroprotection. Here we investigated age-related behavioral and neurochemical alterations in wild-type (Prnp(+/+)), PrP(C) knockout (Prnp(0/0)) and the PrP(C) overexpressing Tg-20 mice. Three- or 11 month-old animals were submitted to a battery of behavioral tasks including open field, activity cages, elevated plus-maze, social recognition and inhibitory avoidance tasks. The 11 month-old Prnp(+/+) and Prnp(0/0) mice exhibited significant impairments in their locomotor activity and social recognition memory and increased anxiety-related responses. Remarkably, Tg-20 mice did not present these age-related impairments. The i.c.v. infusion of STI1 peptide 230-245, which includes the PrP(C) binding site, improved the age-related social recognition deficits in Prnp(+/+). In comparison with the two other age-matched genotypes, the 11 month-old Tg-20 mice also exhibited reduced activity of seric acetylcholinesterase, increased expression of the protein synaptophysin and decreased caspase-3 positive-cells in the hippocampus. The present findings obtained with genetic and pharmacological approaches provide convincing evidence that PrP(C) exerts a critical role in the age-related behavioral deficits in mice probably through adaptive mechanisms including apoptotic pathways and synaptic plasticity.

The hallmarks of Alzheimer's disease include the deposition of beta-amyloid (Abeta), neuroinflammation, and cognitive deficits. The accumulation of activated glial cells in cognitive-related areas is critical for these alterations, although little is known about the mechanisms driving this event. Herein we used macrophage inflammatory protein-1alpha (MIP-1alpha(-/-))- or CC-chemokine receptor 5 (CCR5(-/-))-deficient mice to address the role played by chemokines in molecular and behavioral alterations induced by Abeta(1-40). Abeta(1-40) induced a time-dependent increase of MIP-1alpha mRNA followed by accumulation of activated glial cells in the hippocampus of wild-type mice. MIP-1alpha(-/-) and CCR5(-/-) mice displayed reduced astrocytosis and microgliosis in the hippocampus after Abeta(1-40) administration that was associated with decreased expression of cyclooxygenase-2 and inducible nitric oxide synthase, as well as reduced activation of nuclear factor-kappaB, activator protein-1 and cyclic AMP response element-binding protein. Furthermore, MIP-1alpha(-/-) and CCR5(-/-) macrophages showed impaired chemotaxis in vitro, although cytokine production in response to Abeta(1-40) was unaffected. Notably, the cognitive deficits and synaptic dysfunction induced by Abeta(1-40) were also attenuated in MIP-1alpha(-/-) and CCR5(-/-) mice. Collectively, these results indicate that the MIP-1alpha/CCR5 signaling pathway is critical for the accumulation of activated glial cells in the hippocampus and, therefore, for the inflammation and cognitive failure induced by Abeta(1-40). Our data suggest MIP-1alpha and CCR5 as potential therapeutic targets for Alzheimer's disease treatment.

Background and Purpose: alpha-Humulene and trans-caryophyllene are plant sesquiterpenes with pronounced anti-inflammatory properties. Here, we evaluated the effects of these compounds in an experimental model of airways allergic inflammation., Experimental Approach: Female BALB/c mice, sensitized to and challenged with ovalbumin received daily alpha-humulene or trans-caryophyllene (50 mg.kg(-1), orally) or alpha-humulene (1 mg.mL(-1), by aerosol) as either a preventive (for 22 days) or therapeutic (from the 18th to the 22nd day) treatment. Dexamethasone or budesonide was used as a positive control drug. Inflammation was determined on day 22 post-immunization by leukocyte recruitment, interleukin-5 (IL-5), CCL11, interferon-gamma (IFN-gamma) and leukotriene (LT)B(4) levels in bronchoalveolar lavage fluid (BALF). In addition, transcription factors [nuclear factor kappaB (NF-kappaB), activator protein 1 (AP-1)] and P-selectin in lung tissue were measured by immunohistochemistry and mucus secretion by histochemistry., Key Results: Preventive or therapeutic treatments with alpha-humulene, but not with trans-caryophyllene, significantly reduced the eosinophil recruitment to the BALF. In addition, alpha-humulene recovery INF-gamma and reduced the IL-5, CCL11 and LTB(4) levels in BALF, as well as the IL-5 production in mediastinal lymph nodes (in vitro assay). Furthermore, alpha-humulene decreased the NF-kB and the AP-1 activation, the expression of P-selectin and the increased mucus secretion in the lung., Conclusions and Implications: alpha-Humulene, given either orally or by aerosol, exhibited marked anti-inflammatory properties in a murine model of airways allergic inflammation, an effect that seemed to be mediated via reduction of inflammatory mediators, adhesion molecule expression and transcription factors activation.

The skin is the largest organ in the body and one of its main functions is to protect the body from environmental and endogenous noxious conditions, such as injury, infection and inflammation. The inducible nitric oxide synthase (iNOS) has been implicated as a key component in the inflammatory response. In the present study, we assessed the role of iNOS in the skin inflammation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). Mice deficient in iNOS had reduced edema and cellular infiltration in the skin following topical TPA application. Moreover, the genetic blockage of iNOS signaling inhibited the TPA-induced ERK and p38 activation resulting in reduced COX-2 upregulation. Finally, immunohistochemical studies revealed that iNOS knockout mice exhibited marked inhibition of AP-1, CREB and NF-kappaB transcriptional factors activation. Together, these results indicate that TPA induces the activation of several iNOS-dependent intracellular signaling pathways that have a key role in the control of inflammatory response in the skin. Therefore, selective iNOS inhibitors may be potentially relevant tools for cutaneous skin disease drug development.

The presence of smell loss and the early pathological involvement of the olfactory pathways in the early stages of some neurodegenerative disorders are in accord with the tenants of the olfactory vector hypothesis. This hypothesis postulates that some such diseases may be caused or catalyzed by agents that enter the brain via the olfactory mucosa. In this study, rats infused intranasally (i.n.) with a low concentration of the proneurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) subsequently suffered olfactory, cognitive, and motor function impairments conceivably analogous to those observed during different stages of the development of Parkinson's disease (PD). Such infusion decreased the expression of the enzyme tyrosine hydroxylase in the olfactory bulb and substantia nigra by means of apoptotic mechanisms, reducing dopamine levels in different brain structures, such as the olfactory bulb, striatum, and prefrontal cortex. These findings reinforce the suggestion that the olfactory system may be a particularly sensitive route for the penetration of xenobiotic agents into the central nervous system and that the i.n. MPTP rat model may provide insight into the underlying mechanisms of PD pathogenesis, potentially leading to the development of new therapeutic strategies for this devastating disease.

The cellular prion protein (PrP(C)) has been implicated with the modulation of neuronal apoptosis, adhesion, neurite outgrowth and maintenance which are processes involved in the neocortical development. Malformations of cortical development (MCD) are frequently associated with neurological conditions including mental retardation, autism, and epilepsy. Here we investigated the behavioral performance of female adult PrP(C)-null mice (Prnp(0/0)) and their wild-type controls (Prnp(+/+)) presenting unilateral polymicrogyria, a MCD experimentally induced by neonatal freeze-lesion in the right hemisphere. Injured mice from both genotypes presented similar locomotor activity but Prnp(0/0) mice showed a tendency to increase anxiety-related responses when compared to Prnp(+/+) animals. Additionally, injured Prnp(0/0) mice have a poorer performance in the social recognition task than sham-operated and Prnp(+/+) injured ones. Moreover the step-down inhibitory avoidance task was not affected by the procedure or the genotype of the animals. These data suggest that the genetic deletion of PrP(C) confers increased susceptibility to short-term social memory deficits induced by neonatal freezing model of polymicrogyria in mice.

In addition to classic motor symptoms, Parkinson's disease (PD) is characterized by cognitive and emotional deficits, which have been demonstrated to precede motor impairments. The present study addresses the question of whether a partial degeneration of dopaminergic neurons using 6-hydroxydopamine (6-OHDA) in rats is able to induce premotor behavioral signs. The time-course of nigrostriatal damage was evaluated by tyrosine hydroxylase immunohistochemistry and the levels of dopamine, noradrenaline, and 5-HT in various brain regions were analyzed by high performance liquid chromatography (HPLC). Behavioral tests that assessed a variety of psychological functions, including locomotor activity, emotional reactivity and depression, anxiety and memory were conducted on 6-OHDA lesioned rats. Bilateral infusion of 6-OHDA in the striatum of rats caused early (1 week) damage of dopaminergic terminals in striatum and in cell bodies in substantia nigra pars compacta. The nigrostriatal lesion was accompanied by early loss of dopamine in the striatum, which remained stable through a 3-week period of observation. In addition, a late (3 weeks) loss of dopamine in the prefrontal cortex, but not in the hippocampus, was seen. Additional noradrenergic and serotonergic alterations were observed after 6-OHDA administration. The results indicated that 6-OHDA lesioned rats show decreased sucrose consumption and an increased immobility time in the forced swimming test, an anhedonic-depressive-like effect. In addition, an anxiogenic-like activity in the elevated plus maze test and cognitive impairments were observed on the cued version of the Morris water maze and social recognition tests. These findings suggest that partial striatal dopaminergic degeneration and parallel dopaminergic, noradrenergic and serotonergic alterations in striatum and prefrontal cortex may have caused the emotional and cognitive deficits observed in this rat model of early phase PD.

Lipoxin A(4) (LXA(4)) is a lipid mediator that plays an important role in inflammation resolution. We assessed the anti-inflammatory effect of LXA(4) on endotoxin-induced uveitis (EIU) in rats. The inflammatory cell number and levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), prostaglandin E(2) (PGE(2)), and protein, as well as expression of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF), in the anterior chamber of the eye were determined 24 h after lipopolysaccharide (LPS; 200 mug/paw) intradermal injection. The immunohistochemical reactivities of nuclear factor-kappaB (NF-kappaB) and c-Jun were also examined. Topical LXA(4) (1-10 ng/eye) pretreatment decreased the number of inflammatory cells and the protein leakage into the aqueous humor (AqH). In addition, topical LXA(4) (10 ng/eye) inhibited the LPS-induced production of IL-1beta, TNF-alpha, and PGE(2), and expression of COX-2 and VEGF. A decreased activation of NF-kappaB and c-Jun was also found in LXA(4)-treated eyes. It is very interesting that an anti-inflammatory effect was achieved even when LXA(4) (10 ng/eye) was applied topically after LPS challenge, as indicated by the reduction in the cellular and protein extravasations into the AqH. Moreover, topical treatment of corticosteroid prednisolone (200 mug/eye) beginning before or after LPS injection reduced all of the molecular and biochemical alterations promoted on EIU rats in an efficacy similar to that of LXA(4). Together, the present results provide clear evidence that pharmacological activation of LXA(4) signaling pathway potently reduces the EIU in rats. Therefore, LXA(4) stable analogs could represent promising agents for the management of ocular inflammatory diseases.

Background: The periapical lesion is the result of a local inflammatory reaction caused by bacteria and its products present on the root canal. The interaction between inflammatory cells and bacteria elicit both specific and non-specific immune responses., Objective: Due to the lack of studies evaluating the role of the immune system in periapical lesions of primary teeth and considering the potentially systemic effects that these infections can cause in children, especially because of the immaturity of their immune system, we sought to evaluate the presence of T cells, B cells and macrophages on periradicular lesions in primary teeth., Study Design: 14 periradicular lesions were analyzed. The immunohistochemistry technique was performed using CD45RO, CD20, CD68 monoclonal antibodies aiming to identify T cells, B cells and macrophages, respectively. Cells were quantified by microscopic analysis of histological sections., Results: Mean percentage of positive cells CD45RO was 11.76; CD20 was 5.25; CD68 was 10.92. Our results showed that T and B cells and macrophages comprise the majority of the inflammatory infiltrate., Conclusion: We concluded that both humoral and cell mediated immune reactions take place in periradicular lesions of primary teeth. The immune system plays an important role on the periradicular inflammatory processes in primary teeth.

This paper presents a solution for electrode localization on wearable BCI radio-enabled electrodes. Electrode positioning is a common issue in any electrical physiological recording. Although wireless node localization is a very active research topic, a precise method with few centimeters of range and a resolution in the order of millimeters is still to be found, since far-field measurements are very prone to error. The calculation of 3D coordinates for each electrode is based on anchorless range-based localization algorithms such as Multidimensional Scaling and Self-Positioning Algorithm. The implemented solution relies on the association of a small antenna to measure the magnetic field and a microcontroller to each electrode, which will be part of the wireless sensor network module. The implemented solution is suitable for EEG applications, namely the wearable BCI, with expected range of 20 cm and resolution of 5 mm.

Increased brain deposition of amyloid beta protein (Abeta) and cognitive deficits are classical signals of Alzheimer's disease (AD) that have been highly associated with inflammatory alterations. The present work was designed to determine the correlation between tumor necrosis factor-alpha (TNF-alpha)-related signaling pathways and inducible nitric oxide synthase (iNOS) expression in a mouse model of AD, by means of both in vivo and in vitro approaches. The intracerebroventricular injection of Abeta(1-40) in mice resulted in marked deficits of learning and memory, according to assessment in the water maze paradigm. This cognition impairment seems to be related to synapse dysfunction and glial cell activation. The pharmacological blockage of either TNF-alpha or iNOS reduced the cognitive deficit evoked by Abeta(1-40) in mice. Similar results were obtained in TNF-alpha receptor 1 and iNOS knock-out mice. Abeta(1-40) administration induced an increase in TNF-alpha expression and oxidative alterations in prefrontal cortex and hippocampus. Likewise, Abeta(1-40) led to activation of both JNK (c-Jun-NH2-terminal kinase)/c-Jun and nuclear factor-kappaB, resulting in iNOS upregulation in both brain structures. The anti-TNF-alpha antibody reduced all of the molecular and biochemical alterations promoted by Abeta(1-40). These results provide new insights in mouse models of AD, revealing TNF-alpha and iNOS as central mediators of Abeta action. These pathways might be targeted for AD drug development.

The age-specific incidence of Hodgkin lymphoma (HL) is bimodal with peaks occurring among young adults (15 - 34 years old) and people older than 45 years. Epstein-Barr virus (EBV) is associated with only one-third of HL cases. This study sought to determine if Torque teno virus (TTV) might be independently associated with HL. The presence of EBV was appraised by in situ hybridization and immunohistochemistry in lymph node biopsies from 46 patients (3 - 81 years old) with HL. TTV DNA was assessed by PCR amplification. EBV was detected in 22 (48%) patients. TTV DNA was detected in 24/46 (52%) patients, as well as in 12/20 (60%) control patients with lymphoid unspecific hyperplasia. TTV DNA was not significantly more frequent in EBV negative (54%) than in EBV positive (50%) nodes. However, it was observed that the group of young adults (15 - 34 years, n = 19) showed the lowest EBV frequency (21%) but the highest TTV occurrence (60%). This may suggest an involvement of TTV infection in the pathogenesis of HL in young adults. Further large population-based studies are required to confirm our findings.

The present study examined the outcomes of systemic or topical treatment with thalidomide, a compound that possesses anti-inflammatory, immunomodulatory and anti-angiogenic properties, in rats subjected to endotoxin-induced uveitis (EIU). The effects of thalidomide were evaluated on endotoxin-induced leucocyte and protein infiltration and also on the production of interleukin (IL)-1beta and tumour necrosis factor (TNF)-alpha in rat aqueous humour (AqH). Moreover, the actions of thalidomide were assessed on the cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) protein expression in retinal tissue. EIU was produced by a hindpaw injection of lipopolysaccharide (LPS), in male Wistar rats. Thalidomide (5, 25 and 50 mg/kg) was administered orally 1 h before LPS injection. In another set of experiments, to evaluate the therapeutic efficacy, 5% thalidomide was applied topically to both eyes at 6, 12 and 18 h after LPS administration. The oral pre-treatment with thalidomide decreased, in a dose-dependent manner, the number of inflammatory cells, the protein concentration, and the levels of IL-1beta and TNF-alpha in the AqH. Similar results were found in the AqH of rats that received a topical application of thalidomide. Furthermore, oral (50 mg/kg) and local (5%) thalidomide treatment also reduced expression of the pro-inflammatory proteins COX-2 and iNOS in the posterior segment of the eye. Thalidomide exhibited marked preventive and curative ocular effects in EIU in rats, a property that might be associated with its ability to inhibit the production of inflammatory cytokines and the expression of COX-2 and iNOS. This assembly of data provides additional molecular and functional insights into beneficial effects of thalidomide as an agent for the management of ocular inflammation.

Considerable evidence supports the role of oxidative stress in the pathogenesis of Alzheimer's disease (AD). Previous studies suggest that the central nervous system (CNS) administration of beta-amyloid peptide, the major constituent of senile plaque in AD, induces oxidative stress in rodents which may contribute to the learning and memory deficits verified in the beta-amyloid model of AD. In the present study, we compared the effects of a single intracerebroventricular (i.c.v.) injection of aggregated beta-amyloid peptide-(1-40) (Abeta(1-40)) (400pmol/mouse) on spatial learning and memory performance, synaptic density and the glutathione (GSH)-dependent antioxidant status in adult male C57BL/6 and Swiss albino mice. Seven days after Abeta(1-40) administration, C57BL/6 and Swiss mice presented similar spatial learning and memory impairments, as evaluated in the water maze task, although these impairments were not found in Abeta(40-1)-treated mice. Moreover, a similar decline of synaptophysin levels was observed in the hippocampus (HC) and prefrontal cortex (PFC) of both Swiss and C57BL/6 mice treated with Abeta(1-40), which suggests synaptic loss. C57BL/6 mice presented lower levels of glutathione-related antioxidant defences (total glutathione (GSH-t) levels, glutathione peroxidase (GPx) and glutathione reductase (GR) activity) in the HC and PFC in comparison to Swiss mice. Despite the reduced basal GSH-dependent antioxidant defences observed in C57BL/6 mice, Abeta(1-40) administration induced significant alterations in the brain antioxidant parameters only in Swiss mice, decreasing GSH-t levels and increasing GPx and GR activity in the HC and PFC 24h after treatment. These results indicate strain differences in the susceptibility to Abeta(1-40)-induced changes in the GSH-dependent antioxidant defences in mice, which should be taken into account in further studies using the Abeta model of AD in mice. In addition, the present findings suggest that the spatial learning and memory deficits induced by beta-amyloid peptides in rodents may not be entirely related to glutathione-dependent antioxidant response.