Immunoexpression of HSPA9 and CUL2 in prostatic tissue and adenocarcinoma.

CUL2 plays a crucial role in proteolysis by preserving the balance between normal growth and uncontrolled proliferation. HSPA9 safeguards the integrity of protein interactions and supports cellular homeostasis. In carcinomas, HSPA9 and CUL2 appear to protect neoplastic cells from internal and external damage. In prostate tumors they are apparently associated with increased risk of unfavorable outcomes, but information remains scarce. In this study we evaluated CUL2 and HSPA9 expression in neoplastic and non-neoplastic prostate tissue and Gleason pattern 3 and 4 adenocarcinoma to identify associations with ISUP prognostic groups and postoperative disease progression. The records of 636 radical prostatectomy patients were reviewed retrospectively and microarrays were mounted with paraffin-embedded adenocarcinoma and non-neoplastic tissue. We evaluated the ability of HSPA9 and CUL2 to predict postoperative PSA outcomes, response to adjuvant/salvage therapy and systemic disease. HSPA9 and CUL2 were diffusely expressed. HSPA9 expression was associated with increased risk of high-grade adenocarcinoma, while HSPA9 and CUL2 were associated with biochemical failure after salvage therapy. In conclusion, HSPA9 and CUL2 were highly expressed in prostate tissue, especially in neoplastic cells. HSPA9 and CUL2-positive Gleason pattern 3 adenocarcinoma was more likely to be associated with Gleason pattern 4 or 5, while HSPA9 and CUL2-positive Gleason pattern 4 adenocarcinoma was less likely to belong to ISUP groups 1 and 2. Staining for HSPA9 and CUL2 can help identify patients at increased risk of recurrence after salvage therapy.

Early identification of first-year students at risk of dropping out of high-school entry medical school: the usefulness of teachers' ratings of class participation.

Dropping out from undergraduate medical education is costly for students, medical schools, and society in general. Therefore, the early identification of potential dropout students is important. The contribution of personal features to dropout rates has merited exploration. However, there is a paucity of research on aspects of student experience that may lead to dropping out. In this study, underpinned by theoretical models of student commitment, involvement, and engagement, we explored the hypothesis of using inferior participation as an indicator of a higher probability of dropping out in year 1. Class participation was calculated as an aggregate score based on teachers' daily observations in class. The study used a longitudinal dataset of six cohorts of high-school entry students (N = 709, 67% females) in one medical school with an annual intake of 120 students. The findings confirmed the initial hypothesis and showed that lower scores of class participation in year 1 added predictive ability to pre-entry characteristics (Pseudo-R2 raised from 0.22 to 0.28). Even though the inclusion of course failure in year 1 resulted in higher explanatory power than participation in class (Pseudo-R2 raised from 0.28 to 0.63), ratings of class participation may be advantageous to anticipate dropout identification, as those can be collected prior to course failure. The implications for practice are that teachers' ratings of class participation can play a role in indicating medical students who may eventually drop out. We conclude that the scores of class participation can contribute to flagging systems for the early detection of student dropouts.

Pre-clinical effects of metformin and aspirin on the cell lines of different breast cancer subtypes.

Background Breast cancer is highly prevalent among women worldwide. It is classified into three main subtypes: estrogen receptor positive (ER+), human epidermal growth factor receptor 2 positive (HER2+), and triple negative breast cancer (TNBC). This study has evaluated the effects of aspirin and metformin, isolated or in a combination, in breast cancer cells of the different subtypes. Methods The breast cancer cell lines MCF-7, MDA-MB-231, and SK-BR-3 were treated with aspirin and/or metformin (0.01 mM - 10 mM); functional in vitro assays were performed. The interactions with the estrogen receptors (ER) were evaluated in silico. Results Metformin (2.5, 5 and 10 mM) altered the morphology and reduced the viability and migration of the ER+ cell line MCF-7, whereas aspirin triggered this effect only at 10 mM. A synergistic effect for the combination of metformin and aspirin (2.5, 5 or 10 mM each) was observed in the TNBC cell subtype MDA-MB-231, according to the evaluation of its viability and colony formation. Partial inhibitory effects were observed for either of the drugs in the HER2+ cell subtype SK-BR-3. The effects of metformin and aspirin partly relied on cyclooxygenase-2 (COX-2) upregulation, without the production of lipoxins. In silico, metformin and aspirin bound to the ERα receptor with the same energy. Conclusion We have provided novel evidence on the mechanisms of action of aspirin and metformin in breast cancer cells, showing favorable outcomes for these drugs in the ER+ and TNBC subtypes.

Efficacy and gastrointestinal tolerability of ML3403, a selective inhibitor of p38 MAP kinase and CBS-3595, a dual inhibitor of p38 MAP kinase and phosphodiesterase 4 in CFA-induced arthritis in rats.

OBJECTIVE: Mitogen-activated protein kinase (MAPK) p38 inhibitors have entered the clinical phase, although many of them have failed due to high toxicity and lack of efficacy. In the present study we compared the effects of the selective p38 inhibitor ML3403 and the dual p38-PDE4 inhibitor CBS-3595, on inflammatory and nociceptive parameters in a model of polyarthritis in rats. METHODS: Male Wistar rats (180-200 g) were used for the complete Freund's adjuvant (CFA)-induced arthritis model and they were evaluated at 14-21 days. We also analysed the effects of these pharmacological tools on liver and gastrointestinal toxicity and on cytokine levels. RESULTS: Repeated CBS-3595 (3 mg/kg) or ML3403 (10 mg/kg) administration produced significant anti-inflammatory actions in the chronic arthritis model induced by CFA. CBS-3595 and ML3403 treatment also markedly reduced the production of the proinflammatory cytokine IL-6 in the paw tissue, whereas it widely increased the levels of the anti-inflammatory cytokine IL-10. Moreover, CBS-3595 produced partial anti-allodynic effects in the CFA model at 4 and 8 days after treatment. Notably, ML3403 and CBS-3595 did not show marked signs of hepatoxicity, as supported by unaltered histological observations in the liver sections. Finally, both compounds were safe in the gastrointestinal tract, according to evaluation of intestinal biopsies. CONCLUSION: CBS-3595 displayed a superior profile regarding its anti-inflammatory effects. Thus p38 MAPK/PDE4 blocking might well constitute a relevant strategy for the treatment of RA.

Protective effects of resveratrol on hepatotoxicity induced by isoniazid and rifampicin via SIRT1 modulation.

Acute liver injury was induced in male BALB/c mice by coadministering isoniazid and rifampicin. In this work, the effects of resveratrol (1) were investigated in the hepatotoxicity caused by isoniazid-rifampicin in mice. Compound 1 was administered 30 min prior to isoniazid-rifampicin. Serum biochemical tests, liver histopathological examination, oxidative stress, myeloperoxidase activity, cytokine production (TNF-α, IL-12p70, and IL-10), and mRNA expression of SIRT1-7 and PPAR-γ/PGC1-α were evaluated. The administration of 1 significantly decreased aspartate transaminase and alanine aminotransferase levels, myeloperoxidase activity, and cytokine levels. Furthermore, 1 reverted the decrease of catalase and glutathione activities and ameliorated the histopathological alterations associated with antituberculosis drugs. Modulation of SIRT1 and PPAR-γ/PGC1-α expression is likely involved in the protective effects of 1. The results presented herein show that 1 was able to largely prevent the hepatotoxicity induced by isoniazid and rifampicin in mice, mainly by modulating SIRT1 mRNA expression.

Involvement of purinergic system in inflammation and toxicity induced by copper in zebrafish larvae.

The use of zebrafish (Danio rerio) is increasing as an intermediate preclinical model, to prioritize drug candidates for mammalian testing. As the immune system of the zebrafish is quite similar to that of mammals, models of inflammation are being developed for the screening of new drugs. The characterization of these models is crucial for studies that seek for mechanisms of action and specific pharmacological targets. It is well known that copper is a metal that induces damage and cell migration to hair cells of lateral line of zebrafish. Extracellular nucleotides/nucleosides, as ATP and adenosine (ADO), act as endogenous signaling molecules during tissue damage by exerting effects on inflammatory and immune responses. The present study aimed to characterize the inflammatory status, and to investigate the involvement of the purinergic system in copper-induced inflammation in zebrafish larvae. Fishes of 7 days post-fertilization were exposed to 10 µM of copper for a period of 24 h. The grade of oxidative stress, inflammatory status, copper uptake, the activity and the gene expression of the enzymes responsible for controlling the levels of nucleotides and adenosine were evaluated. Due to the copper accumulation in zebrafish larvae tissues, the damage and oxidative stress were exacerbated over time, resulting in an inflammatory process involving IL-1ß, TNF-α, COX-2 and PGE2. Within the purinergic system, the mechanisms that control the ADO levels were the most involved, mainly the reactions performed by the isoenzyme ADA 2. In conclusion, our data shed new lights on the mechanisms related to copper-induced inflammation in zebrafish larvae.

Analytical method for determination of nitric oxide in zebrafish larvae: toxicological and pharmacological applications.

Zebrafish are currently used at various stages of the drug discovery process and can be a useful and cost-effective alternative to some mammalian models. Nitric oxide (NO) plays an important role in physiology of zebrafish. The availability of appropriate analytical techniques to quantify the NO is crucial for studying its role in physiological and pathological conditions. This work aimed at establishing a high-performance liquid chromatography method for determination of NO levels in zebrafish larvae. Attempts were also made to assess the normal levels of NO at the first days postfertilization and the possible changes under pathological conditions. The method validation was quantitatively evaluated in terms of sensitivity, specificity, precision, accuracy, linearity, and recovery. NO levels from zebrafish larvae at the first days postfertilization and larvae challenged to N(G)-nitro-L-arginine methyl ester, sodium nitroprusside, Escherichia coli lipopolysaccharide, and copper sulfate were analyzed. The samples were derivatized with 2,3-diaminonaphthalene, and fluorescence detection was used for the indirect determination of NO. The method showed a good performance for all validation parameters evaluated and was efficient to monitor changes in NO concentration under physiological and pathophysiological conditions. This method might represent a powerful tool to be applied in NO studies with zebrafish larvae.

Hair cortisol and stressful life events retrospective assessment in crack cocaine users.

BACKGROUND: Some evidence suggests that altered hypothalamic-pituitary-adrenal (HPA) axis functioning in cocaine users might play a role in the pathophysiology of substance abuse. This study aimed to investigate the relationship between exposure to negative life events and cortisol hair concentrations in crack cocaine users during the 3 months prior to admission to a detoxification program. METHODS: A total of 23 treatment-seeking, crack cocaine-dependent women were selected for this study 1 week after admission to an inpatient treatment at a locked treatment facility. The Paykel Life Events Scale measured the occurrence of stressful life events 3 months before admission. Hair cortisol concentration was measured during these three previous months. RESULTS: The partial correlations, using severity of dependence as control variable, revealed that there is a positive association between hair cortisol concentration and the number of negative life events exposure 90 days (r = .56; p = .007) and 30 days (r = .42; p = .048) prior to admission at the hospital. One-way ANOVA suggests that hair cortisol levels and stress load significantly increase over 3 months prior to hospitalization. CONCLUSIONS: The results of this study indicate that there is a positive association between measures of long-term cumulative cortisol secretion and the number of stressful events reported by women receiving inpatient treatment for crack cocaine dependence. Therefore, this study suggests that stress load can be objectively quantified and noninvasively assessed. SCIENTIFIC SIGNIFICANCE: This study is the first to investigate HPA axis functioning using hair cortisol concentrations among crack cocaine-dependent users. It is a promising strategy to assess stress load in substance abusers.

[Occupational Dermatoses in Healthcare Workers during the COVID-19 Pandemic: A Narrative Review]. / Dermatoses Ocupacionais em Profissionais de Saúde durante a Pandemia de COVID-19: Revisão Narrativa.

INTRODUCTION: On the 11th March 2020, the World Health Organization declared the novel coronavirus outbreak as a pandemic. Preventive measures such as the appropriate use of personal protective equipment and proper hand hygiene are essential in decreasing transmissibility. Healthcare workers have been required to wear personal protective equipment and to wash their hands even more frequently. These preventive measures are associated with an increased risk of skin conditions, namely, contact dermatitis and exacerbation of pre-existing skin lesions such as acne and seborrheic dermatitis. The aim of this article is to provide an overview of the main skin lesions, and highlighting the role in occupational dermatology and preventive measures. METHODS: A search was conducted on PubMed and some guidelines from organizations like World Health Organization and Portuguese General Directorate of Health were included. RESULTS: Most skin conditions seen in healthcare professionals throughout the pandemic were associated with hand hygiene and the use of personal protective equipment and comprised hand eczema, mask-induced contact dermatitis, personal protective equipment related irritant contact dermatitis, cheilitis and exacerbation of pre-existing conditions such as acne and seborrheic dermatitis. Prevention and early recognition of dermatitis associated with personal protective equipment and hand hygiene are essential to maximize work performance, healthcare workers' safety and the adherence to preventive measures. CONCLUSION: Protection of healthcare workers' health and safety is an essential measure in the fight against the pandemic. Occupational Health has a fundamental role, acting in terms of disease prevention and health promotion, for example, through educational sessions and orientation of skin conditions associated with work, thus maximizing workers' well-being.

Introdução: A 11 de março de 2020, a Organização Mundial da Saúde declarou a doença provocada pelo novo coronavírus uma pandemia. As medidas de prevenção, nomeadamente, o uso apropriado de equipamento de proteção individual e a higienização das mãos, são essenciais na diminuição da transmissibilidade. Os profissionais de saúde têm particular indicação para o seu uso e para o aumento da frequência e duração da lavagem e desinfeção das mãos. Estas medidas estão associadas a um maior risco de desenvolvimento de patologias cutâneas como a dermatite de contacto e a exacerbação de lesões cutâneas pré-existentes, tais como a acne e a dermatite seborreica. O objetivo deste artigo é apresentar uma descrição das principais lesões cutâneas, e salientar o papel da dermatologia ocupacional e medidas preventivas.Métodos: Foi realizada uma pesquisa na PubMed e incluídas orientações de organizações como a Direção-Geral da Saúde e a Organização Mundial da Saúde.Resultados: As principais patologias cutâneas observadas nos profissionais de saúde ao longo da pandemia associam-se à higienização das mãos e à utilização de equipamentos de proteção individual, consistindo, sucintamente, em eczema das mãos, dermatite de contacto induzida por máscaras, dermatite de contacto irritativa por traumatismo do equipamento de proteção individual, queilite e exacerbação de condições pré-existentes como acne e dermatite seborreica. A prevenção e o reconhecimento atempado das dermatites associadas ao uso de equipamento de proteção individual e ao reforço da higiene das mãos são fundamentais para otimizar o desempenho laboral e a segurança dos profissionais de saúde e maximizar a adesão às medidas preventivas.Conclusão: A proteção da saúde e da segurança dos profissionais de saúde constitui uma medida essencial no combate da pandemia, pelo que a Medicina do Trabalho assume um papel fundamental, atuando a nível da prevenção da doença e promoção da saúde, por exemplo, através da realização de sessões de educação e orientação das várias patologias cutâneas associadas ao trabalho, maximizando o bem-estar do trabalhador.

A Novel Murine Model of a High Dose Brachytherapy-Induced Actinic Proctitis.

Background: Radiation proctitis affects 1-20% of cancer patients undergoing radiation exposure due to pelvic malignancies, including prostate, gynecological and rectum cancers. The patients manifest rectal discomfort, pain, discharge, and bleeding. Notably, the efficacy of prophylactic measures remains controversial due to the lack of adequate animal models that mimic this condition. Objective: The present study then aimed to develop a murine model of high-dose-rate (HDR) brachytherapy-induced proctitis. Material/Methods: C57BL/6 male mice were subjected to HDR (radiation source: iridium-192 [Ir-192]) through a cylindrical propylene tube inserted 2 cm far from the anal verge into the rectum. The animals received radiation doses once a day for three consecutive days (fractions of 9.5 Grays [Gy]), 3.0 mm far from the applicator surface. The sham group received only the applicator with no radiation source. The survival rate was recorded, and a colonoscopy was performed to confirm the tissue lesion development. Following euthanasia, samples of the rectum were collected for histopathology, cytokines dosage (IL-6 and KC), and immunohistochemical analysis (TNF-α and COX-2). Results: HDR significantly reduced animals' survival ten days post first radiation exposure (14% survival vs. 100% in the non-irradiated group). Day seven was then used for further investigation. Mice exposed to radiation presented with rectum injury confirmed by colonoscopy and histopathology (P < 0.05 vs. the control group). The tissue damage was accompanied by an inflammatory response, marked by increased KC and IL-6 tissue levels, and immunostaining for TNF-α and COX-2 (P < 0.05 vs. control group). Conclusions: We established a novel animal model of actinic proctitis induced by HDR brachytherapy, marked by inflammatory damage and low animal mortality.

High-fat diet effect on periapical lesions and hepatic enzymatic antioxidant in rats.

AIMS: To evaluate the effects of a high-fat diet (HFD) on the progression of apical periodontitis (AP), local inflammation, systemic antioxidant status, and blood lipid profile in rats. MAIN METHODS: Sixteen male Wistar rats were fed a standard diet (SD) or a HFD. At the sixth experimental week, the pulp chambers of the mandibular first molars were exposed to develop AP. A glucose tolerance test was performed the week before euthanasia. At the tenth experimental week, the animals were euthanized and the livers were collected to estimate catalase (CAT) and reduced glutathione (GSH) levels. Blood was acquired for biochemical analysis. The size of AP was estimated from radiographs and described as AP size-to-body weight ratio; inflammatory grade of AP was determined by histological analysis. KEY FINDINGS: At the end of the experimental period, the rats fed the HFD had 30% less weight (P < 0.0001) and higher blood glucose levels after 30 min of sucrose intake (P < 0.05) than those fed the SD. Animals from the HFD group had lower levels of CAT (P < 0.01), but the same was not observed in the GSH levels. Plasma insulin and total cholesterol were not affected by the diet. The rats fed the HFD presented greater AP than those fed the SD (P < 0.05). However, the local inflammatory infiltrate was similar in both groups. SIGNIFICANCE: The alterations promoted by the consumption of a HFD were not only observed systemically, but also locally, producing greater AP in rats than a SD.

Prognostic factors on surgically and non-surgically treated oral squamous cell carcinoma: Advances in survival in fifteen years of follow up.

BACKGROUND: Retrospectively to evaluate the influence of radiochemotherapy (RCT) in the treatment of surgically and non-surgically treated Oral Squamous Cell Carcinoma (OSCC). MATERIAL AND METHODS: We analysed 934 patients treated in Hospital Haroldo Juaçaba (2000-2014; 15 years of study) by extraction of data type of cancer, localization of tumour, sex, age, race, education level, risk factors (smoking and alcohol use), year of diagnosis, TNM stage, therapeutic approach, health system used (public or private) and overall survival (OS). Surgically and non-surgically treated OSCC were compared by chi-square and Fisher's exact tests, and their prognostic factors were analysed by log-rank Mantel-Cox plus Cox regression tests (SPSS 20.0, p<0.05). RESULTS: Non-surgically treated OSCC patients had a lower OS than surgically treated OSCC patients (p<0.001), but an increase in OS was shown in both groups. Although the 2010-2014 period (p=0.003), education level (p=0.032), tongue/mouth floor/palate localization (p=0.023) and TNM stage (p<0.05) were important in non-surgically treated OSCC OS, the major prognostic factors were node metastasis (p=0.003) and non-use of RCT (p=0.039) (multivariate analysis). In surgically treated OSCC patients, higher OS was shown in the 2010-2014 period (p<0.001), females (p=0.012), non-drinkers (p=0.011), non-smokers (p=0.009) and those with lower TNM stage (p<0.05), but the major prognostic factor was the 2010-2014 period (p=0.004) (multivariate analysis), which was directly associated with an increase in RCT indication (p<0.001). CONCLUSIONS: The increase in RCT improved the OS in this large cohort of surgically and non-surgically treated OSCC patients. Key words:Mouth neoplasms, neck, radiotherapy, drug therapy, combination.

Cotinine as a biomarker of tobacco exposure: development of a HPLC method and comparison of matrices.

Tobacco dependence reaches one-third of the world population, and is the second leading cause of death around the world. Cotinine, a major metabolite of nicotine, is the most appropriate parameter to evaluate tobacco exposure and smoking status due to its higher stability and half-life when compared to nicotine. The procedure involves liquid-liquid extraction, separation on a RP column (Zorbax XDB C(8)), isocratic pump (0.5 mL/min of water-methanol-sodium acetate (0.1 M)-ACN (50:15:25:10, v/v/v/v), 1.0 mL of citric acid (0.034 M) and 5.0 mL of triethylamine for each liter) and HPLC-UV detection (261 nm). The analytical procedure proved to be sensitive, selective, precise, accurate and linear (r>0.99) in the range of 5-500.0 ng/mL for cotinine. 2-Phenylimidazole was used as the internal standard. The LOD was 0.18 ng/mL and the LOQ was 5.0 ng/mL. All samples from smoking volunteers were collected simultaneously to establish a comparison between serum, plasma, and urine. The urinary cotinine levels were normalized by the creatinine and urine density. A significant correlation was found (p<0.01) between all matrices. Results indicate that the urine normalization by creatinine or density is unnecessary. This method is considered reliable for determining cotinine in serum and plasma of smokers and in environmental tobacco smoke exposure.

Nanoparticle platform to modulate reaction mechanism of phenothiazine photosensitizers.

Herein, we report on the synthesis of photosensitizing nanoparticles in which the generation of different oxidizing species, i.e., singlet oxygen (1O2) or radicals, was modulated. Sol gel and surface chemistry were used to obtain nanoparticles with specific ratios of dimer to monomer species of phenothiazine photosensitizers (PSs). Due to competition between the reactions involving electron transfer within dimer species and energy transfer from monomer triplets to oxygen, the efficiency of 1O2 generation could be controlled. Nanoparticles with an excess of dimer have an 1O2 generation efficiency (S(delta)) of 0.01 while those without dimer have a S(delta) value of 0.4. Furthermore, we demonstrate that the PS properties of the nanoparticles are not subjected to interference from the external medium as is commonly the case for free PSs, i.e., PS ground and triplet states are not reduced by NADH and ascorbate, respectively, and singlet excited states are less suppressed by bromide. The modulated 1O2 generation and the PS protection from external interferences make this nanoparticle platform a promising tool to aid in performing mechanistic studies in biological systems. Also, it offers potential application in technological areas in which photo-induced processes take place.

P2X7 Purinergic Receptor Is Involved in the Pathophysiology of Mania: a Preclinical Study.

The pathophysiology of bipolar disorder remains incompletely elucidated. The purinergic receptor, P2X7 (P2X7R), plays a central role in neuroinflammation, the establishment, and maintenance of microglial activation and neuronal damage/death, all characteristics of bipolar disorder pathology. The present study aims to explore the participation of the P2X7R in a preclinical pharmacological model of mania. We analyzed the modulatory effects of the P2X7R antagonist, brilliant blue, on behavior, monoamines, gene expression, serum purine levels, and cell typing in a pharmacological model of mania induced by D-amphetamine (AMPH) in mice. Our results corroborate an association between the P2X7 receptor and the preclinical animal model of mania, as demonstrated by the decreased responsiveness to AMPH in animals with pharmacologically blocked P2X7R. This study further suggests a possible dopaminergic mechanism for the action of P2X7 receptor antagonism. Additionally, we observed increased peripheral levels of adenosine, a neuroprotective molecule, and increased central expression of Entpd3 and Entpd1 leading to the hydrolysis of ATP, a danger signal, possibly as an attempt to compensate for the damage induced by AMPH. Lastly, P2X7R antagonism in the AMPH model was found to potentially modulate astrogliosis. Our results support the hypothesis that P2X7R plays a vital role in the pathophysiology of mania, possibly by modulating the dopaminergic pathway and astrogliosis, as reflected in the behavioral changes observed. Taken together, this study suggests that a purinergic system imbalance is associated with the AMPH-induced preclinical animal model of mania. P2X7R may represent a promising molecular therapeutic target for bipolar disorder.

Penile cancer: a Brazilian consensus statement for low- and middle-income countries.

PURPOSE: Penile cancer is highly prevalent in low- and middle-income countries, with significant morbidity and mortality rates. The first Brazilian consensus provides support to improve penile cancer patients' outcomes, based on expert's opinion and evidence from medical literature. METHODS: Fifty-one Brazilian experts (clinical oncologists, radiation oncologists, urologists, and pathologists) assembled and voted 104 multiple-choice questions, confronted the results with the literature, and ranked the levels of evidence. RESULTS: Healthcare professionals need to deliver more effective communication about the risk factors for penile cancer. Staging and follow-up of patients include physical examination, computed tomography, and magnetic resonance imaging. Close monitoring is crucial, because most recurrences occur in the first 2-5 years. Lymph-node involvement is the most important predictive factor for survival, and management depends on the location (inguinal or pelvic) and the number of lymph nodes involved. Conservative treatment may be helpful in selected patients without compromising oncological outcomes; however, surgery yields the lowest rate of local recurrence. CONCLUSION: This consensus provides an essential decision-making orientation regarding this challenging disease.

Molecular mapping by low-energy-loss energy-filtered transmission electron microscopy imaging.

Structure-function relationships in supramolecular systems depend on the spatial distribution of molecules, ions, and particles within complex arrays. Imaging the spatial distribution of molecular components within nanostructured solids is the objective of many recent techniques, and a powerful tool is electron spectroscopy imaging in the transmission electron microscope (ESI-TEM) in the low-energy-loss range, 0-80 eV. This technique was applied to particulate and thin film samples of dielectric polymers and inorganic compounds, providing excellent distinction between areas occupied by various macromolecules and particles. Domains differentiated by small changes in molecular composition and minor differences in elemental contents are clearly shown. Slight changes in the molecules produce intensity variations in molecular spectra that are in turn expressed in sets of low-energy-loss images, using the standard energy-filtered transmission electron microscopy (EFTEM) procedures. The molecular map resolution is in the nanometer range and very close to the bright-field resolution achieved for the same sample, in the same instrument. Moreover, contrast is excellent, even though sample exposure to the electron beam is minimal.

Rimonabant: an antagonist drug of the endocannabinoid system for the treatment of obesity.

Obesity, an ever-increasing problem in the industrialized world, has long been a target of research for a cure or, at least, control of its expansion. In the search for treatment, the recently discovered endocannabinoid system has emerged as a new target for controlling obesity and its associated conditions. The endocannabinoid system plays an important role in controlling weight and energy balance in humans. This system is activated to a greater extent in obese patients, and the specific blockage of its receptors is the aim of rimonabant, one of the most recent drugs created for the treatment of obesity. This drug acts as a blockade for endocannabinoid receptors found in the brain and peripheral organs that play an important role on carbohydrate and fat metabolism. Clinical studies have confirmed that, when used in combination with a low calorie diet, rimonabant promotes loss in body weight, loss in abdominal circumference, and improvements in dyslipidemia. Rimonabant is also being tested as a potential anti-smoking treatment since endocannabinoids are related to the pleasurable effect of nicotine. Thus, rimonabant constitutes a new therapeutic approach to obesity and cardiovascular risk factors. Studies show effectiveness in weight loss; however, side effects such as psychiatric alterations have been reported, including depression and anxiety. These side effects have led the FDA (Food and Drug Administration) to not approve this drug in the United States. For a more complete evaluation on the safety of this drug, additional studies are in progress.

Anti-inflammatory effects of red pepper (Capsicum baccatum) on carrageenan- and antigen-induced inflammation.

Inflammation is a pivotal component of a variety of diseases, such as atherosclerosis and tumour progression. Various naturally occurring phytochemicals exhibit anti-inflammatory activity and are considered to be potential drug candidates against inflammation-related pathological processes. Capsicum baccatum L. var. pendulum (Willd.) Eshbaugh (Solanaceae) is the most consumed species in Brazil, and its compounds, such as capsaicinoids, have been found to inhibit the inflammatory process. However, the anti-inflammatory effects of C. baccatum have not been characterized. Thus, this study was designed to evaluate the effects of C. baccatum juice in animal models of acute inflammation induced by carrageenan and immune inflammation induced by methylated bovine serum albumin. Pretreatment (30 min) of rats with pepper juice (0.25-2.0 g kg(-1)) significantly decreased leucocyte and neutrophil migration, exudate volume and protein and LDH concentration in pleural exudates of a pleurisy model. This juice also inhibited neutrophil migration and reduced the vascular permeability on carrageenan-induced peritonitis in mice. C. baccatum juice also reduced neutrophil recruitment and exudate levels of pro-inflammatory cytokines TNF-alpha and IL-1beta in mouse inflammatory immune peritonitis. Furthermore, we demonstrated that the main constituent of C. baccatum juice, as extracted with chloroform, is capsaicin. In agreement with this, capsaicin was able to inhibit the neutrophil migration towards the inflammatory focus. To our knowledge, this is the first demonstration of the anti-inflammatory effect of C. baccatum juice and our data suggest that this effect may be induced by capsaicin. Moreover, the anti-inflammatory effect induced by red pepper may be by inhibition of pro-inflammatory cytokine production at the inflammatory site.

Anti-Inflammatory effects of low-level laser therapy (660 nm) in the early phase in carrageenan-induced pleurisy in rat.

BACKGROUND AND OBJECTIVE: In the classic model of pleurisy there is little evidence about the anti-inflammatory effects of low-level laser therapy (LLLT) as well the dosage characteristics, such as wavelength, total energy, number and pattern of treatment. In this study we investigated the potential effects of LLLT on modulating the pro-inflammatory and anti-inflammatory mediators of acute inflammation in a rat pleurisy model. STUDY DESIGN/MATERIALS AND METHODS: A sample of 48 female Wistar rats were divided into control and experiential groups. An inflammation was induced by carrageenan (0.2 ml) injected into the pleural cavity. At 1, 2, and 3 hours after induction a continuous wave (20 mW) diode laser of the InGaAlP (660 nm) type was used in the four laser groups with different doses and treatment patterns. One group received a single dose of 2.1 J and the other three groups received a total energy of 0.9, 2.1, and 4.2 J. Four hours later the exudate volume, total and differential leukocytes, protein concentration, NO, IL-6, IL-10, TNF-alpha, and MCP-1 were measured from the aspirated liquid. RESULTS: All the treatment patterns and quantity of energy studied show significant reduction of the exudate volume (P<0.05). Using energy of 0.9 J only NO, IL-6, MCP-1 and IL-10 are significantly reduced (P<0.05). On the other hand, higher energies (2.1 and 4.2 J) significantly reduce all variables independently of the treatment pattern. The neutrophil migration has a straight correlation with the TNF-alpha (r = 0.551) and NO (r = 0.549) concentration. CONCLUSIONS: LLLT-660 nm induced an anti-inflammatory effect characterized by inhibition of either total or differential leukocyte influx, exudation, total protein, NO, IL-6, MCP-1, IL-10, and TNF-alpha, in a dose-dependent manner. Under these conditions, laser treatment with 2.1 J was more effective than 0.9 and 4.2 J.