The idiopathic inflammatory myopathies module of the Rheumatic Diseases Portuguese Register.

AIMS: To characterise the idiopathic inflammatory myopathies (IIM) module of the Rheumatic Diseases Portuguese Register (Reuma.pt/myositis) and the patients in its cohort. METHODS: Reuma.pt is a web-based system with standardised patient files gathered in a registry. This was a multicentre open cohort study, including patients registered in Reuma.pt/myositis up to January 2022. RESULTS: Reuma.pt/myositis was designed to record all relevant data in clinical practice and includes disease-specific diagnosis and classification criteria, clinical manifestations, immunological data, and disease activity scores. Two hundred eighty patients were included, 71.4% female, 89.4% Caucasian, with a median age at diagnosis and disease duration of 48.9 (33.6-59.3) and 5.3 (3.0-9.8) years. Patients were classified as having definite (N=57/118, 48.3%), likely (N=23/118, 19.5%), or possible (N=2/118, 1.7%) IIM by 2017 EULAR/ACR criteria. The most common disease subtypes were dermatomyositis (DM, N=122/280, 43.6%), polymyositis (N=59/280, 21.1%), and myositis in overlap syndromes (N=41/280, 14.6%). The most common symptoms were proximal muscle weakness (N=180/215, 83.7%) and arthralgia (N=127/249, 52.9%), and the most common clinical signs were Gottron's sign (N=75/184, 40.8%) and heliotrope rash (N=101/252, 40.1%). Organ involvement included lung (N=78/230, 33.9%) and heart (N=11/229, 4.8%) involvements. Most patients expressed myositis-specific (MSA, N=158/242, 65.3%) or myositis-associated (MAA, 112/242, 46.3%) antibodies. The most frequent were anti-SSA/SSB (N=70/231, 30.3%), anti-Jo1 (N=56/236, 23.7%), and anti-Mi2 (N=31/212, 14.6%). Most patients had a myopathic pattern on electromyogram (N=101/138, 73.2%), muscle oedema in magnetic resonance (N=33/62, 53.2%), and high CK (N=154/200, 55.0%) and aldolase levels (N=74/135, 54.8%). Cancer was found in 11/127 patients (8.7%), most commonly breast cancer (N=3/11, 27.3%). Most patients with cancer-associated myositis had DM (N=8/11, 72.7%) and expressed MSA (N=6/11) and/or MAA (N=3/11). The most used drugs were glucocorticoids (N=201/280, 71.8%), methotrexate (N=117/280, 41.8%), hydroxychloroquine (N=87/280, 31.1%), azathioprine (N=85/280, 30.4%), and mycophenolate mofetil (N=56/280, 20.0%). At the last follow-up, there was a median MMT8 of 150 (142-150), modified DAS skin of 0 (0-1), global VAS of 10 (0-50) mm, and HAQ of 0.125 (0.000-1.125). CONCLUSIONS: Reuma.pt/myositis adequately captures the main features of inflammatory myopathies' patients, depicting, in this first report, a heterogeneous population with frequent muscle, joint, skin, and lung involvements.

Predictors of cardiac involvement in idiopathic inflammatory myopathies.

Objectives: Idiopathic inflammatory myopathies (IIM) are a group of rare disorders that can affect the heart. This work aimed to find predictors of cardiac involvement in IIM. Methods: Multicenter, open cohort study, including patients registered in the IIM module of the Rheumatic Diseases Portuguese Register (Reuma.pt/Myositis) until January 2022. Patients without cardiac involvement information were excluded. Myo(peri)carditis, dilated cardiomyopathy, conduction abnormalities, and/or premature coronary artery disease were considered. Results: 230 patients were included, 163 (70.9%) of whom were females. Thirteen patients (5.7%) had cardiac involvement. Compared with IIM patients without cardiac involvement, these patients had a lower bilateral manual muscle testing score (MMT) at the peak of muscle weakness [108.0 ± 55.0 vs 147.5 ± 22.0, p=0.008] and more frequently had oesophageal [6/12 (50.0%) vs 33/207 (15.9%), p=0.009] and lung [10/13 (76.9%) vs 68/216 (31.5%), p=0.001] involvements. Anti-SRP antibodies were more commonly identified in patients with cardiac involvement [3/11 (27.3%) vs 9/174 (5.2%), p=0.026]. In the multivariate analysis, positivity for anti-SRP antibodies (OR 104.3, 95% CI: 2.5-4277.8, p=0.014) was a predictor of cardiac involvement, regardless of sex, ethnicity, age at diagnosis, and lung involvement. Sensitivity analysis confirmed these results. Conclusion: Anti-SRP antibodies were predictors of cardiac involvement in our cohort of IIM patients, irrespective of demographical characteristics and lung involvement. We suggest considering frequent screening for heart involvement in anti-SRP-positive IIM patients.

Sex differences in axial spondyloarthritis: data from a Portuguese spondyloarthritis cohort.

BACKGROUND: Axial spondyloarthritis (axSpA), particularly ankylosing spondylitis was historically considered a male's disease and has been under-recognized in women. Emerging evidence reveals sex differences in pathophysiology, disease presentation and therapeutic efficacy. OBJECTIVE: To identify differences between sexes in a Portuguese cohort of patients with axSpA regarding clinical manifestations, disease activity, functional capacity, patient related outcomes and presence of sacroiliitis on x-ray or magnetic resonance imaging. METHODS: Patients with ≥18 years fulfilling the ASAS- Assessment of Spondyloarthritis International Society classification criteria for axSpA registered in the electronic Rheumatic Diseases Portuguese Register (Reuma.pt) were included in this multicentric cross-sectional study. Sociodemographic data, clinical features and imaging were collected from the first record in Reuma.pt. These variables were compared between sexes using Mann-Whitney test and Chi-Square test. Variables with a significant association with variable sex were considered in the multiple variable analysis to adjust the sex effect on the outcome variables. Statistical analysis was performed with R version 4.0.2 and p <0.05 was considered statistically significant. RESULTS: A total of 1995 patients were included, 1114 (55.9%) men and 881 (44.1%) women. Men had an earlier disease onset (25.1 vs 28.4, p <0.001), were younger at diagnosis (26.9 vs 30.4, p<0.001) and were more frequently smokers (32.1% vs 15.7%, p <0.001). Comparing to women, men had worse Bath Ankylosing Spondylitis Metrological Index scores (4.0 vs 3.4, p<0.001), higher levels of C-Reactive Protein (10.5 vs 6.9 mg/L, p <0.001) and were more often Human Leukocyte Antigen-B27 positive (67.8% vs 54%, p <0.001). In contrast, women more frequently had inflammatory bowel disease (8.8% vs 4.9%, p =0.004), higher levels of erythrocyte sedimentation rate (25.0 vs 21.0mm/h, p=0.003) and worse patient-related outcomes- Bath Ankylosing Spondylitis Disease Activity Index (5.7 vs 4.5, p<0.001), Patient Global Assessment (60.0 vs 50.0, p <0.001) and fatigue (6.2 vs 5.0, p <0.001). DISCUSSION: In this large multicentric study from a Portuguese axSpA cohort, we confirmed sex differences in patients with axSpA. This work brings awareness to these differences, resulting in less underdiagnosis and misdiagnosis, optimizing treatment strategies, and improving outcomes in axSpA.

Gestational syphilis in the low amazon mesoregion, Brazil, 2008 - 2018 / Sífilis gestacional en mesorregión del bajo amazonas, Brasil, 2008 ­ 2018

Objective: to trace the epidemiological profile of gestational syphilis reported cases in the Low Amazon mesoregion in the period between 2008 and 2018. Materials and Methods: the study was epidemiological, observational, descriptive, retrospective, cross-sectional, and carried out by a quantitative approach. The variables were sociodemographic and epidemiological, and data was available by the Ministry of Health in line with the Department of Surveillance, Prevention, and Control of Sexually Transmitted Infections and Viral Hepatitis. The collected data were tabulated and processed with the aid of Microsoft Excel® 2010 and Action 3.7. Results: when characterizing the epidemiological profile, 949 cases were observed, which did not present normality; an average of 86.3 notifications per year; a median of 81; and a standard deviation of 47.6. The year 2017 stood out with 22.3% of notifications and the average age group was 24 years old. The race/color "brown" predominated with 87.6% and 42.7% did not have completed elementary school. The clinical classification that presented the highest records was "Primary Syphilis" with 49% and gestational age was "Third Trimester" with 50.3% of cases. The most adopted treatment regimen was Penicillin with 82.1%. There were ignored variables in the notification. Conclusion: given the results, it is clear that gestational syphilis is a public health problem in health care for women. Thus, this study can be used as a basis for public agencies to direct projects aimed at prevention and awareness about the consequences generated by the disease..Au

Objetivo: describir el perfil epidemiológico de los casos notificados de sífilis gestacional en la región del Bajo Amazonas de 2008 a 2018. Materiales y métodos: el estudio fue epidemiológico, observacional, descriptivo, transversal, con enfoque cuantitativo. Las variables eran sociodemográficas y epidemiológicas, y los datos fueron facilitados por el Ministerio de Salud de conformidad con el Departamento de Vigilancia, Prevención y Control de las Infecciones de Transmisión Sexual y las Hepatitis Virales. Los datos recogidos fueron tabulados y procesados con la ayuda de Microsoft Excel® 2010 y Action 3.7. Resultados: en la caracterización del perfil epidemiológico se observaron un total de 949 casos que no mostró normalidad, un promedio de 86,3 notificaciones por año, una mediana de 81 y una desviación estándar de 47,6. El año 2017 se destacó, con un 22,3% de las notificaciones. El promedio de edad era de 24 años. La raza/color "Marrón" predominaba con el 87,6% y el 42,7% no había completado la escuela primaria. La clasificación clínica con mayor número de registros fue "Sífilis primaria" con el 49% y la edad gestacional fue el "Tercer trimestre" con el 50,3% de los casos. El esquema de tratamiento más adoptado fue la penicilina con un 82,1%. Hubo variables ignoradas en la notificación. Conclusión: dado esto, está claro que la sífilis gestacional es un problema de salud pública en la atención de la salud de las mujeres. Por lo tanto, este estudio puede usarse como base para que las agencias públicas dirijan proyectos dirigidos a la prevención y la conciencia de las consecuencias generadas por la enfermedad..Au

Treatment of persistent cutaneous atrophy after corticosteroid injection with fat graft / Tratamiento de la atrofia e hipopigmentación cutánea secundaria a infiltración de corticosteroides con injerto de grasa

Subcutaneous fat atrophy and hypopigmentation are potential adverse side effects of local corticosteroid injection that may resolve spontaneously within 1-2 years. This report shows that fat grafting provides a simple, effective and safe correction of corticosteroid induced cutaneous atrophy with very satisfying esthetic and functional results

La atrofia de la grasa subcutánea y la despigmentación de la piel son efectos secundarios adversos potenciales de la inyección local de corticosteroides que pueden resolverse espontáneamente en 1-2 años. Este caso muestra que el injerto de grasa proporciona una corrección simple, eficaz y segura de estas complicaciones con resultados estéticos y funcionales muy satisfactorios

Treatment of Persistent Cutaneous Atrophy After Corticosteroid Injection With Fat Graft.

Subcutaneous fat atrophy and hypopigmentation are potential adverse side effects of local corticosteroid injection that may resolve spontaneously within 1-2 years. This report shows that fat grafting provides a simple, effective and safe correction of corticosteroid induced cutaneous atrophy with very satisfying esthetic and functional results.

Biologic therapy use and pregnancy outcomes in women with immune-mediated inflammatory rheumatic diseases.

INTRODUCTION: Concerns about the side effects and interactions of biologic drugs with reproduction and pregnancy have been always an issue between experts. The safety of these therapies during conception and/or pregnancy is not fully understood. The aim of this study was to assess the exposure to biologic drugs before and/or during conception/pregnancy and the risk of adverse pregnancy outcomes in women with rheumatic diseases. METHODS: We conducted a cohort study of pregnancies reported in women with immune-mediated rheumatic diseases registered at the Rheumatic Diseases Portuguese Registry (Reuma.pt) and exposed to biologic drugs. Data concerning fetal and maternal outcomes (live birth, spontaneous abortion, neonatal and intrauterine death, intrauterine growth restriction, premature delivery, congenital malformations, neonatal lupus, voluntary or medical interruption of pregnancy, disease flares and need for treatment with other drugs) was extracted. RESULTS: In total, 69 pregnancies from 56 females were analysed, the majority with the diagnosis of spondyloarthritis or rheumatoid arthritis. In almost half of the cases (n=32, 46.4%) the biologic was stopped for pregnancy planning, in 31 cases (44.9%) it was stopped when pregnancy was diagnosed and in 6 pregnancies (8.7%) biologic therapy was maintained, at least until the 2nd trimester. There were 76.8% of live births and 22% of spontaneous abortions. Congenital anomalies were reported in 2 newborns. CONCLUSIONS: In half cases, it was decided to stop biologic therapy in the family planning period. Using biologic disease-modifying anti-rheumatic drugs before and/or during pregnancy doesn't seem to affect the overall maternal and fetal outcomes. Pregnancy planning and treatment options should be discussed and a shared decision should be established between physician and patient.

Posterior Ankle Impingement Syndrome / Síndrome del choque posterior del tobillo

No disponible

Caffeic Acid Phenethyl Ester (CAPE) Protects PC12 Cells from Cisplatin-Induced Neurotoxicity by Activating the NGF-Signaling Pathway.

Cisplatin is a highly effective chemotherapeutic drug that is toxic to the peripheral nervous system. Findings suggest that axons are early targets of the neurotoxicity of cisplatin. Although many compounds have been reported as neuroprotective, there is no effective treatment against the neurotoxicity of cisplatin. Caffeic acid phenethyl ester (CAPE) is a propolis component with neuroprotective potential mainly attributed to antioxidant and anti-inflammatory mechanisms. We have recently demonstrated the neurotrophic potential of CAPE in a cellular model of neurotoxicity related to Parkinson's disease. Now, we have assessed the neurotrophic and neuroprotective effects of CAPE against cisplatin-induced neurotoxicity in PC12 cells. CAPE (10 µM) attenuated the inhibition of neuritogenesis and the downregulation of markers of neuroplasticity (GAP-43, synapsin I, synaptophysin, and 200-kD neurofilament) induced by cisplatin (5 µM). This concentration of cisplatin does not affect cell viability, and it was used in order to assess the early neurotoxic events triggered by cisplatin. When a lethal dose of cisplatin was used (IC50 = 32 µM), CAPE (10 µM) increased cell viability. The neurotrophic effect of CAPE is not dependent on NGF nor is it additive to the effect of NGF, but it might involve the activation of the NGF-high-affinity receptors (trkA). The involvement of other neurotrophin receptors such as trkB and trkC is unlikely. This is the first study to demonstrate the protective potential of CAPE against the neurotoxicity of cisplatin and to suggest the involvement of trkA receptors in the neuroprotective mechanism of CAPE. Based on these findings, the beneficial effect of CAPE on cisplatin-induced peripheral neuropathy should be further investigated.

Vulnerabilidades às Infecções Sexualmente Transmissíveis de mulheres privadas de liberdade em Santarém-Pará / Vulnerabilities to Sexually Transmitted Infections of Women Deprived of Liberty in Santarém-Pará

Introdução: As Infecções Sexualmente Transmissíveis (IST) estão entre um dos problemas de saúde mais comuns em todo o mundo e ainda se desconhece sua magnitude, pois do vasto elenco de infecções, apenas a sífilis e a aids são organizadas e contabilizadas estatisticamente, por isso compreender a vulnerabilidade de mulheres em situação de cárcere às IST requer examinar a temática pela lente do estudo de vulnerabilidade em saúde, em intersecção com o direito. Objetivo: analisar a vulnerabilidade às IST de mulheres privadas de liberdade em Santarém-Pará. Método: Esta pesquisa é caracterizada como estudo de caso, exploratório, descritivo, com corte transversal, com abordagem quantitativa e qualitativa. Foi realizada no Complexo Prisional de Santarém, Pará, com 62 mulheres, por meio da aplicação de questionários, entrevistas semiestruturadas, realização de testes rápidos para HIV, Hepatite B e C, Sífilis e exames citopatológicos, no período de setembro de 2016 a fevereiro de 2017. Os dados quantitativos foram analisados por meio do programa SPSS, com teste qui quadrado e correlação de Pearson e os dados qualitativos foram organizados com auxílio do software Nvivo, e analisados pelo método de Análise de Conteúdo, tendo sido identificada três categorias: 1 - Conhecimento das mulheres sobre Infecções Sexualmente Transmissíveis; 2 Identificação das Infecções Sexualmente Transmissíveis como problema no sistema prisional; 3 - Atenção em saúde no Sistema Prisional. Propôs-se uma matriz de análise para o objeto do estudo com base no conceito de vulnerabilidade em saúde, elencando os marcadores de vulnerabilidade extraídos dos resultados. Resultados: Nesta perspectiva, os resultados evidenciam que 56,5% das mulheres têm baixa escolaridade, 91,9% se autodeclararam pardas e negras, 59,7% encontram-se na faixa etária de 21 a 40 anos, 71% estão presas por tráfico de drogas, 45,2% afirmam que o direito a saúde não lhes é assegurado, 40,3% não usam preservativo por dificuldade de uso com o parceiro. As mulheres têm conhecimentos acertados sobre as IST, suas formas de transmissão e prevenção, reforçam a importância da não discriminação aos portadores de IST, dividem opiniões quanto a IST ser um problema no sistema penal, destacam que os atendimentos em saúde são realizados de forma pontual por meio de ações de prevenção e proteção, por instituições em parceira com o sistema penal e, que não acontecem de forma programática. A partir dos dados empíricos, outros marcadores de vulnerabilidade às IST foram agregados em uma matriz de análise e divididos nas três dimensões de vulnerabilidade, com destaque, àqueles que tratam do direito das mulheres privadas de liberdade. Conclusão: Constatou-se que as mulheres privadas de liberdade estão vulneráveis nas três dimensões e que as condições físicas que são oferecidas no complexo prisional não são aquelas determinadas pela Constituição Federal e pela Lei de Execução Penal, violando assim o princípio da dignidade da pessoa humana. Faz-se necessário reconhecer as mulheres em privação de liberdade como sujeito de direito. E para tal, é fundamental que elas tenham condições dignas e oportunidades de promoção e proteção da saúde, bem como atendimento dentro dos princípios garantidos pelas políticas públicas, de acessibilidade, integralidade, resolutividade e humanização da assistência em saúde.

Introduction: Sexually transmitted infections (STI) are among the most common health problems worldwide and its magnitude is still unknown, because of the vast array of infections, only syphilis and aids are organized and statistically recorded, so understanding the vulnerability of women in prison to STI requires examining the theme through the lens of the health vulnerability study, intersecting with the law. Objective: to analyze the vulnerability to STI of women deprived of liberty in Santarém-Pará. Method: This research is characterized as a case study, exploratory, descriptive, with cross-section, with quantitative and qualitative approach. Was carried out in the Prison Complex of Santarém, Pará, Brazil, with 62 women, through the application of questionnaires, semi-structured interviews, rapid tests for HIV, Hepatitis B and C, syphilis and cytopathological exams from September 2016 to February 2017. The quantitative data were analyzed through the SPSS program, with chi-square test and Pearson's correlation, and the qualitative data were organized using the software Nvivo, and analyzed by the Content Analysis method, and three categories were identified: 1 - Women's knowledge of Sexually Transmitted Infections; 2 - Identification of Sexually Transmitted Infections as a problem in the prison system; 3 - Health care in the Prison System. An analysis matrix was proposed for the study object based on the concept of vulnerability in health, listing the vulnerability markers extracted from the results. Results: In this perspective, the results show that 56.5% of the women have low levels of schooling, 91.9% they declared themselves brown and black, 59.7% are between the ages of 21 and 40, 71% are arrested for drug trafficking, 45.2% say that the right to health is not guaranteed, 40.3% do not use condoms because of difficulties in using their partner. Women have a good knowledge of STI, their forms of transmission and prevention, they reinforce the importance of non-discrimination to STI patients, they share opinions about STI being a problem in the penal system, they point out that health care is carried out in a timely manner by means of preventive and protective actions, by institutions in partnership with the penal system, which do not happen in a programmatic way. From the empirical data, other STI vulnerability markers were aggregated into an analysis matrix and divided into the three dimensions of vulnerability, in particular, those who deal with the right of women deprived of their liberty. Conclusion: It was found that women deprived of liberty are vulnerable in all three dimensions and that the physical conditions that are offered in the prison complex are not those determined by the Federal Constitution and the Criminal Execution Law, thus violating the principle of the dignity of the human person. It is necessary to recognize women in deprivation of liberty as a subject of rights. And for this, it is fundamental that they have decent conditions and opportunities for health promotion and protection, as well as care within the principles guaranteed by public policies, accessibility, comprehensiveness, resolution and humanization of health care.

B-cell phenotype and IgD-CD27- memory B cells are affected by TNF-inhibitors and tocilizumab treatment in rheumatoid arthritis.

BACKGROUND: The use of TNF-inhibitors and/or the IL-6 receptor antagonist, tocilizumab, in rheumatoid arthritis (RA) have pleiotropic effects that also involve circulating B-cells. The main goal of this study was to assess the effect of TNF-inhibitors and tocilizumab on B-cell phenotype and gene expression in RA. METHODS: Blood samples were collected from untreated early RA (ERA) patients, established RA patients under methotrexate treatment, established RA patients before and after treatment with TNF-inhibitors and tocilizumab, and healthy donors. B-cell subpopulations were characterized by flow cytometry and B-cell gene expression was analyzed by real-time PCR on isolated B-cells. Serum levels of BAFF, CXCL13 and sCD23 were determined by ELISA. RESULTS: The frequency of total CD19+ B cells in circulation was similar between controls and all RA groups, irrespective of treatment, but double negative (DN) IgD-CD27- memory B cells were significantly increased in ERA and established RA when compared to controls. Treatment with TNF-inhibitors and tocilizumab restored the frequency of IgD-CD27- B-cells to normal levels, but did not affect other B cell subpopulations. TACI, CD95, CD5, HLA-DR and TLR9 expression on B-cells significantly increased after treatment with either TNF-inhibitors and/ or tocilizumab, but no significant changes were observed in BAFF-R, BCMA, CD69, CD86, CXCR5, CD23, CD38 and IgM expression on B-cells when comparing baseline with post-treatment follow-ups. Alterations in B-cell gene expression of BAFF-R, TACI, TLR9, FcγRIIB, BCL-2, BLIMP-1 and ß2M were found in ERA and established RA patients, but no significant differences were observed after TNF-inhibitors and tocilizumab treatment when comparing baseline and follow-ups. Serum levels of CXCL13, sCD23 and BAFF were not significantly affected by treatment with TNF-inhibitors and tocilizumab. CONCLUSIONS: In RA patients, the use of TNF-inhibitors and/ or tocilizumab treatment affects B-cell phenotype and IgD-CD27- memory B cells in circulation, but not B-cell gene expression levels.

Anti-müllerian hormone and ovarian reserve in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic immune-mediated inflammatory disease that affects predominantly females during childbearing age (Lateef and Petri Best Pract Res Clin Rheumatol 27(3):435-447, 2013). Fertility in SLE patients is considered to be normal (Clowse et al. Arthritis Care Res (Hoboken) 64(5):668-674, 2012; Ekblom-Kullberg et al. Scand J Rheumatol 38:375-380, 2009) but several known factors may negatively influence fertility. Immune mechanisms are also thought to be an important cause of premature ovarian senescence, characterized by reduced ovarian reserve markers such as anti-Müllerian hormone (AMH) (Oktem et al. Obstet Gynecol Surv 70(3):196-210, 2015; Bermas and Sammaritano Fertil Res Pract 1:13, 2015; Østensen Int J Clin Rheumtol 8(1):27-37, 2013; Ulug et al. Am J Reprod Immunol 72(1):85-88, 2014; Lawrenz et al. Lupus 20(11):1193-1197, 2011). We evaluated the ovarian reserve of women in reproductive age with SLE, by measuring AMH levels and we compared it to that of non-SLE women. We also analyzed the association of SLE disease characteristics with AMH levels. AMH levels were decreased in this population of SLE women, accounting for a high proportion of women with criteria for low ovarian reserve. Age and SLE damage were associated with abnormally lower AMH levels in our SLE patients. In this way, SLE may have a negative influence on the ovarian reserve.

High-resolution structure of a Kazal-type serine protease inhibitor from the dengue vector Aedes aegypti.

Blood-feeding exoparasites are rich sources of protease inhibitors, and the mosquito Aedes aegypti, which is a vector of Dengue virus, Yellow fever virus, Chikungunya virus and Zika virus, is no exception. AaTI is a single-domain, noncanonical Kazal-type serine proteinase inhibitor from A. aegypti that recognizes both digestive trypsin-like serine proteinases and the central protease in blood clotting, thrombin, albeit with an affinity that is three orders of magnitude lower. Here, the 1.4 Šresolution crystal structure of AaTI is reported from extremely tightly packed crystals (∼22% solvent content), revealing the structural determinants for the observed inhibitory profile of this molecule.

O “Pequeno Hans” lança luz sobre os paradoxos da sexuação do sujeito / Little Hans enlighten us about the paradox of sexuality

Apresentamos algumas posições paradoxais na sexuação do sujeito, relacionadas à experiência analítica de Hans, tomando como paradigma o complexo de Édipo e o complexo de castração. A pulsão é, assim, a mola que faz avançar esse caso clínico. E, na verdade, o que vai definir essa posição heterossexual apassivada de Hans é a topologia do circuito pulsional fazendo uso dos recursos de língua, que está subordinada a uma gramática e não hesita em se fundar em algo que só tem pertinência a certos sistemas linguísticos, que a declina pelas três vozes: ativa, passiva e reflexiva, no nível da pulsão escópica, do ver e ser visto. O objeto aqui é o olhar nos três tempos lógicos do verbo: ativo (eu olho), reflexiva (me olham) e passiva (sou olhado), nesse circuito pulsional do exibicionismo no qual o próprio corpo é objeto de gozo. A heterossexualidade apassivada de Hans se define por uma identificação ao desejo da mãe, ocupa o lugar de falo imaginário da mãe – a mãe desejava ter uma menina. Freud diz que o sujeito “narcisista é, através da identificação, substituído por outro ego estranho”. “O que se olha é aquilo que não se pode ver”(AU)

We present some paradoxical positions on the subject’s sexuality, related to analytical experience of Hans, taking as paradigm the Oedipus complex and the castration complex. The drive is, therefore, the spring which will advance this case. And, in fact, what will set this straight passive position of Hans is the drive circuit topology making use of language resources, which contain a grammar and does not hesitate in foundation something that only has relevance to certain linguistic systems, which conjugates in three voices: active, passive and reflexive, at the level of the scopic pulsion, see and be seen. The object here is to look into three logical times of: active (I look), reflective (look at me) and passive (I’m looked at), this drive circuit of exhibitionism in which the body itself is the subject of jouissance. Hans’ passive heterosexuality is defined by an ID to the desire towards the mother and it wants to take the place of the mother’s imaginary phallus – the mother wished she had a girl. Freud says that the subject “is narcissist, by identification, replaced by another unknown ego”. “What you look at is what you cannot see”(AU)

Multilayered membranes with tuned well arrays to be used as regenerative patches.

Membranes have been explored as patches in tissue repair and regeneration, most of them presenting a flat geometry or a patterned texture at the nano/micrometer scale. Herein, a new concept of a flexible membrane featuring well arrays forming pore-like environments to accommodate cell culture is proposed. The processing of such membranes using polysaccharides is based on the production of multilayers using the layer-by-layer methodology over a patterned PDMS substrate. The detached multilayered membrane exhibits a layer of open pores at one side and a total thickness of 38±2.2µm. The photolithography technology used to produce the molds allows obtaining wells on the final membranes with a tuned shape and micro-scale precision. The influence of post-processing procedures over chitosan/alginate films with 100 double layers, including crosslinking with genipin or fibronectin immobilization, on the adhesion and proliferation of human osteoblast-like cells is also investigated. The results suggest that the presence of patterned wells affects positively cell adhesion, morphology and proliferation. In particular, it is seen that cells colonized preferentially the well regions. The geometrical features with micro to sub-millimeter patterned wells, together with the nano-scale organization of the polymeric components along the thickness of the film will allow to engineer highly versatile multilayered membranes exhibiting a pore-like microstructure in just one of the sides, that could be adaptable in the regeneration of multiple tissues. STATEMENT OF SIGNIFICANCE: Flexible multilayered membranes containing multiple micro-reservoirs are found as potential regenerative patches. Layer-by-layer (LbL) methodology over a featured PDMS substrate is used to produce patterned membranes, composed only by natural-based polymers, that can be easily detached from the PDMS substrate. The combination of nano-scale control of the polymeric organization along the thickness of the chitosan/alginate (CHT/ALG) membranes, provided by LbL, together with the geometrical micro-scale features of the patterned membranes offers a uniqueness system that allows cells to colonize 3-dimensionally. This study provides a promising strategy to control cellular spatial organization that can face the region of the tissue to regenerate.

The cannabinoid beta-caryophyllene (BCP) induces neuritogenesis in PC12 cells by a cannabinoid-receptor-independent mechanism.

Beta-caryophyllene (BCP) is a phytocannabinoid whose neuroprotective activity has been mainly associated with selective activation of cannabinoid-type-2 (CB2) receptors, inhibition of microglial activation and decrease of inflammation. Here, we addressed the potential of BCP to induce neuritogenesis in PC12 cells, a model system for primary neuronal cells that express trkA receptors, respond to NGF and do not express CB2 receptors. We demonstrated that BCP increases the survival and activates the NGF-specific receptor trkA in NGF-deprived PC12 cells, without increasing the expression of NGF itself. The neuritogenic effect of BCP in PC12 cells was abolished by k252a, an inhibitor of the NGF-specific receptor trkA. Accordingly, BCP did not induce neuritogenesis in SH-SY5Y neuroblastoma cells, a neuronal model that does not express trkA receptors and do not respond to NGF. Additionally, we demonstrated that BCP increases the expression of axonal-plasticity-associated proteins (GAP-43, synapsin and synaptophysin) in PC12 cells. It is known that these proteins are up-regulated by NGF in neurons and neuron-like cells, such as PC12 cells. Altogether, these findings suggest that BCP activates trka receptors and induces neuritogenesis by a mechanism independent of NGF or cannabinoid receptors. This is the first study to show such effects of BCP and their beneficial role in neurodegenerative processes should be further investigated.