A kinetic model of T cell autoreactivity in autoimmune diseases.

We construct a mathematical model of kinetic type in order to describe the immune system interactions in the context of autoimmune disease. The interacting populations are self-antigen presenting cells, self-reactive T cells and the set of immunosuppressive cells consisting of regulatory T cells and Natural Killer cells. The main aim of our work is to develop a qualitative analysis of the model equations and investigate the existence of biologically realistic solutions. Having this goal in mind we describe the interactions between cells during an autoimmune reaction based on biological considerations that are given in the literature and we show that the corresponding system of integro-differential equations has finite positive solutions. The asymptotic behaviour of the solution of the system is also studied. We complement our mathematical analysis with numerical simulations that study the sensitivity of the model to parameters related to proliferation of immunosuppressive cells, destruction of self-antigen presenting cells and self-reactive T cells and tolerance of SRTCs to self-antigens.

2016 update of the Portuguese recommendations for the use of biological therapies in children and adolescents with Juvenile Idiopathic Arthritis.

OBJECTIVE: To provide evidence-based guidance for the rational and safe prescription of biological therapies in children and adolescents with juvenile idiopathic arthritis (JIAs) considering the latest available evidence and the new licensed biologics. METHODS: Rheumatologists and Pediatricians with expertise in Pediatric Rheumatology updated the recommendations endorsed by the Portuguese Society of Rheumatology and the Portuguese Society of Pediatrics based on published evidence and expert opinion. The level of agreement with final propositions was voted using an online survey. RESULTS: In total, 20 recommendations to guide the use of biological therapy in children and adolescents with JIAs are issued, comprising 4 general principles and 16 specific recommendations. A consensus was achieved regarding the eligibility and response criteria, maintenance of biological therapy, and procedures in case of non-response, for each JIA category. Specific recommendations concerning safety procedures were also updated. CONCLUSIONS: These recommendations take into account the specificities of each JIA category and are intended to continuously improve the management of JIA patients.

Implication of low level inflammation in the insulin resistance of adipose tissue at late pregnancy.

Insulin resistance is a characteristic of late pregnancy, and adipose tissue is one of the tissues that most actively contributes to the reduced maternal insulin sensitivity. There is evidence that pregnancy is a condition of moderate inflammation, although the physiological role of this low-grade inflammation remains unclear. The present study was designed to validate whether low-grade inflammation plays a role in the development of insulin resistance in adipose tissue during late pregnancy. To this end, we analyzed proinflammatory adipokines and kinases in lumbar adipose tissue of nonpregnant and late pregnant rats at d 18 and 20 of gestation. We found that circulating and tissue levels of adipokines, such as IL-1ß, plasminogen activator inhibitor-1, and TNF-α, were increased at late pregnancy, which correlated with insulin resistance. The observed increase in adipokines coincided with an enhanced activation of p38 MAPK in adipose tissue. Treatment of pregnant rats with the p38 MAPK inhibitor SB 202190 increased insulin-stimulated tyrosine phosphorylation of the insulin receptor (IR) and IR substrate-1 in adipose tissue, which was paralleled by a reduction of IR substrate-1 serine phosphorylation and an enhancement of the metabolic actions of insulin. These results indicate that activation of p38 MAPK in adipose tissue contributes to adipose tissue insulin resistance at late pregnancy. Furthermore, the results of the present study support the hypothesis that physiological low-grade inflammation in the maternal organism is relevant to the development of pregnancy-associated insulin resistance.

Microadenomas hipofisarios: distintas formas de presentación / Pituitary microadenomas: different presentation forms

Los adenomas hipofisarios son tumores dependientes de la glándula pineal, que pueden ser hallazgos casuales o presentarse con clínica. Describimos tres casos de microadenomas hiposfisarios con diferente forma de debut y evolución (AU)

Pituitary adenomas are tumors dependent ton the pineal gland, which may be causal findings or occur with symptoms. We present three cases of pituitary microadenomas with different presentation forms and evolution (AU)

Revisión de los partes por lesiones emitidos en el Centro de Salud de Tres Cantos 1 a los detenidos que acudieron durante el año 2009 / No disponible

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Validation of simple indexes to assess insulin sensitivity during pregnancy in Wistar and Sprague-Dawley rats.

Insulin resistance plays a role in the pathogenesis of diabetes, including gestational diabetes. The glucose clamp is considered the gold standard for determining in vivo insulin sensitivity, both in human and in animal models. However, the clamp is laborious, time consuming and, in animals, requires anesthesia and collection of multiple blood samples. In human studies, a number of simple indexes, derived from fasting glucose and insulin levels, have been obtained and validated against the glucose clamp. However, these indexes have not been validated in rats and their accuracy in predicting altered insulin sensitivity remains to be established. In the present study, we have evaluated whether indirect estimates based on fasting glucose and insulin levels are valid predictors of insulin sensitivity in nonpregnant and 20-day-pregnant Wistar and Sprague-Dawley rats. We have analyzed the homeostasis model assessment of insulin resistance (HOMA-IR), the quantitative insulin sensitivity check index (QUICKI), and the fasting glucose-to-insulin ratio (FGIR) by comparing them with the insulin sensitivity (SI(Clamp)) values obtained during the hyperinsulinemic-isoglycemic clamp. We have performed a calibration analysis to evaluate the ability of these indexes to accurately predict insulin sensitivity as determined by the reference glucose clamp. Finally, to assess the reliability of these indexes for the identification of animals with impaired insulin sensitivity, performance of the indexes was analyzed by receiver operating characteristic (ROC) curves in Wistar and Sprague-Dawley rats. We found that HOMA-IR, QUICKI, and FGIR correlated significantly with SI(Clamp), exhibited good sensitivity and specificity, accurately predicted SI(Clamp), and yielded lower insulin sensitivity in pregnant than in nonpregnant rats. Together, our data demonstrate that these indexes provide an easy and accurate measure of insulin sensitivity during pregnancy in the rat.

Programas domiciliarios de entrenamiento al ejercicio en la epoc: lo bueno y sencillo, dos veces bueno / No disponible

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Lipid metabolism during the perinatal phase, and its implications on postnatal development.

During pregnancy, lipid metabolism plays a major role to warrant the availability of substrates to the foetus. By using different experimental designs in the rat we have been able to answer several questions that were open about the short- and long-term effects of alterations of lipid metabolism during the perinatal stage. The first one was to demonstrate the importance of maternal body fat depot accumulation during the first half of pregnancy. We found that conditions like undernutrition circumscribed to this specific period when foetal growth is still small, that impede such fat accumulation not only restrain intrauterine development but also have long-term consequences, as shown by an impaired glucose tolerance when adults. Secondly, undernutrition during suckling has major long-term effect decreasing body weight, even though food intake was kept normal from the weaning period. Present findings also show that a diet rich in omega-3 fatty acids during pregnancy and lactation has negative effects on offspring development, but cross fostered experiments showed that the effect was a consequence of the intake of these fatty acids during the lactation period rather than during pregnancy. Pups from dams that were fed a fish oil-rich diet during pregnancy and lactation were found to have altered glucose/insulin relationship at the age of 10 weeks. Since a omega-3 fatty acid-rich diet decreases milk yield during lactation, additional experiments were carried out to determine whether decreased food intake, altered dietary fatty acid composition, or both were responsible for the long-term effects on the glucose/insulin axis. Results show that the decreased food intake caused by a omega-3 fatty acid-rich diet rather than the change in milk composition during suckling was responsible for the reduced pancreatic glucose responsiveness to insulin release at 16 weeks of age. In conclusion, present findings indicate that impaired maternal fat accumulation during early pregnancy and food intake during lactation, rather than a difference in dietary fatty acid composition have a greater influence on postnatal development and affect glucose/insulin relationships in adult rats.

Experimental models for studying perinatal lipid metabolism. Long-term effects of perinatal undernutrition.

By using different experimental designs in the rat we have been able to answer several unanswered questions on the short- and long-term effects of alterations of lipid metabolism during the perinatal stage. The first was to demonstrate the importance of maternal body fat accumulation during the first half of pregnancy, since undernutrition in this critical period when fetal growth is slow, impedes fat depot accumulation and not only restrains intrauterine development but has long-term consequences, as shown by an impaired glucose tolerance when adults. Secondly, undernutrition during suckling has major long-term effect of decreasing body weight, even though food intake is kept normal from the weaning period. Our findings also show that a diet rich in n-3 fatty acids during pregnancy and lactation has adverse effects on offspring development, but cross fostered experiments showed that this effect was a consequence of the intake of these fatty acids during the lactation period rather than during pregnancy. Pups from dams that were fed a fish oil-rich diet during pregnancy and lactation were found to have altered glucose/insulin relationship at the age of 10 weeks. Since a n-3 fatty acid-rich diet decreases milk yield during lactation, additional experiments were carried out to determine whether decreased food intake or altered dietary fatty acid composition, or both, were responsible for the long-term effects on the glucose/insulin axis. Results show that the decreased food intake caused by a n-3 fatty acid-rich diet rather than the change in milk composition during suckling was responsible for the reduced pancreatic glucose responsiveness to insulin release at 16 weeks of age. In conclusion, present findings indicate that impaired maternal fat accumulation during early pregnancy and food intake during lactation, rather than a difference in dietary fatty acid composition, have major effects on postnatal development and affect glucose/insulin relationships in adult rats.

Leptin serves as an upstream activator of an obligatory signaling cascade in the embryo-implantation process.

Leptin is essential for mouse reproduction, but the exact roles it serves are yet to be determined. Treatment of cultured endometrial cells with leptin increases the level of beta3-integrin, IL-1, leukemia inhibitory factor, and their corresponding receptors. These leptin-induced effects are eliminated by inhibitors of leptin receptor (OB-R) signaling. Herein the impact of blocking leptin/OB-R signaling in the mouse endometrium was assessed. Intrauterine injection of either leptin peptide antagonists (LPA-1 or -2) or OB-R antibody on d 3 of pregnancy impaired mouse implantation in comparison to intrauterine injection of scrambled peptides (LPA-Sc) or species-matched IgGs. Significant reduction in the number of implantation sites and uterine horns with implanted embryos was found after intrauterine injection of LPA-1 (1 of 22) vs. LPA-1Sc (11 of 15) and LPA-2 (3 of 17) vs. LPA-2Sc (14 of 16). The impact of disruption of leptin signaling on the endometrial expression of several molecules in pregnant mice was assessed by Western blot, immunohistochemistry, and confocal microscopy. Disruption of leptin signaling resulted in a significant reduction of IL-1 receptor type I, leukemia inhibitory factor, vascular endothelial growth factor receptor 2, and beta3-integrin levels. The levels of colony stimulating factor-1 receptor and OB-R were unaltered after treatment with LPAs compared with controls. Expression of OB-R protein was pregnancy dependent and found only in glandular epithelium after implantation occurred. Our findings support previous observations that leptin signaling is critical to the implantation process and suggest that molecules downstream of leptin-activated receptor may serve obligatory roles in endometrial receptivity and successful implantation.

Leptin-induced increase in leukemia inhibitory factor and its receptor by human endometrium is partially mediated by interleukin 1 receptor signaling.

Leptin and leukemia inhibitory factor (LIF) have been implicated as important mediators of implantation. The present study was designed to investigate whether leptin can directly regulate the expression of LIF and its receptor (LIF-R) in human endometrial cells and/or whether leptin-induced effects are linked to, or regulated in part by IL-1 signaling. Primary endometrial cells and endometrial epithelial cell lines (HES and Ishikawa cells) were cultured for 24-48 h in a medium containing insulin (5 microg/ml) and leptin (3, 10, and 62 nm) or IL-1beta (0.6, 3, and 10 nm) in the presence or absence of cytokines and/or receptor antagonists. The endpoints included phosphorylation of signal transducer and activator of transcription 3 (STAT3) and the relative levels of LIF, LIF-R, IL-1beta, IL-1 receptor antagonist (IL-1Ra) and IL-1 receptor type I (IL-1R tI) as determined by ELISA or Western blotting techniques. Leptin treatment increases the level of phosphorylated STAT3, LIF-R, and LIF. Leptin also increases the levels of IL-1 ligand, receptor, and antagonist as was previously reported. Blockade of OB-R with antibodies or with a specific OB-R inhibitor (leptin peptide antagonist-2) abrogated leptin-induced effects, suggesting that leptin binding to its receptor activates Janus kinase 2/STAT3 signaling. Treatment of endometrial cells with IL-1beta also results in elevated levels of LIF-R. Interestingly, the inhibition of IL-1R tI with a specific antibody or with IL-1Ra negatively affects both leptin-induced and IL-1-induced effects on LIF-R levels. Abnormal endometrial LIF expression has been associated with human infertility and leptin has profound effects on the levels of LIF, IL-1, and their cognate receptors in vitro. Thus, it is tempting to speculate that leptin's role in vivo could include the regulation of other key cytokines to be fundamental to endometrial receptivity during implantation (i.e. LIF and IL-1).

Fat accumulation in the rat during early pregnancy is modulated by enhanced insulin responsiveness.

Insulin sensitivity has been implicated in the variation of fat accumulation in early gestation by as-yet-unknown mechanisms. In the present study, we analyzed the insulin sensitivity of lipolysis and lipogenesis in lumbar adipocytes from rats at 0, 7, 14, and 20 days of gestation. In adipocytes of 7-day pregnant rats, we found a twofold decrease in both beta-agonist (isoproterenol and BRL-37344)-stimulated lipolysis and beta3-adrenoceptor protein but not in lipolysis initiated by forskolin or isobutylmethylxanthine, suggesting a modification of the lipolytic pathway at the receptor level. Whereas adipocytes from 7-day pregnant rats showed a twofold increase in fatty acid synthesis from glucose, those from 20-day pregnant animals displayed a decreased lipogenic activity. Insulin responsiveness of the lipolytic and lipogenic pathways was analyzed by dose-response experiments, giving evidence for the involvement of improved insulin responsiveness in the enhanced lipogenic and reduced lipolytic activities of adipocytes in early pregnancy. In contrast, insulin resistance is responsible for lower antilipolytic and lipogenic actions of insulin in late pregnant animals. In conclusion, the present study shows that enhanced adipose tissue insulin responsiveness during early pregnancy contributes to maternal fat accumulation, whereas decreased insulin responsiveness during late gestation modulates fat breakdown.

Model of computerized academic medical clinic.

In the traditional medical graduation course, the student receives a great amount of information while training at the Outpatient Care; the student assumes the physician's role, collecting all the information regarding the patient's clinical history and learns to get along with patients as well. During the attendance process, several factors interfere in the academic teaching, such as limitations of room numbers, amount of patients, difficulties in obtaining medical records, paper illegibility, among other problems. Due to those difficulties, the Model of Computerized Academic Health Clinic, implies in a new learning paradigm in the medical practice, rethinking the traditional process of learning-attendance, where the old model, in which attendance is restricted to a place, is extended in an open atmosphere of shared knowledge, rich of computer resources. The pilot project was implanted in the Pediatrics General Health Clinic of UNIFESP/EPM. It allows that the fifth-year medical students, residents, trainees and tutors use computerized clinics, connected with the academic net of UNIFESP and to the Internet. All the computing and information resources settled at the Outpatient Care improved the organization of its services, increased the medical students' curiosity, improved their participation in learning through interactive programs and clinical attendance.

Educational program on ophthalmology.

To minimize the learning problems, related to the present teaching method, we developed the Educational Program on Ophthalmology, that offers an interactive and self-controlled way of learning, through the multimedia and hypertext (hypermedia) resources to the students. The software has 200 images (pictures and photos), 40 minutes of digitized voice (.WAV), 50 minutes of video animation (.AVI) and more than 200 links. The first evaluation demonstrated a great interest from the medical graduated students, who feel motivated with the utilization of the software.

Decision support system for individualized nursing procedures: SAPIEN-Tx.

The present work proposes a Decision Support System for nursing procedures: SAPIEN-Tx. The discussion includes the acquisition, modeling , and implementation of nursing expertise professionals in Renal Transplant. It was developed to obtain better quality healthcare services, as well as an effective contribution to the nursing professional in the global assistance of their clientele. We used the KADS methodology to develop the system knowledge base. This methodology permitted us to perform the knowledge modeling with quality and organization. In opposition to the old method, errors were detected before the implementation, avoiding possible modification on the whole project structure.

[Giant-cell myocarditis: a systemic disease? Apropos a case]. / Miocarditis de células gigantes: una enfermedad sistémica? A propósito de un caso.

Giant cell myocarditis is a rare disease of unknown etiology, which develops as a myocardial isolated affection or associated to different diseases. Its characteristics are such as necrosis, inflammation and giant cell presence in the myocardium. We present the case of a woman who suffered of giant cell myocarditis, thymoma, myasthenia gravis, chronic lymphocytic thyroiditis, giant cell myositis, granulomatous infiltration in the lymph nodes of the hilus of the lung and hypogammaglobulinemia; multiple association that we have not found in any published medical paper and that suggest the autoimmune origin of this illness. The cardiovascular symptoms and the associated diseases are revised, and we discussed the diagnostic and therapeutic topics, pointing out the necessity to take it into account for any patient with thymoma or myasthenia gravis developing to heart failure or arrhythmias.

Correlation between damping coefficients and externally injected currents in oscillations produced by lithium ions in frog skin.

Oscillations in the electrical parameters elicited by Li+ added to the mucosal side of frog skin in vitro were studied under different experimental conditions. The correlation between the damping coefficient and the size of the externally injected current was ascertained. The size of the overall epithelial resistance in NaCl-Ringer seems to be a good indicator of the qualitative behaviour of the skin in the presence of Li+: the higher the resistance the less probable the occurrence of oscillations. Addition of amiloride allowed the calculation of the electromotive force in Na+- and Li+-Ringer. Calculations of the 'total equivalent inductance' and 'total equivalent capacitance' of an oscillating skin were made using resistance values (R), damping coefficients (sigma) and frequency of oscillation (omega).