Graves' disease induced by Alemtuzumab in relapsing-remitting multiple sclerosis patients: an observational study in a reference center.

OBJECTIVES: Graves' disease induced by Alemtuzumab (GD-IA) is one of the most frequently observed adverse events in patients with multiple sclerosis (MS) treated with this drug. The aim of this study is the sequencing and description of these events, along with the identification of the risk factors leading to their development. MATERIALS AND METHODS: We conducted a retrospective observational study identifying patients with relapsing-remitting multiple sclerosis (RRMS) and GD-IA, studying their baseline clinical features and variables related to the natural history of the disease. RESULTS: A total of 121 participants treated with Alemtuzumab were included, of whom 41 developed GD-IA (33.9%). A higher percentage of first-degree relatives with autoimmune thyroid disease was documented in the subgroup who developed the abovementioned event (14.6% vs 1.5%; p < 0.01). A total of 70.7% of patients diagnosed with GD-IA (n = 29/41) had fluctuations in thyroid function during follow-up, and 24.4% (n = 10/41) required total thyroidectomy for resolution of the condition. In 54.8% of participants diagnosed with GD-IA, a pattern of significant TSH decline was identified in the month prior to diagnosis of the event, with high predictive ability and associated with a more favorable clinical course (fewer weeks to normalization of thyroid function, HR = 8.99; 95% CI [2.11-38.44]; p = 0.0003). CONCLUSION: GD-IA has an atypical course compared to classical forms of the disease. The identification of risk factors for the development of the disease before starting treatment with Alemtuzumab and early monitoring of thyroid function once this treatment is initiated prove to be useful strategies in the diagnosis and clinical management of this condition.

An approach to evaluating and benchmarking the mechanical behavior of a surgical mesh prototype designed for the repair of abdominal wall defects.

Ventral hernia repair is a common surgical procedure in abdominal surgery in which surgical mesh has become an essential tool to improve outcomes. To avoid recurrences the mesh needs to mimic the mechanical behavior of the abdominal wall. In this scenario the mechanical properties at the interface between the mesh and its surrounding tissue is critical for the performance of the device and, therefore, the success after surgery. We aimed to characterize and compare the mechanical behavior of the patented prototype mesh Spider and four commercial meshes at the mesh-tissue interface. The prototype mesh was designed based on the hypothesis that the best performance for a large-sized defect in a ventral hernia is obtained when the mesh presents an isotropic behavior. In contrast, commercial meshes presented significant anisotropic behavior. Mechanical properties of the meshes were characterized through uniaxial tensile tests. Longitudinal and transverse axes were defined for each mesh, and samples were cut in each axis orientation. Samples underwent uniaxial tensile testing, from which the elastic modulus in each axis was determined. The degree of anisotropy was calculated as the ratio between the elastic modulus in each axis. An in silico model of the ventral hernia defect was designed to simulate the mesh-tissue interface behavior via finite element method. Meshes were modeled by an hyperelastic orthotropic constitutive model, which allowed isotropic symmetry as particular case for the prototype mesh. Abdominal wall was modeled using a Neo-Hookean model. Once the simulations were launched, mesh-tissue interface behavior was evaluated through the difference between Von Mises stress values on either size of the interface, both on the external and the internal face of the mesh and abdominal wall. Mechanical response was anisotropic for all commercial meshes and isotropic for the Spider prototype. Among commercial, Ultrapro® was highly anisotropic. Tests revealed Gore-Tex® to be the stiffest, followed by Repol Angimesh®, Spider and Ultrapro®; Duramesh™  was found to be the most compliant. Concerning mesh-tissue behavior, simulation results revealed the Spider prototype and Duramesh™  to be the best; Spider due to its uniformity and lower stress difference thanks to its nearly isotropic behavior, and Duramesh™  due to its compliant behavior. Our results suggest that the compromise between stiffness and anisotropy must be considered in order to improve the mechanical performance of the meshes, bearing in mind that for large-sized ventral defects, nearly isotropic mesh ensures better performance.

Metabolizing profile of the cytochrome pathway CYP2D6, CYP3A4 and the ABCB 1 transporter in Spanish patients affected by Gaucher disease.

Several therapeutic options are available for type 1 Gaucher disease (GD1), including enzymatic replacement therapy (ERT) and substrate reduction therapy (SRT). Eliglustat is a selective inhibitor of glucosylceramide synthase that is extensively metabolized by CYP2D6 and, to a lesser extent by CYP3A4; it is also an inhibitor of the P-gp transporter. The aim of this study is to evaluate the metabolizer profile of these cytochrome isoforms in 61 GD1 patients, and to analyze interferences with concomitant therapies. Patients were selected from the Spanish Gaucher Disease Registry considering clinical data, GBA genotype, severity score index, comorbidities, concomitant drugs, type and response to therapy and adverse effects. The polymorphisms of CYP2D6, CYP3A4 and three ABCB1 transporter variants were analyzed by Polymerase Chain Reaction (PCR). The most frequent metabolizer profile was extensive or intermediate for CYP2D6, extensive for CYP3A4*1B and CYP3A4*22 and normal activity for ABCB1. Correlations between metabolizer profile and other variables were analyzed by multiple regression study. Twenty-eight patients received ERT, 17 eliglustat and seven miglustat. Forty-two patients (68.8%) had associated diseases and 54.5% were taking daily concomitant medication. Nine patients under eliglustat therapy received concomitant drugs that interact with the CYPs and/or ABCB1, five of these did not reach therapeutic goals and three presented mild or moderate adverse effects (headache and gastrointestinal disorders). Detailed analysis in four patients with TTT haplotype, corresponding to lack of activity of the transporter, was performed. In order to apply personalized medicine and avoid interferences and adverse effects, the individual CYP metabolizer profile and transporter must be considered when choosing the concomitant medication and/or making dose adjustments.

Growth differentiation factor-15 is a predictive biomarker in primary ventricular fibrillation: The RUTI-STEMI-PVF study.

BACKGROUND: Primary ventricular fibrillation is an ominous complication of ST-segment elevation myocardial infarction, and proper biomarkers for risk prediction are lacking. Growth differentiation factor-15 is a marker of inflammation, oxidative stress and hypoxia with well-established prognostic value in ST-segment elevation myocardial infarction patients. We explored the predictive value of growth differentiation factor-15 in a subgroup of ST-segment elevation myocardial infarction patients with primary ventricular fibrillation. METHODS: Prospective registry of ST-segment elevation myocardial infarction patients treated with primary percutaneous coronary intervention from February 2011-August 2015. Growth differentiation factor-15 concentrations were measured on admission. Logistic regression and Cox proportional regression analyses were used. RESULTS: A total of 1165 ST-segment elevation myocardial infarction patients treated with primary percutaneous coronary intervention (men 78.5%, age 62.3±13.1 years) and 72 patients with primary ventricular fibrillation (6.2%) were included. Compared to patients without primary ventricular fibrillation, median growth differentiation factor-15 concentration was two-fold higher in ST-segment elevation myocardial infarction patients with primary ventricular fibrillation (2655 vs 1367 pg/ml, p<0.001). At 30 days, mortality was 13.9% and 3.6% in patients with and without primary ventricular fibrillation, respectively (p<0.001), and median growth differentiation factor-15 concentration in patients with primary ventricular fibrillation was five-fold higher among those who died vs survivors (13,098 vs 2415 pg/ml, p<0.001). In a comprehensive multivariable analysis including age, sex, clinical variables, reperfusion time, left ventricular ejection fraction, N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin T, growth differentiation factor-15 remained an independent predictor of 30-day mortality, with odds ratios of 3.92 (95% confidence interval 1.35-11.39) in patients with primary ventricular fibrillation (p=0.012) and 1.72 (95% confidence interval 1.23-2.40) in patients without primary ventricular fibrillation (p=0.001). CONCLUSIONS: Growth differentiation factor-15 is a robust independent predictor of 30-day mortality in ST-segment elevation myocardial infarction patients with primary ventricular fibrillation.

In-hospital prognosis and long-term mortality of STEMI in a reperfusion network. "Head to head" analisys: invasive reperfusion vs optimal medical therapy.

BACKGROUND: ST Segment Elevation Acute myocardial infarction (STEMI) preferred treatment is culprit artery reperfusion with primary percutaneous coronary intervention (PPCI). We ought to analyze the benefit of early reperfusion vs. optimal medical therapy in STEMI before and after the set-up of a regional STEMI network that prioritizes PPCI. METHODS: Between January 2002 and December 2013, 1268 STEMI patients were consecutively admitted in a University Hospital. Patients were classified in two groups: pre-STEMI Network (January 2002-June 2009; n = 670) and post-STEMI network (July 2009-December 2013; n = 598). Vital status was available at 2-year follow-up. RESULTS: The STEMI network increased reperfusion (89.2% vs 64.4%, p < 0.001) mainly using PCI (99.0% vs 43.9%, p < 0.001). In univariate analysis, in-hospital mortality was significantly lower in the post-STEMI network period (2.51% vs. 7.16%, p < 0.001). After multivariate adjustment, including age, sex, comorbidities, severity and reperfusion therapy, a trend to a lower in-hospital mortality was observed (post-Network OR: 0.50, 95% CI:0.16-1.59, p = 0.24); this trend disappeared when optimal medical therapy was included in the model (post-Network OR: 1.14, 95% CI:0.32-4.08, p = 0.840). No differences in 2-year mortality were observed (post-Network HR: 0.83; CI 95%: 0.55-1.25, p = 0.37). CONCLUSION: A STEMI network with PPCI 24/7 improved reperfusion therapy, resulting in an increase on PPCI. Despite in-hospital mortality decreased with a STEMI network, 2-year mortality remained similar in both periods, pre- and post-Network. Optimal medical therapy could be as important as reperfusion therapy in a STEMI reperfusion network.

Modern approach to an old technique: Narrative revision of techniques used to locate the epidural space. / Visión moderna sobre una técnica antigua: revisión narrativa de técnicas de localización del espacio epidural.

Since the first description of the epidural technique during the 1920s, the continuous progress of knowledge of the anatomy and physiology of the epidural space has allowed the development of different techniques to locate this space while increasing both the safety and efficacy of the procedure. The most common techniques used today are based on the two main characteristics of the epidural space: the difference in distensibility between the ligamentum flavum and the epidural space, and the existence of negative pressure within the epidural space. However, over recent years, technological advances have allowed the development of new techniques to locate the epidural space based on other physical properties of tissues. Some are still in the experimental phase, but others, like ultrasound-location have reached a clinical phase and are being used increasingly in daily practice.

Autoantibodies against TIF-1-γ and CADM-140 in Spanish patients with clinically amyopathic dermatomyositis (CADM): clinical significance and diagnostic utility.

BACKGROUND: Patients with clinically amyopathic dermatomyositis (CADM) appear to be at risk for developing cancer and interstitial lung diseases, but population data to confirm this hypothesis are limited. Moreover, CADM presents cutaneous and histological findings that may overlap with subacute cutaneous lupus erythematosus (SCLE). OBJECTIVES: To determine the association between myositis-specific autoantibodies, myositis-associated autoantibodies and CADM in Spanish patients. In addition, to study the usefulness of these autoantibodies in the differential diagnosis between CADM and SCLE. METHODS: Serum samples were tested for myositis-specific autoantibodies and myositis-associated autoantibodies through immunoprecipitation and other standardized methods. RESULTS: Anti-CADM-p140 and anti-p155 antibodies were the only myositis-specific autoantibodies found and were associated with interstitial lung diseases and cancer respectively. No myositis-associated autoantibodies were found in CADM. Moreover, clinical subsets and proportions seemed to differ from Asian cohorts, where anti-CADM-p140 is considered a CADM hallmark antibody and a risk factor for the development of interstitial lung disease. Interestingly, anti-SSA was highly associated with SCLE, whereas no myositis-specific autoantibodies were found in this entity. LIMITATIONS OF THE STUDY: Association between CADM and myositis-specific autoantibodies and differences between CADM and SCLE were tested on a relatively small cohort of patients. CONCLUSION: There is an association between cancer-associated myositis and interstitial lung diseases and their hallmark autoantibodies in our cohort. In addition, the combined determination of myositis-specific autoantibodies and SSA autoantibodies may help to accurately discriminate SCLE from CADM.

Development of an autoimmune syndrome affecting the skin and internal organs in P-selectin glycoprotein ligand 1 leukocyte receptor-deficient mice.

OBJECTIVE: To define and characterize the progression of the spontaneous autoimmune disease that develops in mice in the absence of the leukocyte adhesion receptor P-selectin glycoprotein ligand 1 (PSGL-1). METHODS: Skin-resident immune cells from PSGL-1-deficient mice and C57BL/6 control mice of different ages were isolated and analyzed by flow cytometry. Biochemical parameters were analyzed in mouse serum and urine, and the presence of serum autoantibodies was investigated. Skin and internal organs were extracted, and their structure was analyzed histologically. RESULTS: Skin-resident innate and adaptive immune cells from PSGL-1(-/-) mice had a proinflammatory phenotype with an imbalanced T effector cell:Treg cell ratio. Sera from PSGL-1(-/-) mice had circulating autoantibodies commonly detected in connective tissue-related human autoimmune diseases. Biochemical and histologic analysis of skin and internal organs revealed skin fibrosis and structural and functional abnormalities in the lungs and kidneys. Furthermore, PSGL-1(-/-) mice exhibited vascular alterations, showing loss of dermal vessels, small vessel medial layer remodeling in the lungs and kidneys, and ischemic processes in the kidney that promote renal infarcts. CONCLUSION: Our study demonstrates that immune system overactivation due to PSGL-1 deficiency triggers an autoimmune syndrome with characteristics similar to systemic sclerosis, including skin fibrosis, vascular alterations, and systemic organ involvement. These results suggest that PSGL-1 expression contributes to the maintenance of the homeostasis of the immune system and could act as a barrier for autoimmunity in mice.

Prevalence of antiphospholipid antibodies in patients with subacute and chronic cutaneous lupus erythematosus.

BACKGROUND AND OBJECTIVES: The prevalence of antiphospholipid antibodies (APLAs) has been extensively studied in patients with systemic lupus erythematosus (SLE) but not in those with cutaneous lupus erythematosus (CLE). We determined the prevalence of APLAs among our patients with CLE, and analyzed their clinical and serologic characteristics. MATERIALS AND METHODS: This retrospective study analyzed 182 patients with subacute or chronic CLE who had been in follow-up for 5 years. We selected those positive for 1 or more of the following APLAs in 2 measurements at least 12 weeks apart: lupus anticoagulant (LA), anticardiolipin antibodies (ACAs), and anti-ß2-glycoprotein i (anti-ß2-GPI) antibodies. In the case of ACAs and anti-ß2-GPI antibodies, only patients with titers greater than or equal to 40 U/mL were selected. RESULTS: We obtained a series of 13 patients (4 with subacute disease and 9 with chronic disease). Seven met the diagnostic criteria for SLE and only 1 met the diagnostic criteria for antiphospholipid syndrome (APS). The prevalence of APLAs was 38% among patients with SLE and 3.65% among those without SLE. The most prevalent APLA was LA, present in 10 patients. Antinuclear antibodies (ANAs) were detected in 12 patients and anti-double-stranded DNA antibodies in 11. CONCLUSIONS: The prevalence of APLAs among our patients with CLE who did not meet the diagnostic criteria for SLE was similar to that reported in the general population. This, along with the strong assocation between the presence of ANAs and the presence of APLAs, would bring into question the value of determining APLAs in patients with CLE who are negative for ANAs. We also note that there was a high prevalence of discoid lesions but a low prevalence of APS among our patients with CLE who were positive for APLAs.

[Influence of family environment of the development of obesity and overweight in a population of school children in Granada (Spain)]. / Influencia del entorno familiar en el desarrollo del sobrepeso y la obesidad en una población de escolares de Granada (España).

According to recent research, eating behaviour should be understand as a cyclical and interactive process in which parental eating habits cause children to develop specific eating strategies as well as their own eating habits. Needless to say, this interactive process is reflected and has a direct impact on the nutritional indicators of the children in a family. The objectives of this study were the following: (i) to verify the existence of a significant association between the educational level of parents and the nutritional state of children in the same family; (ii) to discover if there is a direct relation between the nutritional state of children and the person that decides the menu and/or prepares family meals; (iii) to determine if there is a link between the nutritional state of children and the time that they spend on sedentary leisure activities. The sample population was composed of 718 school children and adolescents, 9-17 years of age, who A descriptive, transversal, and multicentric study was performed that evaluated the nutritional state of the entire sample by using anthropometric techniques to assess weight, height, and body mass index.

[Comparative study of the effectiveness of body mass index and the body-fat percentage as methods for the diagnosis of overweight and obesity in children]. / Estudio comparativo de la eficacia del índice de masa corporal y el porcentaje de grasa corporal como métodos para el diagnóstico de sobrepeso y obesidad en población pediátrica.

The World Health Organization (WHO) regards obesity as one of the most serious public health problems in the world that can affect young children and adolescents. Accordingly, a major priority is to find ways to more effectively study and analyze the various methods used to diagnose and evaluate the nutritional state of the pediatric and adolescent population. The nutritional indicators currently employed for this purpose are the body mass index and body-fat percentage. However, there is a certain controversy related to the body-fat percentage since it tends to overestimate overweight and obesity. The main objectives of this study were the following: (i) to determine the prevalence of overweight and obesity in a population of primary and secondary school children between 9-17 years of age at 13 educational centers in the city and province of Granada; (ii) to verify possible differences regarding the accuracy of the body mass index and the body-fat percentage in the diagnosis of overweight and obesity.

[Analysis of the nutritional state and body composition of school children in Granada (Spain)]. / Análisis del estado nutricional y composición corporal de una población de escolares de Granada.

The objective of this study was to first determine the nutritional state of a sample population of school children, and then analyze the distribution pattern of their subcutaneous fat layer. The sample was composed of 977 school children from the city and province of Granada (Spain). All of the children (524 girls and 452 boys) were 9-17 years of age. To study their nutritional state and the distribution of the subcutaneous fat layer, they were given a complete anthropometric evaluation, which included measuring their weight, height, body mass index, skin folds, and body perimeters. The results obtained showed a 23.01% prevalence of overweight in the female subjects and 20.81% in the male subjects. Furthermore, the female subjects had an obesity prevalence of 12.70% in comparison to the male subjects, whose obesity prevalence was 4.98%. The distribution pattern of subcutaneous fat was found to be mainly located in the central part of body. The high percentage of overweight and obesity along with the development of a central fat distribution pattern (neck, chest, and abdomen) in these school children is clear evidence of potential cardiovascular risk.

[Prevalence of nutritional overweight and obesity and hypertension as well as their relationship with anthropometric indicators in a population of students in Granada and its provinces]. / Prevalencia de sobrepeso y obesidad nutricional e hipertensión arterial y su relación con indicadores antropométricos en una población de escolares de Granada y su provincia.

INTRODUCTION: Several authors have found correlations between anthropometric parameters and blood pressure levels in overweight and obese subjects. This paper is an update on the potential of these parameters as a tool for predicting cardiovascular risk. AIMS: to estimate the prevalence of overweight and obesity. Second verify the existence of a significant correlation between the main anthropometric indicators and the blood pressure levels. SAMPLE: The population consisted of 977 children and adolescents between 9 and 17 years of age belonging to 13 schools in the province of Granada and city. METHODOLOGY: anthropometric evaluation in which they were assessed six skinfolds, waist circumference, hip and determination of blood pressure in three consecutive occasions. The anthropometric assessment phase began in March 2008 lasted until April 2009. RESULTS: We found that the prevalence of overweight in girls varied between 18.3% and 32.2%. For its part, the prevalence among boys was between 10.9% and 26.1%. Regarding the prevalence of obesity, the girls had similar rates between 4.5% and 15.1%. Among boys the prevalence of obesity was similar, and found rates between 4.7% and 12.6%. Of all the parameters measured, body mass index and waist circumference were the anthropometric indicators that showed a better correlation to blood pressure. CONCLUSIONS: BMI and WC are useful anthropometric indicators to predict cardiovascular risk in non adults.

[Obesity in a school children population from Granada: assessment of the efficacy of an educational intervention]. / Obesidad de una población de escolares de Granada: evaluación de la eficacia de una intervención educativa.

OBJECTIVES: The objective of this research was to study the prevalence of obesity and excess weight in a population of school children and adolescents, and to verify the effectiveness of an educational intervention, as reflected in the variation of their body mass index values. MATERIALS: The population sample was composed of 977 school children and adolescents from 9 to 17 years of age, belonging to 13 public elementary schools and high schools in the city and province of Granada (Spain). METHODOLOGY: This longitudinal cohort study was analytical, muticentric, and observational. It was carried out in three phases. The first phase involved the evaluation of the nutritional state of the sample population by means of anthropometric measurements (weight, height, body mass index, six skin folds and four body perimeters) as well as arterial blood pressure. The second phase entailed an educational intervention focusing on good nutritional habits and physical exercise. The third and final phase evaluated the effectiveness of the intervention. RESULTS: A higher obesity prevalence (15.1%) was found in school girls between 12 and 13. In the case of boys, obesity prevalence was lower up to age 13 though afterwards, it progressively increased (12.6%). The educational intervention produced an important reduction in body mass index values in both sexes though this reduction was more significant in young females. CONCLUSIONS: There is a currently an alarming increase in obesity and overweight prevalence among the population evaluated in this study. The significant reduction in body mass index values resulting from this research confirmed the effectiveness of the educational intervention to reduce excess weight.

Calcinosis cutis and Sjögren's syndrome.

Cutaneous calcinosis can be classified into four types: dystrophic, metastatic, idiopathic and iatrogenic. Dystrophic calcification constitutes the most frequent variant and is associated with a large number of illnesses, among which are included some collagen diseases such as CREST syndrome, scleroderma, dermatomyositis and lupus erythematosus. We present a case of dystrophic calcinosis cutis, affecting the fingertip of a woman with a 10-year history of primary Sjögren's syndrome (SS). She has been receiving diltiazem as a treatment for the last 15 months, resulting in the partial resolution of the lesions. We emphasize the fact that the presence of calcinosis cutis has not been described previously in patients with SS, and that diltiazem has partially improved our patient's cutaneous lesions.

[Antiphospholipid antibodies and antiphospholipid syndrome: diagnosis and management]. / Anticuerpos antifosfolípido y síndrome antifosfolípido: actitudes diagnósticas y terapéuticas.

Antiphospholipid syndrome is an acquired autoimmune thrombophilia that produces significant morbidity and mortality. Its diagnosis requires the presence of antiphospholipid antibodies and clinical manifestations that include thrombotic phenomena and/or recurrent miscarriages. Antiphospholipid antibodies may be detected in many instances, including healthy subjects. Clinical manifestations are varied and may occur in episodes and also appear in other situations. Therefore, it is important to have clear guidelines in order to establish a correct diagnosis, carry out an adequate treatment, and to know which are the prophylactic measures and when they should be undertaken. In this article we explain the most recent diagnostic criteria reviewed in the 11th International Congress on Antiphospholipid Antibodies (Sydney 2004), comment on the varied clinical manifestations with special focus on cutaneous lesions, and review current guidelines for the treatment and prophylaxis of thrombotic and obstetric pathology.