Immunoglobulins in systemic sclerosis management. A large multicenter experience.

OBJECTIVE: To analyze the effectiveness and safety of intravenous immunoglobulin (IVIG) given in routine care to patients with systemic sclerosis (SSc). METHODS: A retrospective multicenter observational study was conducted in SSc patients treated with IVIG. We collected data on epidemiological parameters and clinical outcomes. Firstly, we assessed changes in organ manifestations during IVIG treatment. Secondly, we analyzed the frequency of adverse effects. The following parameters were collected from baseline to the last follow-up: the patient's weight, modified Rodnan Skin Score (mRSS), modified manual muscle strength scale (MRC), laboratory test(creatine kinase(CK), hemoglobin and protein levels), The University of California Los Angeles Scleroderma Clinical Trials Consortium gastrointestinal tract 2.0 (UCLA GIT 2.0) questionnaire, pulmonary function tests, and echocardiography. RESULTS: Data were collected on 78 patients (82% females; 59% with diffuse SSc). Inflammatory idiopathic myopathy was the most frequent concomitant overlap disease (41%). The time since Raynaud's phenomenon and SSc onset were 8.8 ± 18 and 6.2 ± 6.7 years respectively. The most frequent IVIG indication was myositis (38/78), followed by gastrointestinal (27/78) and cutaneous (17/78) involvement. The median number of cycles given were 5. 54, 53 and 9 patients have been treated previously with glucocorticoids, synthetic disease-modifying antirheumatic drugs and biologic therapies respectively. After IVIG use we found significant improvements in muscular involvement (MRC ≥ 3/5 92% IVIG, p = 0.001 and CK levels from 1149 ± 2026 UI to 217 ± 224 UI, p = 0.02), mRSS (15 ± 12.4 to 13 ± 12.5, p = 0.015) and improvement in total score of UCLA GIT 2.0 (p = 0.05). None Anti-RNA polymerase III patients showed an adequate response in gastrointestinal involvement (0/7) in comparison with other antibodies (0 vs. 25, p = 0,039). Cardiorespiratory involvement remained stable. A total of 12 adverse events were reported with only one withdrawn due to serious adverse effect. CONCLUSIONS: this study suggest that IVIG may improve myositis, gastrointestinal and skin involvement in SSc patients treated in routine care and seems to have a good safety profile.

Satisfaction and medication adherence in women with vulvovaginal atrophy: the CRETA.

OBJECTIVE: This study aimed to evaluate the self-reported satisfaction of Spanish postmenopausal women currently treated for vulvovaginal atrophy (VVA) symptoms. METHODS: The CRETA (CRoss sectional European sTudy on Adherence) is a multicenter cross-sectional study conducted in 29 public and private hospitals in Spain, which enrolled postmenopausal women receiving treatment with ospemifene, local hormone therapy (HT) or vaginal moisturizers for VVA. After the prior informed consent of the patients, sociodemographic and treatment perception data were collected using a structured questionnaire. RESULTS: Among 752 women who completed the survey, the satisfaction score was significantly higher for the group treated with ospemifene (mean 8.3 ± 1.4) compared with the local HT group (7.2 ± 1.7) and the vaginal moisturizer group (6.5 ± 2.1) according to a 10-point Likert scale (p < 0.0001). Compared to vaginal moisturizers and local HT, participants treated with ospemifene reported the highest adherence (96.7% vs. 70.2% and 78.6%, respectively) and the lowest number of missed doses in the last month (0.6 ± 1.3 standard deviation [SD] vs. 3.5 ± 4.3 SD and 2.0 ± 2.8 SD, respectively) (p < 0.0001). Ospemifene was significantly perceived as easy to use (83.9% vs. 44.9% and 58.6%, respectively; p < 0.0001), efficacious in reducing the time to relieve symptoms (17.1% vs. 7.0% and 6.7%, p = 0.0005 and p = 0.0006, respectively) and convenient for sexual life (53.1% vs. 25.6% and 42.3%, p < 0.0001 and p = 0.0234, respectively). CONCLUSIONS: Among postmenopausal women with VVA, treatment with ospemifene has the most positive perceptions and the highest overall satisfaction level and could be an optimal therapeutic approach, maximizing patient adherence.

Epidemiología de la enfermedad celíaca pediátrica en dos Áreas Sanitarias de Asturias / EPIDEMIOLOGY OF PEDIATRIC CELIAC DISEASE IN TWO HEALTH AREAS OF ASTURIAS (SPAIN)

Introducción y objetivos. En las últimas décadas se ha descrito un aumento de la incidencia de enfermedad celíaca (EC) y un predominio de formas de presentación menos sintomáticas. El objetivo de este estudio es describir las características clínicas de la EC en población pediátrica de dos Áreas Sanitarias de Asturias y estimar su incidencia. Pacientes y métodos. Estudio observacional, prospectivo y multicéntrico de pacientes de las Áreas Sanitarias III (Avilés) y V (Gijón) incluidos en el Registro Español de Pacientes Celíacos pediátricos REPAC2 (2011-2017). Se recogieron datos demográficos, síntomas, somatometría y pruebas diagnósticas. Se utilizaron criterios ESPGHAN 2020 para el estudio descriptivo y el cálculo de la incidencia, y criterios ESPGHAN 2012 para el análisis comparativo con el resto de España. Resultados. Se incluyen 99 casos (50,5% niñas): 72 del Área V y 27 del Área III. Mediana de edad: 3,1 años (P25-P75: 1,6-7,7). La forma de presentación más frecuente fue la EC clásica (76,8%), con un 2,0% de asintomáticos. Los síntomas más frecuentes fueron la pérdida/estancamiento de peso (55,7%) y la diarrea (49,5%). Respecto al resto de España (4.681 casos), en Asturias (82 casos) se registró una menor frecuencia de asintomáticos (2,4% vs. 9,8%, p=0,026) y de realización de biopsias (28% vs. 62,1%, p<0,001). La tasa de incidencia de EC basada en diagnósticos hospitalarios fue de 32,1 (IC95%: 26,1-39,1) por 100.000 personas/año. Conclusiones. Se identifican diferencias geográficas en la presentación y diagnóstico de EC, y una mayor incidencia respecto a estudios previos. (AU)

Introduction and aims. Over the last few decades, it has been reported an increase in the incidence of celiac disease (CD) and a predominance of less symptomatic clinical presentations. This study aimed to describe the clinical characteristics of CD in the paediatric population of two Health Areas of Asturias and to estimate its incidence. Patients and methods. Observational, prospective, multicentre study of patients from Health Areas III (Avilés) and V (Gijón) included in the Spanish Registry of Paediatric Celiac Patients REPAC2 (2011-2017). Demographic data, symptoms, somatometry and diagnostic tests were collected. The incidence rate was calculated using the municipal register. ESPGHAN 2020 diagnostic criteria were used for the descriptive study and incidence calculation, and ESPGHAN 2012 criteria were used for the comparative analysis with the rest of Spain. Results. 99 patients (50.5% girls) were included: 72 from Area V and 27 from Area III. Median age: 3.1 years (P25-P75: 1.6-7.7). The most frequent clinical presentation was classic CD (76.8%), whereas 2.0% were asymptomatic. The most frequent symptoms were failure to thrive (55.7%) and diarrhoea (49.5%). Compared with the rest of Spain (4681 patients), Asturias (82 patients) had fewer asymptomatic patients (2.4% vs. 9.8%, p=0.026) and fewer biopsies performed (28% vs. 62.1%, p<0.001). The incidence rate of CD based on hospital diagnoses according to ESPGHAN 2020 criteria was 32.1 (95%CI: 26.1-39.1) per 100,000 person-years. Conclusions. Geographic differences were identified in the presentation and diagnosis of CD, with a higher incidence compared to previous studies. (AU)

Nox4 expression in osteo-progenitors controls bone development in mice during early life.

Tightly regulated and cell-specific NADPH-oxidases (Nox) represent one of the major sources of reactive oxygen species (ROS) signaling molecules that are involved in tissue development and stem cell self-renewal. We have characterized the role of Nox4 in osteo-progenitors during postnatal bone development. Nox4 expression in bone and ROS generation were increased during early osteoblast differentiation and bone development. Stromal osteoblastic cell self-renewal, proliferation and ROS production were significantly lower in samples from whole-body Nox4 knockout mice (Nox4-/-) and conditional knockout (CKO) mice with depletion of Nox4 in the limb bud mesenchyme compared with those from control mice (Nox4fl/fl), but they were reversed after 9 passages. In both sexes, bone volume, trabecular number and bone mineral density were significantly lower in 3-week old CKO and Nox4-/- mice compared with Nox4fl/fl controls. This was reflected in serum levels of bone formation markers alkaline phosphatase (ALP) and procollagen 1 intact N-terminal propeptide (P1NP). However, under-developed bone formation in 3-week old CKO and Nox4-/- mice quickly caught up to levels of control mice by 6-week of age, remained no different at 13-week of age, and was reversed in 32-week old male mice. Osteoclastogenesis showed no differences among groups, however, CTX1 reflecting osteoclast activity was significantly higher in 3-week old male CKO and Nox4-/- mice compared with control mice, and significantly lower in 32-week old Nox4-/- mice compared with control mice. These data suggest that Nox4 expression and ROS signaling in bone and osteoblastic cells coordinately play an important role in osteoblast differentiation, proliferation and maturation.

Soy Formula Is Not Estrogenic and Does Not Result in Reproductive Toxicity in Male Piglets: Results from a Controlled Feeding Study.

Soy infant formula which is fed to over half a million infants per year contains isoflavones such as genistein, which have been shown to be estrogenic at high concentrations. The developing testis is sensitive to estrogens, raising concern that the use of soy formulas may result in male reproductive toxicity. In the current study, male White-Dutch Landrace piglets received either sow milk (Sow), or were provided milk formula (Milk), soy formula (Soy), milk formula supplemented with 17-beta-estradiol (2 mg/kg/d) (M + E2) or supplemented with genistein (84 mg/L of diet; (M + G) from postnatal day 2 until day 21. E2 treatment reduced testis weight (p < 0.05) as percentage of body weight, significantly suppressed serum androgen concentrations, increased tubule area, Germ cell and Sertoli cell numbers (p < 0.05) relative to those of Sow or Milk groups. Soy formula had no such effects relative to Sow or Milk groups. mRNAseq revealed 103 differentially expressed genes in the M + E2 group compared to the Milk group related to endocrine/metabolic disorders. However, little overlap was observed between the other treatment groups. These data suggest soy formula is not estrogenic in the male neonatal piglet and that soy formula does not significantly alter male reproductive development.

Binge Ethanol Exposure in Mice Represses Expression of Genes Involved in Osteoblast Function and Induces Expression of Genes Involved in Osteoclast Differentiation Independently of Endogenous Catalase.

Excessive ethanol consumption is a risk factor for osteopenia. Since a previous study showed that transgenic female mice with overexpression of catalase are partially protected from ethanol-mediated trabecular bone loss, we investigated the role of endogenous catalase in skeletal ethanol toxicity comparing catalase knockout to wild-type mice. We hypothesized that catalase depletion would exacerbate ethanol effects. The mice were tested in a newly designed binge ethanol model, in which 12-week-old mice were exposed to 4 consecutive days of gavage with ethanol at 3, 3, 4, and 4.5 g ethanol/kg body weight. Binge ethanol decreased the concentration of serum osteocalcin, a marker of bone formation. The catalase genotype did not affect the osteocalcin levels. RNA sequencing of femoral shaft RNA from males was conducted. Ethanol exposure led to significant downregulation of genes expressed in cells of the osteoblastic lineage with a role in osteoblastic function and collagen synthesis, including the genes encoding major structural bone proteins. Binge ethanol further induced a smaller set of genes with a role in osteoclastic differentiation. Catalase depletion affected genes with expression in erythroblasts and erythrocytes. There was no clear interaction between binge ethanol and the catalase genotype. In an independent experiment, we confirmed that the binge ethanol effects on gene expression were reproducible and occurred throughout the skeleton in males. In conclusion, the binge ethanol exposure, independently of endogenous catalase, reduces expression of genes involved in osteoblastic function and induces expression of genes involved in osteoclast differentiation throughout the skeleton in males.

Granulomas in Dermatopathology: Principal Diagnoses - Part 1. / Granulomas en dermatopatología: principales entidades. Parte I.

This series of 2 articles on dermatopathologic diagnoses reviews conditions in which granulomas form. Part 1 clarifies concepts, discusses the presentation of different types of granulomas and giant cells, and considers a large variety of noninfectious diseases. Some granulomatous diseases have a metabolic origin, as in necrobiosis lipoidica. Others, such as granulomatous mycosis fungoides, are related to lymphomas. Still others, such as rosacea, are so common that dermatologists see them nearly daily in clinical practice.

Granulomas in Dermatopathology: Principal Diagnoses - Part 2. / Granulomas en dermatopatología: principales entidades. Parte II.

Part 2 of this series on granulomatous diseases focuses on skin biopsy findings. Whereas the first part treated noninfectious conditions (metabolic disorders and tumors, among other conditions), this part mainly deals with various types of infectious disease along with other conditions seen fairly often by clinical dermatologists.

Fontan-associated liver disease. / Enfermedad hepática crónica asociada a la cirugía de Fontan.

OBJECTIVE: To review the pathophysiology of Fontan-associated liver disease, its histologic changes, and its radiologic manifestations. CONCLUSIONS: Fontan-associated liver disease is the result of a set of structural and functional changes in the liver that occur secondary to hemodynamic changes brought about by Fontan surgery. The radiologic manifestations of Fontan-associated liver disease consist of changes in the size and shape of the liver, alterations in the signal intensity or pattern of enhancement, abnormalities in the vascular structures, and focal lesions, which include benign nodules with intense uptake in the arterial phase and hepatocellular carcinoma. Radiologists need to be familiar with this disease and its complications, because the number of patients who undergo Fontan surgery continues to increase, and these patients undergo an increasing number of imaging tests.

Clinical and Histopathologic Characteristics of the Main Causes of Vascular Occlusion - Part I: Thrombi. / Dermatopatología de la oclusión intraluminal vascular: parte I (trombos).

Vascular occlusion has multiple, diverse clinical manifestations, some of which can have grave consequences for patients. The causes of vascular occlusion are also highly variable, ranging from thrombi triggered by the uncontrolled activation of coagulation mechanisms, on the one hand, to endothelial dysfunction or occlusion by material extrinsic to the coagulation system on the other. In a 2-part review, we look at the main causes of vascular occlusion and the key clinical and histopathologic findings. In this first part, we focus on vascular occlusion involving thrombi.

Protocol for the Histologic Diagnosis of Cutaneous Melanoma: Consensus Statement of the Spanish Society of Pathology and the Spanish Academy of Dermatology and Venereology (AEDV) for the National Cutaneous Melanoma Registry. / Protocolo de diagnóstico histológico para muestras de pacientes con melanoma cutáneo. Documento de consenso de la SEAP y la AEDV para el Registro Nacional de Melanoma.

This article describes a proposed protocol for the histologic diagnosis of cutaneous melanoma developed for the National Cutaneous Melanoma Registry managed by the Spanish Academy of Dermatology and Venereology (AEDV). Following a review of the literature, 36 variables relating to primary tumors, sentinel lymph nodes, and lymph node dissection were evaluated using the modified Delphi method by a panel of 8 specialists (including 7 pathologists). Consensus was reached on the 30 variables that should be included in all pathology reports for cutaneous melanoma and submitted to the Melanoma Registry. This list can also serve as a model to guide routine reporting in pathology departments.

Clinical and Histopathologic Characteristics of the Main Causes of Vascular Occusion - Part II: Coagulation Disorders, Emboli, and Other. / Dermatopatología de la oclusión intraluminal vascular: parteII (coagulopatías, émbolos y miscelánea).

Vascular occlusion has multiple, diverse clinical manifestations, some of which can have grave consequences for patients. It also has a wide variety of causes, including thrombi, which we recently addressed in partI of this review. In this second part, we look at additional causes of vascular occlusion.

Influence of nutrition education in paediatric coeliac disease: impact of the role of the registered dietitian: a prospective, single-arm intervention study.

BACKGROUND: The diagnosis of coeliac disease (CD) involves a change in the diet of the individual, which may influence their quality of life and nutritional status. The present study aimed to determine whether nutrition education by a registered dietitian is able to improve eating habits and body composition in children with CD. METHODS: Dietary, physical activity and body composition changes were analysed, comparing baseline assessments with those 1 year after receiving education on healthy eating. At both time points, a 3-day dietary survey, a food frequency consumption questionnaire, an adherence to the Mediterranean diet test (Kidmed), duration of activity and an electrical bioimpedance study were conducted. Student's paired t-test and the McNemar test were also employed. RESULTS: Seventy-two subjects (42 girls) with an mean (range) age of 10 (2-16) years were included. Before the intervention, an unbalanced diet was observed, rich in protein and fat, and deficient in complex carbohydrates. Only 14% consumed an adequate Mediterranean diet. After nutrition intervention, a significant increase in the consumption of plant-based foods and a concomitant decrease in meat, dairy and processed food intake (P < 0.001) were observed. Moreover, 92% of the patients (P < 0.001) managed to consume an adequate Mediterranean diet. Similarly, an increase was observed in the duration of physical activity undertaken [mean (SD) 1.02 (1.79) h, P < 0.001] and improvements in body composition were recorded, with a 17% decrease in fat mass percentage (P < 0.001). CONCLUSIONS: Nutrition intervention focused on healthy eating is effective with respect to improving the nutritional status and diet quality in CD patients.