Muscle cell-derived Ccl8 is a negative regulator of skeletal muscle regeneration.

Skeletal muscles undergo robust regeneration upon injury, and infiltrating immune cells play a major role in not only clearing damaged tissues but also regulating the myogenic process through secreted cytokines. Chemokine C-C motif ligand 8 (Ccl8), along with Ccl2 and Ccl7, has been reported to mediate inflammatory responses to suppress muscle regeneration. Ccl8 is also expressed by muscle cells, but a role of the muscle cell-derived Ccl8 in myogenesis has not been reported. In this study, we found that knockdown of Ccl8, but not Ccl2 or Ccl7, led to increased differentiation of C2C12 myoblasts. Analysis of existing single-cell transcriptomic datasets revealed that both immune cells and muscle stem cells (MuSCs) in regenerating muscles express Ccl8, with the expression by MuSCs at a much lower level, and that the temporal patterns of Ccl8 expression were different in MuSCs and macrophages. To probe a function of muscle cell-derived Ccl8 in vivo, we utilized a mouse system in which Cas9 was expressed in Pax7+ myogenic progenitor cells (MPCs) and Ccl8 gene editing was induced by AAV9-delivered sgRNA. Depletion of Ccl8 in Pax7+ MPCs resulted in accelerated muscle regeneration after barium chloride-induced injury in both young and middle-aged mice, and intramuscular administration of a recombinant Ccl8 reversed the phenotype. Accelerated regeneration was also observed when Ccl8 was depleted in Myf5+ or MyoD+ MPCs by similar approaches. Our results suggest that muscle cell-derived Ccl8 plays a unique role in regulating the initiation of myogenic differentiation during injury-induced muscle regeneration.

Effectiveness of contact tracing to reduce fatality from COVID-19: preliminary evidence from Colombia.

OBJECTIVES: Conducting contact tracing (CT) programs in low- and middle-income countries is challenging, and there is no evidence of their effectiveness in Latin America. We evaluated the effectiveness of CT on reducing fatality from COVID-19 in Colombia. STUDY DESIGN: The study design is a retrospective cohort study with nation-wide data of suspected and confirmed cases of severe acute respiratory syndrome (SARS-CoV-2) infection and their registered contacts. METHODS: We analyzed confirmed and suspected COVID-19 cases and their chains of contact using a nation-wide registry from March 28, 2020 to January 13, 2021. To estimate the effect of CT on fatality, we adjusted a multilevel negative binomial model using the number of deaths and the number of people within a chain of contacts as the outcome variable and offset variable, respectively. Sensitivity analysis was conducted using different cutoff values of contacts traced and a logistic model for the effect of CT on death at an individual level. RESULTS: We analyzed 1.4 million cases, 542,936 chains of contact, and 46,087 deaths. Only, 5.8% of total cases and contacts were included in a chain of a case and five or more contacts. We found that tracing of at least five contacts per case reduces fatality by 48% (95% confidence interval: 45-51), and, at the current levels of tracing in Colombia, it prevents 1.8% of deaths. Results obtained from the sensitivity analysis were consistent with the reduction of fatality at an individual level and higher protective effect with the higher number of contacts traced. CONCLUSIONS: In Colombia, tracing of at least five contacts per case reduces fatality from COVID-19. The coverage and intensity of tracing needs to be increased as a strategy to mitigate fatality in Colombia.

Correction to: Ouabain Accelerates Collective Cell Migration Through a cSrc and ERK1/2 Sensitive Metalloproteinase Activity.

The original version of the article unfortunately contained an error in the author group. Dr. Isabel Larré was not submitted and published in the original version.

Ouabain Accelerates Collective Cell Migration Through a cSrc and ERK1/2 Sensitive Metalloproteinase Activity.

Studies made in the Madin-Darby canine kidney (MDCK) epithelial cell line showed that ouabain regulates cell adhesion and cell-adhesion-related biological processes, such as migration. Here, we demonstrated that 10 nM ouabain accelerates collective cell migration and heals wounds in cultured MDCK cell monolayers. Ouabain-induced acceleration of cell migration depends on activation of the cSrc-ERK1/2 signaling cascade, as it was inhibited by the kinase inhibitors PP2 and PD98059. Activation of the cSrc-ERK1/2 signaling cascade increased expression and activation of the extracellular matrix metalloproteinase-2 (MMP-2). Inhibition of MMP activity using the generic inhibitor GM6001 or the potent iMMP-2 inhibitor prevented the accelerative effect of ouabain. Likewise, Focal Adhesion Kinase (FAK) inhibition with the transfection of dominant negative peptide FRNK impaired the effect of ouabain. These results suggest that ouabain binding to the Na+,K+-ATPase accelerates collective migration of MDCK cells through activation of the cSrc-ERK1/2-FAK signaling cascade and promoting secretion and MMP activity.

Novel clinical and molecular findings in Spanish patients with naevoid basal cell carcinoma syndrome.

BACKGROUND: Naevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by developmental alterations and multiple basal cell carcinomas. Mutations in PTCH1, which encodes a membrane receptor for Sonic Hedgehog, are associated with the development of the disease. Most of them produce a truncated protein, which is unable to suppress Smoothened protein and continuously activates the downstream pathway. OBJECTIVES: We aimed to characterize 22 unrelated Spanish patients with NBCCS, the largest cohort with Gorlin syndrome reported to date in Spain. METHODS: Genomic analysis of PTCH1 was performed in patients with NBCCS and controls, and mutations were analysed using bioinformatics tools. RESULTS: We report for the first time two young patients, one each with uterus didelphys and ganglioneuroma, within the context of NBCCS. One patient showing a severe phenotype of the disease had developed basal cell carcinomas since childhood. Sanger sequencing of PTCH1 in this cohort identified 17 novel truncating mutations (11 frameshift, five nonsense and one mutation affecting an exon-intron splice site) and two novel missense mutations that were predicted to be pathogenic. The patients showed great clinical variability and inconsistent genotype-phenotype correlation, as seen in relatives carrying similar mutations. CONCLUSIONS: This study contributes to increase the pool of clinical manifestations of NBCCS, as well as increasing the number of pathogenic mutations identified in PTCH1 predisposing to the condition. The inconsistencies found between phenotype and genotype suggest the involvement of other modifying factors, genetic, epigenetic or environmental.

Halogenated Natural Products in Dolphins: Brain-Blubber Distribution and Comparison with Halogenated Flame Retardants.

Halogenated natural products (MHC-1, TriBHD, TetraBHD, MeO-PBDEs, Q1, and related PMBPs) and halogenated flame retardants (PBDEs, HBB, Dec 602, Dec 603, and DP) in blubber and brain are reported from five Alboran Sea delphinids (Spain). Both HNPs and HFRs were detected in brain, implying that they are able to surpass the blood-brain barrier and reach the brain, which represents a new finding for some compounds, such as Q1 and PMBPs, MHC-1, TriBHD, TetraBHD, or Dec 603. Moreover, some compounds (TetraBHD, BDE-153, or HBB) presented higher levels in brain than in blubber. This study evidence the high concentrations of HNPs in the marine environment, especially in top predators. It shows the importance of further monitoring these natural compounds and evaluating their potential toxicity, when most studies focus on anthropogenic compounds only. While no bioaccumulation was found for ∑HNPs, ∑HFRs increased significantly with body size for both common and striped dolphins. Studies evaluating BBB permeation mechanisms of these compounds together with their potential neurotoxic effects in dolphins are recommended.

Changes in thyroid function with age: results from the Pizarra population-based longitudinal study.

BACKGROUND: Results of studies examining the influence of age on thyroid function and TSH levels, in the absence of thyroid disease, remain controversial. The aim of this study was to determine the course of thyroid function over 11 years in a population with normal thyroid function. METHODS: This is a population-based prospective study started in 1995-1997 (first phase), and reassessed 6 (second phase) and 11 years later (third phase). RESULTS: The TSH and FT4 in the third phase were significantly increased (p=0.001 and p=0.001, respectively), with the values being higher particularly from the age of 50 years. In those persons with a baseline TSH≥1.2 and <3 µIU/mL, the OR of having a TSH of 3-5 µIU/mL in the third phase was 6.10 (p=0.004). In those with a baseline TSH≥3 and ≤5 µIU/mL, the OR of having a TSH of 3-5 µIU/mL in the third phase was 20.8 (p<0.0001). Similar results were found for FT4. CONCLUSION: In a population free of clinical thyroid disease, TSH and FT4 values rise over the years. This increase occurs in all age groups, but depends mainly on the basal concentrations of TSH and FT4.

[Association between intracellular zinc levels and nutritional status in HIV-infected and uninfected children exposed to the virus]. / Asociación entre los niveles de zinc intracelular y el estado nutricional de los niños infectados por el virus de la inmunodeficiencia humana (VIH) y los niños expuestos al virus no infectados.

INTRODUCTION: Malnutrition, growth retardation and opportunistic infections outlast the metabolic, immune and gastrointestinal disorders produced by HIV. Zinc deficiency has been associated with deteriorating nutritional status, growth failure, and risk of infection. The aim of this study is to determine the association between zinc levels in peripheral blood mononuclear cells (PBMC) and the nutritional status of HIV-infected and uninfected children exposed to the virus. PATIENTS AND METHODS: An analytical, observational, cross-sectional study was conducted on 17 infected and 17 exposed children, aged 2-10 years. Anthropometric measurements, clinical and nutritional history, 24h recall, measurement of physical activity, and zinc in PBMC by flow cytometry analysis were recorded. RESULTS: Height according to age, energy consumption and adequacy of energy, protein and dietary zinc were significantly higher in children exposed to the virus compared to those infected with HIV (P <.05). No significant differences were found in BMI, levels of zinc in monocytes, CD4 + and CD4- lymphocytes between the two study groups (P >.05). However, the median levels of zinc in monocytes of infected patients was higher (218.6) compared to the control group (217.0). No association was found between zinc intake and levels of intracellular zinc. CONCLUSIONS: The deterioration of nutritional status and growth retardation in children were associated with HIV, but not with the levels of intracellular zinc. The dietary intake of this nutrient was not associated with levels of zinc in monocytes or CD4 + and CD4- lymphocytes.

Seroprevalence of trypanosomosis and associated risk factors in cattle from coast and amazonian provinces of Ecuador.

Trypanosomosis is a tropical disease caused by various protozoan haemoparasites, which affects wild and domestic animals, the latter ones related to worldwide livestock production systems. Species such as Trypanosoma vivax and Trypanosoma evansi have been described using serological and molecular tools in several countries from South and Central America. However, Ecuador presents a relevant knowledge gap in the associated general epidemiology and risk factors of the disease. Therefore, the objective of this study was to determine the seroprevalence of trypanosomosis in cattle from different regions of Ecuador. 745 serum samples from 7 Coastal and 3 Amazon provinces were screened for IgG anti-Trypanosoma spp. antibodies, using an in-house indirect ELISA. The seropositivity was explored and associated with several variables such as sex, age, breed, region, management, and province, using statistical tools. The general seroprevalence of trypanosomosis was 19.1% (95% CI: 16.30-22.1%). The Amazonian provinces of Sucumbíos and Napo and the Coastal province of Esmeraldas presented the highest seroprevalence values of 36.7% (95% CI: 27.67-46.47%), 23.64% (95% CI: 16.06-32.68%) and 25% (95% CI: 15.99-35.94%), respectively. Statistical significance was found for the region, province, and management variables, indicating as relevant risk factors the extensive management and Amazon location of the cattle analyzed. Specific actions should be taken to identify the exact species on reservoirs and susceptible hosts, evaluate the implication of farm management and cattle movement as risk factors, and implement surveillance and treatment plans for affected herds.

Well-being among university students in the post-COVID-19 era: a cross-country survey.

University students have to handle crucial challenges for their future lives, such as succeeding in academic studies and finding attachment figures. These processes could potentially involve their well-being and mental health, with possible sociocultural differences based on the country of study. In order to explore such potential differences, a cross-sectional, multi-center survey was performed involving students from the University of Torino (Italy), Sevilla (Spain), and Lusòfona (Portugal). The survey, conducted from May to November 2023, investigated students' demographic and educational details, socioeconomic status, social support, mental health, academic environment, perceived COVID-19 pandemic impact, and future plans. Demographic profiles showed a predominance of female participants and straight sexual orientation, followed by bisexuality. Italian students showed the lowest levels of mental well-being and the highest rates of mental problems (anxiety and depression) and suicidal risk across the three countries despite the relatively similar profiles of social support. The prevalence of the students' confidence in their professional future is higher in Spain than in Italy and Portugal. This study provides a comprehensive examination of university students' mental health and well-being in three Southern European countries, addressing the major mental health challenges among university students and offering valuable insights for public health purposes.

Androgen depletion augments antibacterial prostate host defences in rats.

The defence of the male reproductive tract against microorganisms is critical for fertilization. The prostate gland has been reported to express several molecules of the innate immune system. However, little information is available about how androgens may modulate host defences within the prostate. We therefore aimed to examine in the rat the expression of the TLR4 system, which is strongly involved in pathogen recognition, and the secretion of the antibacterial substances rBD-1 and SP-D after androgen withdrawal. Immunoblotting and immunocytochemical analysis revealed a time-dependent increase in these molecules after orchiectomy, with epithelial and stromal cells being an important source of prostatic host defence proteins. In view of this, we evaluated the potential improvement in antibacterial ability of the prostatic fluid from orchiectomized animals ex vivo. Only samples from rats at 5 days post-orchiectomy showed a slight inhibition of Escherichia coli growth. Finally, E. coli was inoculated into the ventral prostate of orchiectomized or control rats, with bacterial growth being counted at 5 days after infection. Animals with androgen depletion presented a lower bacterial count, and showed few histological signs of prostatic inflammation compared with controls. In vitro studies confirmed that isolated lipopolysaccharide (LPS)-treated prostatic cells in the absence of testosterone increased SP-D. Moreover, media from these cells showed a higher antimicrobial activity than supernatants from testosterone- and LPS-treated cells. Our findings indicate that testosterone maintains a reduced expression of key elements for innate immunity and diminishes the antibacterial ability of the rat prostate. These data may represent an important mechanism underlying the immunosuppressive activity of testosterone in the gland. However, this immunosuppressive function of androgens is understandable as a means of avoiding uncontrolled immune responses against the haploid male gamete in the reproductive tract.

Mixed testicular neoplasia in a short beaked common dolphin Delphinus delphis.

A diagnosis of mixed testicular neoplasia in a short beaked common dolphin Delphinus delphis involving a Sertoli cell tumor, an interstitial (Leydig) cell tumor and a seminoma is presented. Lymphatic spread of the Sertoli cell tumor to an adjacent retroperitoneal lymph node was observed. Testicular neoplasms have been infrequently reported in marine mammals. Demonstration of clinical signs and further health implications is extremely challenging when dealing with non accessible wildlife species, such as dolphins. However, metastatic potential for these neoplastic conditions should be considered.

Pandemic's impact on inguinal hernia management in infants. / Impacto de la pandemia en el manejo de la hernia inguinal en lactantes.

INTRODUCTION: The SARS-CoV-2 pandemic brought about a reduction in surgical activity. The objective of this work was to analyze its impact on inguinal hernia morbidity. MATERIAL AND METHODS: A retrospective study of cases and controls was carried out. Patients under 18 months of age undergoing inguinal hernia surgery from January 1, 2019 to August 31, 2020 were included. They were divided into two groups: patients undergoing surgery before (group A) or after (group D) the state of alarm was declared in Spain. Primary variables: episodes of incarceration and postoperative complications. Secondary variable: urgent or scheduled surgery. Demographic variables: sex, gestational age (GA), previous pathologies, age at diagnosis (AD), and age at surgery (AS) (months). RESULTS: 64 patients were included - 43 in group A and 21 in group D. In group A, median GA was 37+3, 90.5% of patients were male, median AD was 2.33, and median AS was 3.27. In group D, median GA was 31+2, 72.1% of patients were male, median AD was 3, and median AS was 3.63. There were no statistically significant differences. However, differences in terms of previous pathologies were significant (16.3% for Group A vs. 38.1% for group D) (p = 0.05). Regarding the primary variable, 25.6% of patients in group A had incarcerations vs. 33.3% of patients in group D (p = 0.51), whereas 9.3% of patients in group A had postoperative morbidity vs. 14.3% of patients in group D (p = 0.41). Regarding the secondary variable, 88.4% of surgeries in group A were scheduled vs. 90.5% of surgeries in group D (p = 0.583). CONCLUSION: In spite of reduced surgical activity, inguinal hernia morbidity did not surge in our environment. An increase in patients with previous pathologies was noted, which means severe patients should be prioritized.

INTRODUCCION: La pandemia del SARS-CoV-2 supuso una reducción de las jornadas quirúrgicas. Analizamos el efecto en la morbilidad de la hernia inguinal. MATERIAL Y METODOS: Estudio retrospectivo de casos y controles. Incluimos menores de 18 meses intervenidos de hernia inguinal desde 01/01/2019 hasta 31/08/2020, divididos en 2 grupos: intervenidos antes (grupo A) o después (grupo D) de la declaración del estado de alarma. Variables principales: episodios de incarceraciones y complicaciones postoperatorias. Variable secundaria: intervención urgente o programada. Variables poblacionales: sexo, edad gestacional (EG), patología previa, edad al diagnóstico(ED) y a la intervención (EI) (meses). RESULTADOS: Incluimos 64 pacientes, 43 grupo A y 21 grupo D. En el grupo A la mediana de EG fue 37+3, el 90,5% fueron varones, la mediana ED fue 2,33 y EI 3,27. En el grupo B la mediana de EG fue 31+2, el 72,1% fueron varones, la mediana ED fue 3 y EI 3,63. No hubo diferencias estadísticamente significativas. Si fueron significativas las diferencias en patología previa 16,3% A y 38,1% D (p = 0,05). Sobre la variable principal: 25,6% del A sufrieron incarceraciones frente a 33,3% del D (p = 0,51) y un 9,3% tuvieron morbilidad postoperatoria en A frente a 14,3% en D (p = 0,41). Respecto a la variable secundaria un 88,4% se realizaron de forma programada en el grupo A y un 90,5% en el grupo D (p = 0,583). CONCLUSION: Pese a la reducción de jornadas quirúrgicas no ha aumentado la morbilidad de la hernia inguinal en nuestro medio. Hemos observado un aumento de pacientes con patología previa, implicando la priorización de los pacientes más graves.

Have acute appendicitis complications increased in children as a result of SARS-CoV-2? / ¿Han aumentado las complicaciones de las apendicitis agudas en niños por el impacto del SARS-CoV-2?

INTRODUCTION: The impact of the SARS-CoV-2 pandemic on healthcare has already been described, since it has caused an increase in diagnostic delay and morbidity. Our objective was to assess its influence on the development of complications in children with acute appendicitis. MATERIALS AND METHODS: A retrospective cohort study was carried out. It included acute appendicitis patients under 15 years of age treated from January 1, 2019 to December 31, 2020. They were classified according to diagnosis date as before the pandemic (B) (January 2019-February 2020) and during the pandemic (D) (March 2020-December 2020). According to operative findings, they were classified as complicated appendicitis (perforated/abscess/plastron/peritonitis) and non-complicated appendicitis (catarrhal/phlegmonous/gangrenous). Demographic data, progression time, and postoperative complications were analyzed. RESULTS: A total of 309 patients were included, 193 (62.5%) in Group B, and 116 (37.5%) in Group D, with an age of 9.2 ± 0.4 and 9.4 ± 0.6 years, respectively (CI = 95%). Diagnostic time was 1.35 and 1.43 days (p>0.05) in Groups B and D, respectively, with ≥ 3 days representing 15.5% of cases in Group B, and 16.4% of cases in Group D (p = 0.84). The proportion of complicated appendicitis was 23.3% in Group B vs. 21.6% in Group D (p>0.05). Postoperative complications were observed in 11.4% of patients in Group B, and in 13.8% of patients in Group D (p>0.05), with intra-abdominal abscess being the most frequent complication in both groups (54.5% of the total complications in Group B vs. 65.5% in Group D; p>0.05). CONCLUSIONS: The management of acute appendicitis and its complications in pediatric patients has not been impacted by the SARS-CoV-2 pandemic or the safety measures enforced.

INTRODUCCION: Se ha descrito el impacto de la pandemia del SARS-CoV-2 en la atención sanitaria, al suponer un aumento del retraso diagnóstico y morbilidad. Nuestro objetivo es evaluar su influencia en el desarrollo de complicaciones en las apendicitis agudas en niños. METODOLOGIA: Estudio retrospectivo de cohortes, incluyendo los pacientes menores de 15 años tratados por apendicitis aguda desde 01/01/2019 hasta 31/12/2020. Se distribuyeron según su fecha de diagnóstico en: antes de la pandemia (A) (enero/2019-febrero/2020) y durante la pandemia (P) (marzo-diciembre/2020). Según los hallazgos quirúrgicos se clasificaron en: apendicitis complicadas (perforadas/abscesos/plastrones/peritonitis) y no complicadas (catarrales/flemonosas/gangrenosas). Se analizaron datos demográficos, tiempo de evolución y complicaciones postoperatorias. RESULTADOS: Se incluyeron un total de 309 pacientes, 193 pacientes (62,5%) en el grupo A y 116 (37,5%) en el P, con edades de 9,2 ± 0,4 y 9,4 ± 0,6 años respectivamente (IC = 95%). Los días al diagnóstico fueron 1,35 y 1,43 (p>0,05) en A y P respectivamente, siendo ≥ 3 días en 15,5% de A y 16,4% en P (p = 0,84). La proporción de apendicitis complicada fue un 23,3% en A vs. 21,6% en P; con p>0,05. Se observaron complicaciones postoperatorias en 11,4% de A y 13,8% de P (p>0,05), siendo la más frecuente el absceso intraabdominal en ambos grupos (54,5% del total de complicaciones vs 65,5%; en A y P respectivamente; p>0,05). CONCLUSIONES: La atención sanitaria de la apendicitis aguda y sus complicaciones en pacientes pediátricos no se ha visto modificada por la pandemia del SARS-CoV-2 o las medidas de seguridad adoptadas durante la misma.

Homocysteine enriched diet leads to prolonged QT interval and reduced left ventricular performance in telemetric monitored mice.

BACKGROUND AND AIMS: Homocysteine (Hcy) is a sulfur-containing, non-protein amino acid produced in the metabolic pathway of methionine. Hyperhomocysteinemia is associated with cerebro- and cardiovascular disease in industrialized countries, mostly resulting from protein rich diet and sedentary life style. Matrix metalloproteinases are involved in cardiac remodeling, leading to degradation of intercellular junctions, cardiac connexins and basement membranes. The study was designed to investigate the relationship between Hcy, cardiac remodeling, cardiac performance, and rhythm disturbances in an animal model of hyperhomocysteinemia. We tested the hypothesis that induction of matrix metalloproteinase-2 and matrix metalloproteinase-9 leads to connexin 40, connexin 43, connexin 45 expression changes contributing to decreased cardiac performance and disturbed atrioventricular conduction. METHODS AND RESULTS: Hcy was added to drinking water of male C57/BL6J mice to achieve moderate Hcy blood levels. ECG was monitored in conscious mice with a telemetric ECG device; echocardiography was used for assessment of left ventricular function. Immunoblotting was used to evaluate matrix metalloproteinase-2, matrix metalloproteinase-9, connexin 40, connexin 43, and connexin 45 expression in cardiac tissue. Animals fed Hcy showed significant prolongation of QRS, QTc, and PR intervals along with reduced left ventricular function. Western blotting showed increased expression of matrix metalloproteinase-2, matrix metalloproteinase-9 and decreased expression of connexin 40, 43, and 45. CONCLUSION: Hcy has been identified as a nutritional factor contributing to cardiovascular disease. Cardiac remodeling induced by matrix metalloproteinase-2 and matrix metalloproteinase-9 and decreased expression of connexin 40, 43, and 45 appears to play a role in the pathomechanism of atrioventricular conduction delay and ventricular dilatation in hyperhomocysteinemia.

Holistic numerical calibration of the iMESA electrostatic analyzer.

A drifted Maxwellian velocity distribution is the most common model used to interpret the data from low-energy charged-particle instruments onboard spacecraft that are used to investigate the ambient plasma environment in the low Earth orbit (LEO). An original method is presented for determining the flow parameters (density, temperature, and flow energy) of such a distribution from the output of the integrated miniaturized electrostatic analyzer, which has been successfully flown on several LEO missions. Rather than attempting to deconvolve from the on-orbit data the analyzer's response to an ideal, monoenergetic input, numerical simulation is used to predict and parameterize the response of the device to an input distribution that includes an isotropic, non-zero temperature, yielding a straightforward method for extracting the flow parameters from the spacecraft data. The method is computationally simple enough to be incorporated into a robust algorithm suitable for rapid batch processing or real-time analysis of data.

Multidisciplinary Management of the Adverse Effects of Apremilast. / Manejo de los efectos adversos de apremilast desde un abordaje multidisciplinar.

We present a series of general and specific recommendations based on pathophysiologic considerations for managing the most common adverse effects of apremilast that lead to treatment discontinuation: diarrhea, nausea, and headache. The recommendations are based on a review of the literature and the experience of a multidisciplinary team of 14 experts including dermatologists, rheumatologists, neurologists, gastroenterologists, pharmacists, and nurses. We propose a series of simple algorithms that include clinical actions and suggestions for pharmacologic treatment. The adverse effects of apremilast can be managed from a multidisciplinary approach. The purpose of optimizing management is to bring clinical benefits to patients.

Parallel activation of Ca(2+)-induced survival and death pathways in cardiomyocytes by sorbitol-induced hyperosmotic stress.

Hyperosmotic stress promotes rapid and pronounced apoptosis in cultured cardiomyocytes. Here, we investigated if Ca(2+) signals contribute to this response. Exposure of cardiomyocytes to sorbitol [600 mosmol (kg water)(-1)] elicited large and oscillatory intracellular Ca(2+) concentration increases. These Ca(2+) signals were inhibited by nifedipine, Cd(2+), U73122, xestospongin C and ryanodine, suggesting contributions from both Ca(2+) influx through voltage dependent L-type Ca(2+) channels plus Ca(2+) release from intracellular stores mediated by IP(3) receptors and ryanodine receptors. Hyperosmotic stress also increased mitochondrial Ca(2+) levels, promoted mitochondrial depolarization, reduced intracellular ATP content, and activated the transcriptional factor cyclic AMP responsive element binding protein (CREB), determined by increased CREB phosphorylation and electrophoretic mobility shift assays. Incubation with 1 mM EGTA to decrease extracellular [Ca(2+)] prevented cardiomyocyte apoptosis induced by hyperosmotic stress, while overexpression of an adenoviral dominant negative form of CREB abolished the cardioprotection provided by 1 mM EGTA. These results suggest that hyperosmotic stress induced by sorbitol, by increasing Ca(2+) influx and raising intracellular Ca(2+) concentration, activates Ca(2+) release from stores and causes cell death through mitochondrial function collapse. In addition, the present results suggest that the Ca(2+) increase induced by hyperosmotic stress promotes cell survival by recruiting CREB-mediated signaling. Thus, the fate of cardiomyocytes under hyperosmotic stress will depend on the balance between Ca(2+)-induced survival and death pathways.

A laminated energetic electrostatic analyzer for 0-5 keV charged particles.

A compact electrostatic energy bandpass filter based on a laminated analyzer design has been developed to measure charged particle fluxes at energies ranging from 0 to 5 keV. The sensor head has been successfully tested against a low energy magnetically filtered plasma source and an ion beam source capable of producing energetic ions in the range of 100-1250 eV. Additionally, the instrument has demonstrated the ability to accurately measure negative spacecraft frame charging using a low Earth orbit plasma simulator. The effects of the spacecraft frame charging on the measured energy distribution measurements and the impact regarding the derived charged particle density and temperature parameters are also examined.

The integrated miniaturized electrostatic analyzer: A space plasma environment sensor.

The integrated Miniaturized Electrostatic Analyzer (iMESA) was a satellite-based ionospheric sensor that operated on NASA's Space Test Program Satellite (STPSat-3) from December 2013 to July 2019. The instrument's scientific objective was to (1) measure the plasma density in low Earth orbit, (2) measure the plasma temperature in low Earth orbit, and (3) quantify the spacecraft potential with respect to the ambient plasma potential in the ionosphere. iMESA sampled the ionosphere every 10 s by measuring the ion current density through the ESA as a result of the motion of the spacecraft through the plasma. Current density spectra were transmitted to the ground where they were post-processed into ion density spectra and then analyzed numerically to determine the ion density, ion temperature, and spacecraft potential. This article discusses the instrument design and simulation, the determination of a geometric factor, and data processing procedures and evaluates the final data product with regard to the mission success criteria. The ion density and ion temperature captured by the iMESA instrument are on the same order and range as the values predicted in the literature. The spacecraft potential was also quantified. The conclusion after the evaluation of the instrument's data product is that the scientific mission is successful on all three points.