Lin-CD117+CD34+FcεRI+ progenitor cells are increased in chronic spontaneous urticaria and predict clinical responsiveness to anti-IgE therapy.

BACKGROUND: Chronic spontaneous urticaria (CSU) is a common, debilitating skin disorder characterized by recurring episodes of raised, itchy and sometimes painful wheals lasting longer than 6 weeks. CSU is mediated by mast cells which are absent from peripheral blood. However, lineage-CD34hiCD117int/hiFcεRI+ cells in blood have previously been shown to represent a mast cell precursor. METHODS: We enumerated FcεRI-, FcεRI+ and FcεRIhi lineage-CD34+CD117+ cells using flow cytometry in blood of patients with CSU (n = 55), including 12 patients receiving omalizumab and 43 not receiving omalizumab (n = 43). Twenty-two control samples were studied. Disease control and patient response to omalizumab was evaluated using the urticaria control test. We performed single-cell RNA sequencing (scRNA-Seq) on lineage-CD34hiCD117hi blood cells from a subset of patients with CSU (n = 8) and healthy controls (n = 4). RESULTS: CSU patients had more lineage-CD34+CD117+FcεRI+ blood cells than controls. Lineage-CD34+CD117+FcεRI+ cells were significantly higher in patients with CSU who had an objective clinical response to omalizumab when compared to patients who had poor disease control 90 days after initiation of omalizumab. scRNA-Seq revealed that lineage-CD34+CD117+FcεRI+ cells contained both lymphoid and myeloid progenitor lineages, with omalizumab responsive patients having proportionally more myeloid progenitors. The myeloid progenitor lineage contained small numbers of true mast cell precursors along with more immature FcεRI- and FcεRI+ myeloid progenitors. CONCLUSION: Increased blood CD34+CD117+FcεRI+ cells may reflect enhanced bone marrow egress in the setting of CSU. High expression of these cells strongly predicts better clinical responses to the anti-IgE therapy, omalizumab.

Circulating mast cell progenitors increase during natural birch pollen exposure in allergic asthma patients.

BACKGROUND: Mast cells (MCs) develop from a rare population of peripheral blood circulating MC progenitors (MCps). Here, we investigated whether the frequency of circulating MCps is altered in asthma patients sensitized to birch pollen during pollen season, compared to out of season. METHODS: Asthma patients were examined during birch pollen season in late April to early June (May), and out of season in November-January. Spirometry measurements, asthma and allergy-related symptoms, asthma control questionnaire (ACQ), and asthma control test (ACT) scores were assessed at both time points. The MCp frequency was determined by flow cytometry in ficoll-separated blood samples from patients with positive birch pollen-specific IgE, and analyzed in relation to basic and disease parameters. RESULTS: The frequency of MCps per liter of blood was higher in May than in November (p = .004), particularly in women (p = .009). Patients that reported moderate to severe asthma symptoms (<.0001), nose or eye symptoms (p = .02; p = .01), or reduced asthma control (higher ACQ, p = .01) had higher MCp frequency in May than those that did not report this. These associations remained significant after adjusting for sex and BMI. The change in asthma control to a lower ACT score in May correlated with an increase in MCp frequency in May (p = .006, rho = 0.46). CONCLUSIONS: The data suggest that the frequency of MCps increases in symptomatic patients with allergic asthma. Our results unravel a link between asthma symptoms and circulating MCps, and bring new insight into the impact of natural allergen exposure on the expansion of MCs.

Social cognition interventions for adolescents with autism spectrum disorder. A systematic review.

Early intervention during childhood in patients with Autism Spectrum Disorder (ASD) has been strongly advocated. As adolescence is reached, new, more complex social demands emerge. These demands require a therapeutic approach that has not been widely studied. The aim of this review is to examine and synthesize the existing literature on social cognition interventions in adolescence and lay the groundwork for future interventions.

Effectiveness of uterine tamponade devices for refractory postpartum haemorrhage after vaginal birth: a systematic review.

OBJECTIVES: To evaluate uterine tamponade devices' effectiveness for atonic refractory postpartum haemorrhage (PPH) after vaginal birth and the effect of including them in institutional protocols. SEARCH STRATEGY: PubMed, EMBASE, CINAHL, LILACS, POPLINE, from inception to January 2021. STUDY SELECTION: Randomised and non-randomised comparative studies. OUTCOMES: Composite outcome including surgical interventions (artery ligations, compressive sutures or hysterectomy) or maternal death, and hysterectomy. RESULTS: All included studies were at high risk of bias. The certainty of the evidence was rated as very low to low. One randomised study measured the effect of the condom-catheter balloon compared with standard care and found unclear results for the composite outcome (relative risk [RR] 2.33, 95% CI 0.76-7.14) and hysterectomy (RR 4.14, 95% CI 0.48-35.93). Three comparative studies assessed the effect of including uterine balloon tamponade in institutional protocols. A stepped wedge cluster randomised controlled trial suggested an increase in the composite outcome (RR 4.08, 95% CI 1.07-15.58) and unclear results for hysterectomy (RR 4.38, 95% CI 0.47-41.09) with the use of the condom-catheter or surgical glove balloon. One non-randomised study showed unclear effects on the composite outcome (RR 0.33, 95% CI 0.11-1.03) and hysterectomy (RR 0.49, 95% CI 0.04-5.38) after the inclusion of the Bakri balloon. The second non-randomised study found unclear effects on the composite outcome (RR 0.95, 95% CI 0.32-2.81) and hysterectomy (RR 1.84, 95% CI 0.44-7.69) after the inclusion of Ebb or Bakri balloon. CONCLUSIONS: The effect of uterine tamponade devices for the management of atonic refractory PPH after vaginal delivery is unclear, as is the role of the type of device and the setting. TWEETABLE ABSTRACT: Unclear effects of uterine tamponade devices and their inclusion in institutional protocols for atonic refractory PPH after vaginal delivery.

Tachykinins modulate nociceptive responsiveness and sensitization: In vivo electrical characterization of primary sensory neurons in tachykinin knockout (Tac1 KO) mice.

Since the failure of specific substance P antagonists to induce analgesia, the role of tachykinins in the development of neuropathic pain states has been discounted. This conclusion was reached without studies on the role of tachykinins in normal patterns of primary afferents response and sensitization or the consequences of their absence on the modulation of primary mechanonociceptive afferents after injury. Nociceptive afferents from animals lacking tachykinins (Tac1 knockout) showed a disrupted pattern of activation to tonic suprathreshold mechanical stimulation. These nociceptors failed to encode the duration and magnitude of natural pronociceptive stimuli or to develop mechanical sensitization as consequence of this stimulation. Moreover, paw edema, hypersensitivity, and weight bearing were also reduced in Tac1 knockout mice 24 h after paw incision surgery. At this time, nociceptive afferents from these animals did not show the normal sensitization to mechanical stimulation or altered membrane electrical hyperexcitability as observed in wild-type animals. These changes occurred despite a similar increase in calcitonin gene-related peptide immunoreactivity in sensory neurons in Tac1 knockout and normal mice. Based on these observations, we conclude that tachykinins are critical modulators of primary nociceptive afferents, with a preeminent role in the electrical control of their excitability with sustained activation or injury.

Stillbirth rates in 20 countries of Latin America: an ecological study.

OBJECTIVE: To describe country-level stillbirth rates and their change over time in Latin America, and to measure the association of stillbirth rates with socio-economic and health coverage indicators in the region. DESIGN: Ecological study. SETTING: 20 countries of Latin America. POPULATION OR SAMPLE: Aggregated data from pregnant women with countries as units of analysis. METHODS: We used stillbirth estimates, and socio-economic and healthcare coverage indicators reported from 2006 to 2016 from UNICEF, United Nations Development Programme and World Bank datasets. We calculated Spearman's correlation coefficients between stillbirths rates and socioeconomic and health coverage indicators. MAIN OUTCOME MEASURES: National estimates of stillbirth rates in each country. RESULTS: The estimated stillbirth rate for Latin America for 2015 was 8.1 per 1000 births (range 3.1-24.9). Seven Latin America countries had rates higher than 10 stillbirths per 1000 births. The average annual reduction rate for the region was 2% (range 0.1-3.8%), with the majority of Latin America countries ranging between 1.5 and 2.5%. National stillbirth rates were correlated to: women's schooling (rS = -0.7910), gross domestic product per capita (rS = -0.8226), fertility rate (rS = 0.6055), urban population (rS = -0.6316), and deliveries at health facilities (rS = -0.6454). CONCLUSIONS: Country-level estimated stillbirth rates in Latin America varied widely in 2015. The trend and magnitude of reduction in stillbirth rates between 2000 and 2015 was similar to the world average. Socio-economic and health coverage indicators were correlated to stillbirth rates in Latin America. TWEETABLE ABSTRACT: Stillbirth rates decreased in Latin America but remain relatively high, with wide variations among countries.

TARDBP mutation associated with semantic variant primary progressive aphasia, case report and review of the literature.

Semantic variant primary progressive aphasia (svPPA) is a clinical syndrome included in the frontotemporal dementia (FTD) spectrum. Unlike other forms of FTD, it is sporadic in the majority of cases and not commonly associated with motor neuron disease (MND). We describe a case of svPPA associated with MND in the same family, due to a mutation of the transactive response DNA binding protein (TARDBP) gene, and review the literature.

Relationship between dental occlusion and functional dependence in elderly Caucasians.

OBJECTIVE: To determine whether a relationship exists between the number of functional masticatory units (FMUs) and the level of functional dependence of elderly. SUBJECTS AND METHODS: The study group comprised 502 elderly Caucasians living in nursing homes in north-west Spain and Portugal. The number of FMUs was counted on direct visual inspection. The degree of dependence was assessed using the Barthel index. The results were validated in a group of 156 elderly. Statistical analysis of the results was performed using a generalised linear model (GLM), a logistic GLM, a ROC-GLM curve and a confusion matrix. RESULTS: The number of FMUs significantly affected the Barthel index score (explained deviance = 27.5%). The number of FMUs was significantly associated with a lower probability of dependence, both for women (explained deviance = 31%) and for men (explained deviance = 33%). The model based on FMUs showed a good discriminatory capacity for dependence (AUC = 0.84 in women and 0.82 in men). The predictive capacity of the dependence model based on FMUs was very high (sensitivity = 0.9 in women and 0.8 in men). CONCLUSIONS: In institutionalised elderly Caucasians, the number of FMUs is significantly associated with the Barthel index score and could be a predictive factor for dependence.

Cannabis and Cannabinoids for Chronic Pain.

PURPOSE OF REVIEW: The purpose of this study was to provide the most up-to-date scientific evidence of the potential analgesic effects, or lack thereof, of the marijuana plant (cannabis) or cannabinoids, and of safety or tolerability of their long-term use. RECENT FINDINGS: We found that inhaled (smoked or vaporized) cannabis is consistently effective in reducing chronic non-cancer pain. Oral cannabinoids seem to improve some aspects of chronic pain (sleep and general quality of life), or cancer chronic pain, but they do not seem effective in acute postoperative pain, abdominal chronic pain, or rheumatoid pain. The available literature shows that inhaled cannabis seems to be more tolerable and predictable than oral cannabinoids. Cannabis or cannabinoids are not universally effective for pain. Continued research on cannabis constituents and improving bioavailability for oral cannabinoids is needed. Other aspects of pain management in patients using cannabis require further open discussion: concomitant opioid use, medical vs. recreational cannabis, abuse potential, etc.

Doppler ultrasound study and venous mapping in chronic venous insufficiency.

Chronic venous insufficiency of the lower limbs is very prevalent. In recent decades, Doppler ultrasound has become the method of choice to study this condition, and it is considered essential when surgery is indicated. This article aims to establish a method for the examination, including venous mapping and preoperative marking. To this end, we review the venous anatomy of the lower limbs and the pathophysiology of chronic venous insufficiency and explain the basic hemodynamic concepts and the terminology required to elaborate a radiological report that will enable appropriate treatment planning and communication with other specialists. We briefly explain the CHIVA (the acronym for the French term "cure conservatrice et hémodynamique de l'insuffisance veineuse en ambulatoire"=conservative hemodynamic treatment for chronic venous insufficiency) strategy, a minimally invasive surgical strategy that aims to restore correct venous hemodynamics without resecting the saphenous vein.

Immunization of adult dairy cattle with a new heat-killed vaccine is associated with longer productive life prior to cows being sent to slaughter with suspected paratuberculosis.

The objective of this study was to evaluate the efficacy of a new heat-killed Mycobacterium avium ssp. paratuberculosis (MAP) vaccine for control of premature culling in tuberculosis-free dairy cattle. Feces and gastrointestinal tissues were collected from 50 vaccinated cows and 38 nonvaccinated cows at slaughter and analyzed by bacteriological culture and histopathology. Vaccination was associated with a significant reduction of the frequency of vaccinated animals with MAP in feces and gut tissues compared with the nonvaccinated animals. In addition, the frequency of vaccinated animals with heavy bacterial load in gut tissues was 40% lower than the frequency of the nonvaccinated animals with the same MAP load. The peak age of paratuberculosis-associated culling was from 4.5 to 5 yr old (21%) in the vaccinated animals and from 3 to 4.5 yr old (60%) in the nonvaccinated animals. The vaccinated and nonvaccinated animals with suspected paratuberculosis were culled at an average age of 4.7 and 3.7 yr old, respectively. Therefore, a significant increase in the productive life of the vaccinated animals sent to slaughter with suspected paratuberculosis was observed. In addition, our analysis revealed a positive effect of the vaccine on the carcass weights of the animals with severe histopathological lesions at slaughter compared with the nonvaccinated animals. In summary, our findings suggest a therapeutic effect of the vaccine and a significant attenuation of pre-existing infection in cows naturally infected with paratuberculosis that were adults at the time of vaccination.

Genetic variation of toll-like receptor genes and infection by Mycobacterium avium ssp. paratuberculosis in Holstein-Friesian cattle.

Toll-like receptors (TLR) are membrane proteins that play a key role in innate immunity, by recognizing pathogens and subsequently activating appropriate responses. Mutations in TLR genes are associated with susceptibility to inflammatory and infectious diseases in humans. In cattle, 3 members of the TLR family, TLR1, TLR2, and TLR4, are associated with Mycobacterium avium ssp. paratuberculosis infection, although the extent of this association for the TLR1 and TLR4 receptors has not yet been determined. Moreover, the causal variant in the TLR2 gene has not yet been unequivocally established. In this study, 24 single nucleotide polymorphisms (SNP) in the bovine TLR1, TLR2, and TLR4 genes were selected from the literature, databases, and in silico searches, for a population-based genetic association study of a Spanish Holstein-Friesian sample. Whereas previous results regarding the TLR1 gene were not corroborated, a risk haplotype was detected in TLR2; however, its low frequency indicates that this detected association should be interpreted with caution. In the case of the TLR4 gene, 3 tightly linked SNP were found to be associated with susceptibility to M. avium ssp. paratuberculosis infection. Moreover, one of these SNP, the SNP c.-226G>C, which is localized in the 5'UTR region of the TLR4 gene, has been reported to be able to alter TLR4 expression, raising the possibility that this mutation may contribute to the response of the individual to infection.

[Landscape components favouring the occurrence of anthrax in the Flooding Pampa grasslands (Buenos Aires province, Argentina)]. / Componentes del paisaje que favorecen la aparición de carbunco en la Pampa Deprimida (provincia de Buenos Aires, Argentina).

The authors studied the landscape components that favour the occurrence of anthrax in the Flooding Pampa grasslands (Buenos Aires province, Argentina). They made spatial locations of anthrax outbreaks diagnosed by registered veterinary laboratories in the study area's zone of influence. As variables for study, they differentiated areas that are flooded for 20% of the time or more from primary and secondary runoff channels. They also identified areas with low-productivity pasture. Logistic regression analysis of farm populations revealed that landscape components favouring the occurrence of anthrax outbreaks are shared runoff channels (odds ratio (OR) = 2.3; confidence interval (CI) = 1.2; 4.7) and > or = 40% low-productivity pasture (OR = 5.4; CI = 3.5; 8.3). Contrary to initial assumptions, susceptibility to flooding was not a significant variable (OR = 1.1; CI = 0.5; 2.1). The authors concluded that the first step in decision-making and ensuring more efficient implementation of future anthrax control and eradication plans was to identify risk variables.

[Efficiency of the information given at discharge and adherence of polymedicated patients]. / Eficacia de la información al alta en la adherencia del paciente polimedicado.

OBJECTIVE: To evaluate the utility of a post-discharge pharmaceutical care programme. METHOD: Three-month prospective study where patients were randomised into two groups according to whether or not they received verbal and written information about their treatment at hospital discharge. Treatment compliance was assessed by the Morisky Green test at discharge and at 30-50 days via a telephone interview, also collecting information on patient medication. RESULTS: A total of 59 patients were included, 30 in the control group and 29 in the experimental group. 42.1 ± 9.6days had elapsed between discharge and the telephone interview. While a higher percentage of patients were adherent to treatment at discharge in the control group (83.3 versus 62.1%, OR=0.33, 95% CI: 0.1-1.1, P=.07), in the telephone interview the percentage in the experimental group was greater (62.5 versus 88.5%, OR=4.6, 95% CI: 1.1-19.8, P=.03). The differences between the two groups for the rest of the variables (deaths, visits to emergency department and hospital readmissions) were not statistically significant. In the telephone interview, 70% of patients' treatment was changed in some way since hospital discharge. CONCLUSION: A post-discharge pharmaceutical care programme is a tool to improve treatment compliance, which needs continuity due to the large number of treatment changes suffered by these patients.

Signaling and biological effects of glucagon-like peptide 1 on the differentiation of mesenchymal stem cells from human bone marrow.

Glucagon-like peptide 1 (GLP-1) functions as an incretin hormone with antidiabetogenic properties. However, the role of GLP-1 in human bone marrow-derived mesenchymal stem cells (hMSCs), if any, remains unknown. The effects of GLP-1 on hMSCs were tested with regard to cell proliferation, cytoprotection, and cell differentiation into adipocytes. The signaling pathways involved in these processes were also analyzed. Cells were characterized with biochemical and morphological approaches before and after being induced to differentiate into adipocytes. PCNA protein levels were used as a proliferation index, whereas cell apoptosis was studied by deprivation of fetal bovine serum. Isolated hMSCs expressed stem cell markers as well as mRNA and GLP-1 receptor protein. GLP-1 increased the proliferation of hMSCs, which decreased when they were induced to differentiate into adipocytes. This process produced biochemical and morphological changes in cells expressing PPARgamma, C/EBPbeta, AP2, and LPL in a time-dependent pattern. Notably, GLP-1 significantly reduced the expression of PPARgamma, C/EBPbeta, and LPL. These effects were exerted at least through the MEK and PKC signaling pathways. In addition, GLP-1 significantly reduced cell apoptosis. Our data indicate that, in hMSCs, GLP-1 promotes cellular proliferation and cytoprotection and prevents cell differentiation into adipocytes. These latter findings underscore the potential therapeutic role of GLP-1 in preventing the adipocyte hyperplasia associated with obesity and, additionally, could bolster the maintenance of hMSC stores by promoting the proliferation and cytoprotection of undifferentiated hMSC.

SP110 as a novel susceptibility gene for Mycobacterium avium subspecies paratuberculosis infection in cattle.

The intracellular pathogen resistance 1 (Ipr1) gene has been reported to play a role in mediating innate immunity in a mouse model of Mycobacterium tuberculosis infection, and polymorphisms of its human ortholog, SP110 nuclear body protein, have been suggested to be associated with tuberculosis. Thus, the bovine SP110 gene was considered to be a promising candidate for a genetic association study of bovine paratuberculosis, or Johne's disease, a chronic granulomatous enteritis caused by Mycobacterium avium ssp. paratuberculosis (MAP). Initially, single nucleotide polymorphisms (SNP) within the bovine SP110 gene were identified, and subsequently a population-based genetic association study was carried out. Seventeen new SNP along the SP110 gene were identified in Holstein-Friesian cattle, and 6 more were compiled from public databases. A total of 14 SNP were included in the association study of 2 independent populations. The SNP c.587A>G was found to be significantly associated with MAP infection, with the major allele A appearing to confer greater disease susceptibility in one of the analyzed populations. In addition, 2 haplotypes containing this SNP were also found to be associated with infection in the same population. The SNP c.587A>G is a nonsynonymous mutation that causes an amino acid change in codon 196 from asparagine to serine. In silico analyses point to SNP c.587A>G as a putative causal variant for susceptibility to MAP infection. The elucidation of the precise mechanism by which this SNP can exert its effect in the protein and, as a result, in the risk of infection, requires future functional analyses. Likewise, the absence of genetic association in one of the analyzed populations renders it necessary to carry out this study in other independent populations, with the aim of substantiating the repeatability of the present results. Nevertheless, the present results deepen our understanding of the genetic basis of susceptibility and resistance mechanisms related to MAP infection in cattle and, in turn, constitute a step forward toward the implementation of marker-assisted selection in breeding programs aimed at controlling paratuberculosis.

[Regulatory requirements; What steps must be taken before starting a biomedical research study?] / Requerimientos normativos: ¿Qué pasos tengo que seguir antes de iniciar un estudio de investigación biomédica?

Studies of research with human beings, their biological specimens, or their personal data in the field of biomedicine have been subject to regulation since the middle of the last century. Initially a regulation based on recommendations such as the Nuremberg Code, the Belmont Report or the first versions of the Declaration of Helsinki. All of them documents in which the principles (autonomy, beneficence, non-maleficence, and justice) were conceptualized, and that all researchers had to follow in the development of their research. This first phase is known as a period of self-regulation, because it is considered that the researchers themselves could, by following these recommendations, carry out their investigations without further control. Subsequently, it went through a clearly regulatory period in which the premises of these recommendations were progressively incorporated into the legal system of the different countries, and with this, arose the external control of the investigation by the administrations and other bodies, such as the Research Ethics Committees. The purpose of this article is to serve as a guide to professionals whose main activity is care in the field of Primary Care and who, in turn, are interested in initiating research studies to respond to uncertainties in the context of their daily activity that may arise.

[Profile of the Family Doctor who gains access to positions with teaching tutorship of Family and Community Medicine by means of relocation examination in Galicia]. / Perfil del médico de familia que accede a plazas con tutoría docente de Medicina Familiar y Comunitaria mediante concurso de traslados en Galicia.

OBJECTIVE: To analyse the profile of Family Doctors who gain access to positions, both to the general quota, as well those reserved for teaching tutors of Family and Community Medicine, by means of a relocation competition. MATERIAL AND METHODS: A descriptive observational study was conducted in which 2 comparison groups were established: A Non-Teaching group that did not include Family Doctors who did not request or gain access to tutor positions, and a Teaching group with those that gained access to positions reserved for tutors. The information was obtained from the marks of the relocation competition carried out in Galicia in 2018. A total of 426 General Practitioners that entered the examination were included, of which 301 were female (70.7%) and 125 (29.3%) males. The variables were the obtaining of a position reserved for tutor, gender, and the merits considered in the competition: professional experience, training, scientific publications, and Galician language. The non-parametric statistics tests of Mann-Whitney and Kruskal-Wallis were used, after checking for non-normal distribution. RESULTS: Statistically significant differences were found in the distribution by gender in favour of males in the Teaching group compared to the Non-Teaching group (P<.01). The Teaching group obtained better results in training and publications. The females obtained statistically significant results in their favour in the training variable, and the males in experience. CONCLUSIONS: For the choice of teaching places in relocation interviews and examinations, publications and training had an important weighting; but, taking the gender perspective into account, a lower percentage of women had gained access to teaching positions due to having lower score in the experience category.

[Correlation between the six-minute walk test and maximal exercise test in patients with type ii diabetes mellitus]. / Correlación entre prueba de marcha de 6 minutos y prueba de esfuerzo máxima en pacientes con diabetes mellitus de tipo ii.

INTRODUCTION: The 6-minute walk test is an exercise test that has been used in diabetic patients to assess the effectiveness of exercise programmes and has been correlated with clinical parameters; however, the correlation with the maximum workload registered during stress testing has not been determined in diabetic patients. OBJECTIVE: To establish the correlation between the 6-minute walk test and the maximum workload registered during a stress test in patients with type ii diabetes mellitus and its association with glycemic control. MATERIALS AND METHODS: We included 42 patients with type ii diabetes mellitus and mean age of 61.1 years, who underwent physical examination, a 6-minute walk test, a treadmill stress test and laboratory studies. RESULTS: The 6-minute walk test had high reproducibility in diabetic patients and showed a moderate-low correlation with maximum workload on the treadmill (r=49, p=0.001). A significant association was found between the 6-minute walk test and glycosylated haemoglobin A1C values (RP 1.57, χ2 <0.05). CONCLUSION: The 6-minute walk test is a highly reproducible test and has a significant correlation with maximum physical workload in the diabetic patients tested. Therefore, it can be used as a test for assessing functional capacity in this population.