The role of IgG1 and IgG4 as dominant IgE-blocking antibodies shifts during allergen immunotherapy.

BACKGROUND: The induction of allergen-specific IgE-blocking antibodies is a hallmark of allergen immunotherapy (AIT). The inhibitory bioactivity has largely been attributed to IgG4; however, our recent studies indicated the dominance of IgG1 early in AIT. OBJECTIVES: Here, the IgE-blocking activity and avidity of allergen-specific IgG1 and IgG4 antibodies were monitored throughout 3 years of treatment. METHODS: Serum samples from 24 patients were collected before and regularly during AIT with birch pollen. Bet v 1-specific IgG1 and IgG4 levels were determined by ELISA and ImmunoCAP, respectively. Unmodified and IgG1- or IgG4-depleted samples were compared for their inhibition of Bet v 1-induced basophil activation. The stability of Bet v 1-antibody complexes was compared by ELISA and by surface plasmon resonance. RESULTS: Bet v 1-specific IgG1 and IgG4 levels peaked at 12 and 24 months of AIT, respectively. Serological IgE-blocking peaked at 6 months and remained high thereafter. In the first year of therapy, depletion of IgG1 clearly diminished the inhibition of basophil activation while the absence of IgG4 hardly reduced IgE-blocking. Then, IgG4 became the main inhibitory isotype in most individuals. Both isotypes displayed high avidity to Bet v 1 ab initio of AIT, which did not increase during treatment. Bet v 1-IgG1 complexes were enduringly more stable than Bet v 1-IgG4 complexes were. CONCLUSIONS: In spite of the constant avidity of AIT-induced allergen-specific IgG1 and IgG4 antibodies, their dominance in IgE-blocking shifted in the course of treatment. The blocking activity of allergen-specific IgG1 should not be underestimated, particularly early in AIT.

Cannabidiol repairs behavioral and brain disturbances in a model of fetal alcohol spectrum disorder.

Fetal alcohol spectrum disorder (FASD) includes neuropsychiatric disturbances related to gestational and lactational ethanol exposure. Available treatments are minimal and do not modulate ethanol-induced damage. Developing animal models simulating FASD is essential for understanding the underlying brain alterations and searching for efficient therapeutic approaches. The main goal of this study was to evaluate the effects of early and chronic cannabidiol (CBD) administration on offspring exposed to an animal model of FASD. Ethanol gavage (3 g/kg/12 h, p.o.) was administered to C57BL/6 J female mice, with a previous history of alcohol consumption, between gestational day 7 and postnatal day 21. On the weaning day, pups were separated by sex, and CBD administration began (30 mg/kg/day, i.p.). After 4-6 weeks of treatment, behavioral and neurobiological changes were analyzed. Mice exposed to the animal model of FASD showed higher anxiogenic and depressive-like behaviors and cognitive impairment that were evaluated through several experimental tests. These behaviors were accompanied by alterations in the gene, cellular and metabolomic targets. CBD administration normalized FASD model-induced emotional and cognitive disturbances, gene expression, and cellular changes with sex-dependent differences. CBD modulates the metabolomic changes detected in the hippocampus and prefrontal cortex. Interestingly, no changes were found in mitochondria or the oxidative status of the cells. These results suggest that the early and repeated administration of CBD modulated the long-lasting behavioral, gene and protein alterations induced by the FASD model, encouraging the possibility of performing clinical trials to evaluate the effects of CBD in children affected with FASD.

Consultorio de Salud Ambiental en un Hospital Privado de Comunidad de la Ciudad de Buenos Aires / Environmental Health consulting office in a Private Community Hospital of the Buenos Aires City

En los últimos años surge el concepto de Una Sola Salud que reconoce la interdependencia sistémica al observar que los cambios en la salud humana se expresan de manera sincrónica e indivisible de la salud del ambiente. Nuevas enfermedades y daños crónicos inespecíficos ocurren a la par de la pérdida de biodiversidad y vitalidad. En las últimas décadas venimos observando el surgimiento de "adaptaciones sistémicas" que requieren un abordaje desde la clínica y la toxicología a nivel individual y desde la epidemiología de la complejidad a nivel poblacional. Luego de un largo recorrido de investigaciones, el Hospital Italiano formalizó el consultorio de Salud Ambiental con la intención de brindar respuesta a la demanda de pacientes que atribuyen síntomas y signos a la polución ambiental. (AU)

In recent years, the concept of One Health has emerged, recognizing the systemic interdependence and the changes in human health that are expressed synchronously and indivisible from the environment. New diseases and nonspecific chronic damage are occuring in parallel with the loss of biodiversity and vitality.In recent decades we have observed the appearance of "systemic adaptations" that require a clinical and toxicological approach at the individual level, and address the population level from an epidemiological and complexity science paradigm. After many years of research, the Hospital Italiano de Buenos Aires formalized the Environmental Health consulting office and the measurement of glyphosate levels, giving answer to the demand of patients who associate their signs and symptoms to environmental pollution. (AU)

The secretome of irradiated peripheral blood mononuclear cells attenuates activation of mast cells and basophils.

BACKGROUND: IgE-mediated hypersensitivity is becoming increasingly prevalent and activation of mast cells and basophils represent key events in the pathophysiology of allergy. We have previously reported that the secretome of γ-irradiated peripheral blood mononuclear cells (PBMCsec) exerts beneficial anti-inflammatory effects. Yet, its ability to alleviate allergic symptoms has not been investigated so far. METHODS: Several experimental in vitro and in vivo models have been used in this basic research study. A murine ear swelling model was used to study the effects of PBMCsec on 48/80-induced mast cell degranulation in vivo. The transcriptional profile of murine mast cells was analysed by single cell RNA sequencing (scRNAseq). Mast cell activation was studied in vitro using primary skin mast cells. Basophils from individuals allergic to birch pollens were used to investigate basophile activation by allergens. Transcriptomic and lipidomic analyses were used to identify mRNA expression and lipid species present in PBMCsec, respectively. FINDINGS: Topical application of PBMCsec on mouse ears (C57BL/6) significantly reduced tissue swelling following intradermal injection of compound 48/80, an inducer of mast cell degranulation. Single cell RNA sequencing of PBMCsec-treated murine dermal mast cells (Balb/c) revealed a downregulation of genes involved in immune cell degranulation and Fc-receptor signalling. In addition, treatment of primary human dermal mast cells with PBMCsec strongly inhibited compound 48/80- and α-IgE-induced mediator release in vitro. Furthermore, PBMCsec remarkably attenuated allergen driven activation of basophils from allergic individuals. Transcriptomic analysis of these basophils showed that PBMCsec downregulated a distinct gene battery involved in immune cell degranulation and Fc-receptor signalling, corroborating results obtained from dermal mast cells. Finally, we identified the lipid fraction of PBMCsec as the major active ingredient involved in effector cell inhibition. INTERPRETATION: Collectively, our data demonstrate that PBMCsec is able to reduce activation of mast cells and basophils, encouraging further studies on the potential use of PBMCsec for treating allergy. FUNDING: Austrian Research Promotion Agency (852748 and 862068, 2015-2019), Vienna Business Agency (2343727, 2018-2020), Aposcience AG, Austrian Federal Ministry of Education, Science and Research (SPA06/055), Danube Allergy Research Cluster, Austrian Science Fund (I4437 and P32953).

Resistencia antimicrobiana y producción porcina de cría intensiva / Antimicrobial resistance and intensive swine production: mini review

Introducción: el impacto de la resistencia antimicrobiana (RAM) generará un aumento de las muertes relacionadas de 10 millones anuales hacia 2050. El 70% de la dispensación de antimicrobianos (ATB) se utiliza en la agroveterinaria y no en salud humana. Es fundamental conocer la portación de RAM en trabajadores de cría de animales y en los animales, para acciones tempranas de salud pública. Métodos: bajo metodología PRISMA se realizó la búsqueda bibliográfica en distintas fuentes disponibles hasta octubre de 2020. Se priorizaron revisiones sistemáticas, metanálisis, ensayos clínicos y estudios observacionales para determinar la RAM en trabajadores de cría de cerdos. De 990 artículos identificados se incluyeron 8 estudios. Resultados: la tasa de colonización por Staphylococcus aureus resistente a la meticilina (SAMR) en trabajadores fue mayor que la de la población general. La prevalencia de SAMR fue significativamente mayor en trabajadores en contacto directo con animales y los de granjas de cría intensiva con respecto a los de extensiva. En cerdos, la prevalencia de RAM en cría intensiva fue significativamente mayor que la de los de cría extensiva. También fue significativa la asociación entre el suministro de antibióticos en la cría intensiva y la presencia de RAM. Las granjas de más de 1250 cerdos presentaron mayor prevalencia de RAM (p < 0,001). El fenotipo de SAMR en cerdos, trabajadores y el ambiente fue el mismo. Conclusiones: existe evidencia de asociación entre la producción agrícola de cría intensiva y la RAM en cerdos y trabajadores. No se encontraron estudios de vigilancia epidemiológica en la Argentina en trabajadores de cría de animales. (AU)

Introduction: it is estimated that the impact of antimicrobial resistance (AMR) will generate an increase of 10 million deaths by 2050, being reflected to a greater extent in low-income countries. 70% of the annual use of antimicrobials is concentrated in agroveterinary but not in human health. Considering the presence of AMR in ranchers and agricultural workers is essential for early public health actions. Methods: using the PRISMA methodology, bibliography was searched in different sources until October 2020. Systematic reviews, meta-analyses, clinical trials and observational studies were prioritized to determine AMR in pig workers. Eight studies of the 990 found have been included. Results: the rate of colonization by methicillin-resistant Staphylococcus aureus (MRSA) in farming workers was higher than the general population. MRSA prevalence was significantly higher in workers who reported direct contact with animals. And also in those workers of intensive farms compared to those of extensive farms. The same situation is observed in swines, in which the prevalence of AMR in intensive farming was significantly higher than in extensive farming. The association between the supply of antibiotics in intensive farming workers and the presence of AMR was also significant. Farms with more than 1,250 swines had a higher prevalence of AMR (p<0.001). The MRSA phenotype found in swine, agricultural workers, and the environment was the same. Conclusions: there is scientific evidence of an association between agricultural production in intensive livestock farming and AMR in swine and farming workers. There aren't Argentine studies of epidemiological surveillance in farming workers. (AU)

Molecular Alterations of the Endocannabinoid System in Psychiatric Disorders.

The therapeutic benefits of the current medications for patients with psychiatric disorders contrast with a great variety of adverse effects. The endocannabinoid system (ECS) components have gained high interest as potential new targets for treating psychiatry diseases because of their neuromodulator role, which is essential to understanding the regulation of many brain functions. This article reviewed the molecular alterations in ECS occurring in different psychiatric conditions. The methods used to identify alterations in the ECS were also described. We used a translational approach. The animal models reproducing some behavioral and/or neurochemical aspects of psychiatric disorders and the molecular alterations in clinical studies in post-mortem brain tissue or peripheral tissues were analyzed. This article reviewed the most relevant ECS changes in prevalent psychiatric diseases such as mood disorders, schizophrenia, autism, attentional deficit, eating disorders (ED), and addiction. The review concludes that clinical research studies are urgently needed for two different purposes: (1) To identify alterations of the ECS components potentially useful as new biomarkers relating to a specific disease or condition, and (2) to design new therapeutic targets based on the specific alterations found to improve the pharmacological treatment in psychiatry.

Exploring Agaricomycetes from the Paranaense rainforest (Misiones, Argentina) as an unconventional source of fibrinolytic enzymes.

Fungal fibrinolytic enzymes, secreted by some Agaricomycetes, are recognized as important thrombolytic agents due to their ability to rapidly dissolve thromboembolic clots. The present work evaluated fibrinolytic and proteolytic secretion abilities of 35 Agaricomycetes isolates from the Paranaense rainforest (Misiones, Argentina). We detected proteolytic activity in 40% of the strains while nine strains showed fibrinolytic activity. Schizophyllum commune LBM 026, Schizophyllum commune LBM 223, and Hornodermoporus martius LBM 224 exhibited the highest levels of fibrinolytic activity. Fibrin zymography from S. commune LBM 026 and LBM 223 showed an enzyme of 27.5 kDa, while H. martius LBM 224 presented an enzyme of 29 kDa. The evaluation of the enzymatic stability of culture supernatant of these strains revealed that the fibrinolytic activity was highly stable over a wide temperature and pH range. Long-term stability of fibrinolytic activity at physiological conditions evidenced that the strains had a half-life of at least 72 h. Fibrinolytic enzymes produced by S. commune LBM 026 and LBM 223 were inhibited in the presence of EDTA indicating that they are metalloproteases. This work reveals the potential of S. commune LBM 026, S. commune LBM 223, and H. martius LBM 224 as an unconventional source of thrombolytic agents.

Regulation of growth, invasion and metabolism of breast ductal carcinoma through CCL2/CCR2 signaling interactions with MET receptor tyrosine kinases.

With over 60,000 cases diagnosed annually in the US, ductal carcinoma in situ (DCIS) is the most prevalent form of early-stage breast cancer. Because many DCIS cases never progress to invasive ductal carcinomas (IDC), overtreatment remains a significant problem. Up to 20% patients experience disease recurrence, indicating that standard treatments do not effectively treat DCIS for a subset of patients. By understanding the mechanisms of DCIS progression, we can develop new treatment strategies better tailored to patients. The chemokine CCL2 and its receptor CCR2 are known to regulate macrophage recruitment during inflammation and cancer progression. Recent studies indicate that increased CCL2/CCR2 signaling in breast epithelial cells enhance formation of IDC. Here, we characterized the molecular mechanisms important for CCL2/CCR2-mediated DCIS progression. Phospho-protein array profiling revealed that CCL2 stimulated phosphorylation of MET receptor tyrosine kinases in breast cancer cells. Co-immunoprecipitation and proximity ligation assays demonstrated that CCL2-induced MET activity depended on interactions with CCR2 and SRC. Extracellular flux analysis and biochemical assays revealed that CCL2/CCR2 signaling in breast cancer cells enhanced glycolytic enzyme expression and activity. CRISPR knockout and pharmacologic inhibition of MET revealed that CCL2/CCR2-induced breast cancer cell proliferation, survival, migration and glycolysis through MET-dependent mechanisms. In animals, MET inhibitors blocked CCR2-mediated DCIS progression and metabolism. CCR2 and MET were significantly co-expressed in patient DCIS and IDC tissues. In summary, MET receptor activity is an important mechanism for CCL2/CCR2-mediated progression and metabolism of early-stage breast cancer, with important clinical implications.

Sexually dimorphic organization of open field behavior following moderate prenatal alcohol exposure.

BACKGROUND: Prenatal alcohol exposure (PAE) can produce deficits in a wide range of cognitive functions but is especially detrimental to behaviors requiring accurate spatial information processing. In open field environments, spatial behavior is organized such that animals establish "home bases" marked by long stops focused around one location. Progressions away from the home base are circuitous and slow, while progressions directed toward the home base are non-circuitous and fast. The impact of PAE on the organization of open field behavior has not been experimentally investigated. METHODS: In the present study, adult female and male rats with moderate PAE or saccharin exposure locomoted a circular high walled open field for 30 minutes under lighted conditions. RESULTS: The findings indicate that PAE and sex influence the organization of open field behavior. Consistent with previous literature, PAE rats exhibited greater locomotion in the open field. Novel findings from the current study indicate that PAE and sex also impact open field measures specific to spatial orientation. While all rats established a home base on the periphery of the open field, PAE rats, particularly males, exhibited significantly less clustered home base stopping with smaller changes in heading between stops. PAE also impaired progression measures specific to distance estimation, while sex alone impacted progression measures specific to direction estimation. CONCLUSIONS: These findings support the conclusion that adult male rats have an increased susceptibility to the effects of PAE on the organization of open field behavior.

Flower essential oil of Tagetes minuta mitigates oxidative stress and restores BDNF-Akt/ERK2 signaling attenuating inflammation- and stress-induced depressive-like behavior in mice.

Essential oils (EO) are plant extracts widely used for various pharmacological applications and their antioxidant and anti-inflammatory effects have received a lot of attention because they hold the potential to reduce oxidative stress, and neuroinflammation, alterations involved in the pathophysiology of major depressive disorder. This study examined the benefits of administration of flower EO of the Tagetes minuta (10 and 50 mg/kg, intragastric route) in attenuating behavioral, neurochemical, and neuroendocrine changes in animal models of depressive-like behavior induced by acute restraint stress and lipopolysaccharide (0.83 mg/kg, intraperitoneally). We demonstrated that the treatment of mice with flower EO of the T. minuta reversed the depressive-like behavior induced by stress or inflammatory challenge in mice. This effect is most likely due to the reversal of oxidative stress in the hippocampus of mice, the decrease in plasma corticosterone levels, and restoration of the mRNA levels of brain-derived neurotrophic factor, phosphatidylinositol-3-kinase, protein kinase B, and extracellular signal-regulated kinase 2. As an outcome, flower EO of the T. minuta has promising antidepressant properties and could be considered for new therapeutic strategies for major depressive disorder.

"Help! I Need Somebody": Music as a Global Resource for Obtaining Wellbeing Goals in Times of Crisis.

Music can reduce stress and anxiety, enhance positive mood, and facilitate social bonding. However, little is known about the role of music and related personal or cultural (individualistic vs. collectivistic) variables in maintaining wellbeing during times of stress and social isolation as imposed by the COVID-19 crisis. In an online questionnaire, administered in 11 countries (Argentina, Brazil, China, Colombia, Italy, Mexico, the Netherlands, Norway, Spain, the UK, and USA, N = 5,619), participants rated the relevance of wellbeing goals during the pandemic, and the effectiveness of different activities in obtaining these goals. Music was found to be the most effective activity for three out of five wellbeing goals: enjoyment, venting negative emotions, and self-connection. For diversion, music was equally good as entertainment, while it was second best to create a sense of togetherness, after socialization. This result was evident across different countries and gender, with minor effects of age on specific goals, and a clear effect of the importance of music in people's lives. Cultural effects were generally small and surfaced mainly in the use of music to obtain a sense of togetherness. Interestingly, culture moderated the use of negatively valenced and nostalgic music for those higher in distress.

IgE-cross-blocking antibodies to Fagales following sublingual immunotherapy with recombinant Bet v 1.

BACKGROUND: Evidence has accumulated that birch pollen immunotherapy reduces rhinoconjunctivitis to pollen of birch homologous trees. Therapeutic efficacy has been associated with IgE-blocking IgG antibodies. We have recently shown that sera collected after 16 weeks of sublingual immunotherapy with recombinant Bet v 1 (rBet v 1-SLIT) display strong IgE-blocking bioactivity for Bet v 1. Here, we assessed whether rBet v 1-SLIT-induced IgG antibodies display cross-blocking activity to related allergens in Fagales pollen. METHODS: IgE, IgG1 and IgG4 reactivity to recombinant Bet v 1, Aln g 1, Car b 1, Ost c 1, Cor a 1, Fag s 1, Cas s 1 and Que a 1 were assessed in pre- and post-SLIT samples of 17 individuals by ELISA. A basophil inhibition assay using stripped basophils re-sensitized with a serum pool containing high Bet v 1-specific IgE levels was established and used to assess CD63 expression in response to allergens after incubation with pre-SLIT or post-SLIT samples. IgG1 and IgG4 were depleted from post-SLIT samples to assess its contribution to IgE-cross-blocking. RESULTS: Sublingual immunotherapy with recombinant Bet v 1 boosted cross-reactive IgE antibodies and induced IgG1 and IgG4 antibodies with inter- and intra-individually differing reactivity to the homologs. Highly variable cross-blocking activities of post-SLIT samples to the different allergens were found. IgG1 and IgG4 antibodies displayed cross-blocking activity with individual variance. CONCLUSIONS: Our mechanistic approach suggested that immunotherapy with the reference allergen Bet v 1 induces individual repertoires of cross-reactive IgG1 and IgG4 antibodies. The cross-blocking bioactivity of these antibodies was also highly variable and neither predictable from protein homology nor IgE-cross-reactivity.

IgE-blocking antibodies following SLIT with recombinant Mal d 1 accord with improved apple allergy.

BACKGROUND: We recently reported that 16 weeks of sublingual immunotherapy (SLIT) with recombinant (r) Mal d 1, but not rBet v 1, significantly improved birch pollen-related apple allergy. Allergen-specific IgE-blocking IgG antibodies have been associated with clinical efficacy. OBJECTIVE: We compared the quantity, quality, and IgE-blocking bioactivity of SLIT-induced Mal d 1-specific IgG antibodies in both treatment groups. METHODS: Pre- and post-SLIT sera were assessed for rMal d 1-specific IgG antibodies in ELISA and for their ability to inhibit apple allergen-induced upregulation of CD63 on basophils from nontreated individuals with birch pollen-related apple allergy. Post-SLIT sera depleted of IgG1 or IgG4 were compared for their IgE-blocking activity. IgG1 binding to rMal d 1 was competed with rMal d 1 and rBet v 1 in ELISA. RESULTS: SLIT with rMal d 1 and rBet v 1 induced comparable levels of rMal d 1-specific IgG1, IgG2, IgG3, and IgG4 antibodies. Only post-rMal d 1 SLIT sera displayed IgE-blocking activity, which was significantly reduced by depletion of IgG1 and less so by IgG4 depletion. In competition ELISA, IgG1 binding to Mal d 1 in post-rMal d 1 SLIT sera was fully inhibited with rMal d 1 but not with rBet v 1. Correspondingly, Bet v 1 was the more potent competitor for IgG1 binding to Mal d 1 in post-rBet v 1 SLIT sera. CONCLUSION: rMal d 1 SLIT for 16 weeks induced functional, primarily Mal d 1-specific IgE-blocking antibodies, whereas rBet v 1 SLIT induced Bet v 1-specific, Mal d 1-cross-reactive IgG antibodies with limited cross-blocking activity. These results provide a possible explanation for the limited effectiveness of birch pollen immunotherapy in birch pollen-related food allergy and indicate a dominant protective role of functional IgE-blocking IgG1 antibodies in the early phase of allergy treatment.

Repeated maternal separation: Alcohol consumption, anxious behavior and corticosterone were reversed by a non-pharmacological treatment.

Adverse events in early life have been related to a maladaptive stress response during adulthood, which could predispose individuals to psychiatric and physiological disorders. The purpose of this work was to study the implications of repeated maternal separation (RMS) plus a physical stressor (cold stress), voluntary ethanol consumption and plasmatic levels of corticosterone (Cor) via conflict behavior tests. To this aim, pups were separated daily from their mothers for one hour and subjected to cold stress (4 °C) between postnatal days (PD) 2 and 20. Control groups were left undisturbed with their mothers. Afterwards, all groups were exposed to voluntary ethanol (6%) or dextrose (1%) intake for 7 days. After a 30-day period of environmental enrichment (EE), the animals were again exposed to the voluntary intake protocol for 7 days. At 66 days, they were subjected to different conflict tests. Thereafter, rats were sacrificed by decapitation and blood trunk was collected to determine plasma corticosterone levels. We demonstrated that early RMS increased both voluntary alcohol intake and Cor levels. Moreover, young adult animals showed excessive activity in conflict tests. Whereas in animals exposed to a non-pharmacological treatment, known as environmental enrichment (EE), the effects previously obtained were reversed and/or prevented. In summary, we can conclude that the combination of maternal separation in early life plus cold stress increase both the voluntary exposure to alcohol and disruptive behaviors. This is a risk factor for the development of chronic diseases such as alcoholism and long-term depression. However, we found that an enriched environment may have a beneficial effect with respect to alcohol intake and aggressive behaviors.

Análisis de las Campañas de Vacunación Antigripal destinadas al personal de salud del HIBA: período 2016-2018 / Analysis of Influenza Vaccination Campaigns for HIBA health personnel: 2016-2018 period

Introducción: la vacunación antigripal es la forma más eficaz para prevenir la enfermedad por virus Influenza y sus complicaciones. La cobertura en los profesionales sanitarios es un indicador de calidad hospitalaria. Material y métodos: estudio descriptivo de corte transversal. A partir de registros vacunales, se calculó la cobertura para las campañas 2013 a 2018. Se compararon las coberturas por trienios. Se describieron características generales de las campañas de 2016 a 2018. Resultados: en 2016 se alcanzó la mayor tasa del período (59,79%, IC 95%:58,75-60,81); en 2017, la menor (34,46%, IC 95%:33,48-35,46). La campaña 2018 obtuvo una cobertura de 54,90% (IC 95%: 53,88-55,92) y se inició más tempranamente que otras. Al comparar las tasas trienales del período se observó una diferencia de proporción de -1,3% (IC 95%: -2.84-0.24). Durante los tres últimos años, el personal vacunado correspondió mayormente al sexo femenino, a la Sede Central y tenía relación contractual directa. Las mayores coberturas específicas correspondieron a la sede de San Justo y a los profesionales de enfermería. El puesto ambulante fue el que aplicó más vacunas. Conclusión: si bien hubo variaciones en las coberturas alcanzadas a lo largo de los años, siendo la del año 2016 la más elevada y la del año 2017 la más baja, no se observaron diferencias estadísticamente significativas en las coberturas alcanzadas al comparar trienios. Resulta necesario continuar realizando intervenciones adaptadas al contexto local que permitan alcanzar los objetivos de cobertura esperados. Discusión: se reconocieron varios obstáculos para alcanzar las coberturas esperadas. La educación al personal de salud, la evaluación sistematizada de los ESAVI (Eventos supuestamente atribuibles a vacunación e inmunización) y la descripción de los elementos que facilitaron las coberturas específicas elevadas de algunas subpoblaciones podrían contribuir para mejorar los resultados. (AU)

Introduction: influenza vaccination is the most effective way to prevent influenza virus disease and its complications. Coverage in health professionals measurement is an indicator of hospital quality. Material and methods: descriptive cross-sectional study. From vaccination records, the coverage was calculated for the 2013 to 2018 campaigns. The coverage for three years was compared. General characteristics of the campaigns from 2016 to 2018 were described. Results: in 2016, the highest was achieved during the period (59.79%, IC 95%: 58.75 -60.81). In 2017, the lowest (34.46%, IC 95%: 33.48-35,46). The 2018 campaign achieved a coverage of 54.90% (IC 95%: 53.88-55.92) and started earlier than others. When comparing the triennial rates of the period, a difference of proportion of -1.3% was observed (IC 95%: -2.84-0.24). During the last three years, the vaccinated staff corresponded mostly to the female sex, to the headquarters and had a direct contractual relationship. The largest specific coverage corresponded to the San Justo headquarters and to nursing professionals. The ambulatory position was the post that applied the most vaccines. Conclusion: although there were variations in the coverage achieved over the years, with 2016 being the highest and 2017 being the lowest, there were no statistically significant differences in the coverage achieved when comparing trienniums. It is necessary to continue carrying out interventions adapted to the local context to achieve the expected coverage objectives. Discussion: several obstacles were recognized to reach the expected coverage. The education of health personnel, the systematic evaluation of the ESAVIs and the description of the elements that facilitated the high specific coverage of some subpopulations could contribute to improve the results. (AU)

Polymer-based carriers for ophthalmic drug delivery.

Despite the wide range of diseases affecting the eye, ocular bioavailability remains a challenge in ophthalmic drug delivery. Nowadays an extensive variety of polymers are being explored to develop colloidal drug carriers which show better performance than the more popular drug solutions. For instance, regardless of the type of polymer used, these systems prolong the residence time of the drug in the absorption site with respect to conventional aqueous eye drops which are rapidly cleared from eye surface. Furthermore, colloidal drug carriers can be internalized by cells. In addition, positively charged particles penetrate the cornea more effectively than neutral or negatively charged ones. These phenomena lead to higher ocular bioavailability. This review overviews the different polymers available to produce drug-loaded gels, microparticles and nanoparticles, highlighting the advantageous features and biocompatibility of each polymer and the major achievements in the field of ocular delivery. In addition, the design of more complex delivery systems that combine several delivery platforms is presented. Finally, regulatory aspects relevant to the clinical translation of advanced ophthalmic drug delivery systems are also discussed. All together, this manuscript is aimed at guiding pharmaceutical research and development towards the rationale polymer selection to produce drug delivery systems that improve the performance of drugs for the therapy of ophthalmic diseases.

Nicotine-induced molecular alterations are modulated by GABAB receptor activity.

It has been demonstrated that GABAB receptors modulate nicotine (NIC) reward effect; nevertheless, the mechanism implicated is not well known. In this regard, we evaluated the involvement of GABAB receptors on the behavioral, neurochemical, biochemical and molecular alterations associated with the rewarding effects induced by NIC in mice, from a pharmacological and genetic approach. NIC-induced rewarding properties (0.5 mg/kg, subcutaneously, sc) were evaluated by conditioned place preference (CPP) paradigm. CPP has three phases: preconditioning, conditioning and postconditioning. GABAB receptor antagonist 2-hydroxysaclofen (0.25, 0.5 and 1 mg/kg; intraperitoneally, ip) or the GABAB receptor agonist baclofen (3 mg/kg; ip) was injected before NIC during the conditioning phase. GABAB1 knockout (GABAB1 KO) mice received NIC during the conditioning phase. Vehicle and wild-type controls were employed. Neurochemical (dopamine, serotonin and their metabolites), biochemical (nicotinic receptor α4ß2, α4ß2nAChRs) and molecular (c-Fos) alterations induced by NIC were analyzed after the postconditioning phase by high-performance liquid chromatography (HPLC), receptor-ligand binding assays and immunohistochemistry, respectively, in nucleus accumbens (Acb), prefrontal cortex (PFC) and ventral tegmental area (VTA). NIC induced rewarding effects in the CPP paradigm and increased dopamine levels in Acb and PFC, α4ß2nAChRs density in VTA and c-Fos expression in Acb shell (AcbSh), VTA and PFC. We showed that behavioral, neurochemical, biochemical and molecular alterations induced by NIC were prevented by baclofen. However, in 2-hydroxysaclofen pretreated and GABAB1 KO mice, these alterations were potentiated, suggesting that GABAB receptor activity is necessary to control alterations induced by NIC-induced rewarding effects. Therefore, the present findings provided important contributions to the mechanisms implicated in NIC-induced rewarding effects.

Long-term effects of repeated maternal separation and ethanol intake on HPA axis responsiveness in adult rats.

It has been shown that early life manipulations produce behavioral, neural, and hormonal effects. The long term consequences of repeated maternal separation (RMS) plus cold stress and ethanol intake were evaluated during adolescence and adult rats on hypothalamic-pituitary-adrenal (HPA) axis in male adult Wistar rats. RMS+ cold stress was applied from postnatal day (PD) 2 in which the pups were separated from their mothers and exposed to cold stress (4°C) 1h per day for 20days; controls remained with their mothers. Then they were exposed to either voluntary ethanol (6%) or dextrose (1%) intake for 7days: PD22-29 and PD59-66. Half of the animals were sacrificed, while the others were exposed to acute stress (AS) for 2h and then they were killed. RMS+ cold stress: a) increased voluntary ethanol intake in adolescent and adult rats; b) reduced protein expression (Western measurements) in corticotropin-releasing hormone (CRH) in hypothalamus (Hyp) and mineralocorticoid receptor (MR) in hippocampus (Hic) while increased glucocorticoid receptor (GR) in Hic; c) decreased plasmatic levels of adrenocorticotropic hormone (ACTH) and increased corticosterone (COR) levels in HPA axis, d) adult rats exposure a new AS incremented ACTH and COR levels. However, this modification did not alter the HPA axis capacity to respond to a new type of stressor. These results demonstrate the consequences of early life stress on the vulnerability of ethanol consumption and HPA axis responsiveness to a stressor in adult rats.

Argentinean Society of Experimental Pharmacology: Brief history and main scientific contributions to the discipline.

Argentina Biomedical Science has been historically strong. The development of Human and Veterinary Pharmacology in our country as a pivotal discipline has been acknowledged worldwide because of the quality of its contributions. Argentinean Society of Experimental Pharmacology (SAFE) is a non- profit association whose research fields include Experimental and Clinical Pharmacology. SAFE main goals are described as follow (a) To meet active researchers for studying concerns regarding Experimental and Clinical Pharmacology (b) To launch an initiative for development of the discipline in mainly our country and other collaborative countries worldwide (c) To spread the pharmacological know-how obtained from different research teams (d) To strengthen relations between pharmacologists (e) To facilitate the presentation and discussion of scientific papers. This current article shows the SAFE's more important scientific contribution to pharmacology through its former research scientists to the present.