Neuro-immune interactions in health and disease: Insights from FENS-Hertie 2022 Winter School.

In a great partnership, the Federation of European Neuroscience Societies (FENS) and the Hertie Foundation organized the FENS-Hertie 2022 Winter School on 'Neuro-immune interactions in health and disease'. The school selected 27 PhD students and 13 postdoctoral fellows from 20 countries and involved 14 faculty members experts in the field. The Winter School focused on a rising field of research, the interactions between the nervous and both innate and adaptive immune systems under pathological and physiological conditions. A fine-tuned neuro-immune crosstalk is fundamental for healthy development, while disrupted neuro-immune communication might play a role in neurodegeneration, neuroinflammation and aging. However, much is yet to be understood about the underlying mechanisms of these neuro-immune interactions in the healthy brain and under pathological scenarios. In addition to new findings in this emerging field, novel methodologies and animal models were presented to foment research on neuro-immunology. The FENS-Hertie 2022 Winter School provided an insightful knowledge exchange between students and faculty focusing on the latest discoveries in the biology of neuro-immune interactions while fostering great academic and professional opportunities for early-career neuroscientists from around the world.

Functional Status in Peripheral Arterial Disease: Rehabilitated Versus Nonrehabilitated.

BACKGROUND: To analyze patient perception of functional status related to activity and participation of rehabilitated and nonrehabilitated individuals with peripheral arterial disease. METHODS: Cross-sectional study assessing the activity and participation domain using the Human Activity Profile (HAP) questionnaire and the Participation Scale, respectively. Groups were compared using Chi-squared test and unpaired t-test. RESULTS: A total of 87 individuals (36 rehabilitated) with 65.28 ± 8.29 years (66.7% male) were included. HAP classified 58.6% of individuals with weak or inactive physical activity level, and approximately half of the sample did not have participation restriction. HAP scores and Participation Scale (locomotion inside and outside home) were lower in nonrehabilitated than in rehabilitated individuals. CONCLUSIONS: Individuals with peripheral arterial disease presented little participation restriction and a great activity limitation, the last one being more evident among nonrehabilitated.

Molecular sensitization profile to grass and olive pollens in Portugal.

Summary: Background. Grass and olive pollens have overlapping pollination periods and are common allergens in the Iberian Peninsula. The objective is to determine the sensitization pattern to major Phleum pratense and Olea europaea pollens in the Portuguese population with pollen allergic rhinitis (AR) using molecular allergen diagnosis (MAD). Methods. Seasonal AR patients (≥ 12 years), with positive skin prick tests (SPT) to Phleum and Olea were recruited from 16 centers. Using ALEX2, specific IgE to Phl p1, Phl p2, Phl p5, Phl p6, Phl p7, Phl p 12, Ole e1, Ole e7 and Ole e9 were determined. Immunoblotting of Olea allergic patients was performed. Results. Included 175 patients (55.4% female; mean age 31.6 ± 13.3 years; 85.7% adults; 40% asthmatic, Coast 28%/Inland 72% and North 29.1%/Centre 20.6%/South 50.3%). Considering Phleum MAD, 85.7% were sensitized to Phl p1, 45.7% to Phl p2, 50.3% to Phl p5, 45.7%, to Phl p6, 10.9% to Phl p7 and 22.9% to Phl p12. Sensitization to Ole e1 was found in 56.6%, to Ole e7 in 1.7% and Ole e9 in 3.4% patients. Sensitization to Phl p7 was more frequent in asthmatics (17.4% vs 6.6%; p = 0.044). Sensitization to Phl p5, Phl p6, Phl p12 and Ole e1 was more frequent in inland. Regarding sensitization patterns: 53.1% patients were sensitized to both species genuine´ sIgE, 38.3% to Phleum and 3.4% only to Olea species' sIgE. Immunoblotting of Olea allergic patients showed a high intensity band that may correspond to Ole e12. Conclusions. MAD showed "genuine" Grass and Olea sensitization in approximately 50% of our patients.

Nocardia cyriacigeorgica Elicits Gut Disturbances in a Leaky Gut Model of Colitis, but Not the Harmful Cascade Leading to Gut-First Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder with an unknown cause. Recent research has highlighted the importance of the gut in neuronal and immune maturation through the exchange of nutrients and cellular signals. This has led to the "gut-first PD" hypothesis, which aims to explain many of the sporadic cases and their prodromal intestinal symptoms, such as constipation and intestinal α-synuclein (aSyn) aggregation. The link between mitochondrial dysfunction and aSyn deposition is central to PD pathophysiology, since they can also trigger pro-inflammatory signals associated with aSyn deposition, potentially contributing to the onset of PD. As mitochondria are derived from ancestral alpha-proteobacteria, other bacteria may specifically target this organelle. We sought to use Nocardia cyriacigeorgica, a bacterium previously associated with parkinsonism, and dextran sulfate sodium (DSS) as pro-inflammatory modulators to gain further insight into the onset of PD. This study indicates that aSyn aggregation plus mitochondrial dysfunction without intestinal barrier leakage are not sufficient to trigger gut-first PD.

Footprints of a microbial toxin from the gut microbiome to mesencephalic mitochondria.

OBJECTIVE: Idiopathic Parkinson's disease (PD) is characterised by alpha-synuclein (aSyn) aggregation and death of dopaminergic neurons in the midbrain. Recent evidence posits that PD may initiate in the gut by microbes or their toxins that promote chronic gut inflammation that will ultimately impact the brain. In this work, we sought to demonstrate that the effects of the microbial toxin ß-N-methylamino-L-alanine (BMAA) in the gut may trigger some PD cases, which is especially worrying as this toxin is present in certain foods but not routinely monitored by public health authorities. DESIGN: To test the hypothesis, we treated wild-type mice, primary neuronal cultures, cell lines and isolated mitochondria with BMAA, and analysed its impact on gut microbiota composition, barrier permeability, inflammation and aSyn aggregation as well as in brain inflammation, dopaminergic neuronal loss and motor behaviour. To further examine the key role of mitochondria, we also determined the specific effects of BMAA on mitochondrial function and on inflammasome activation. RESULTS: BMAA induced extensive depletion of segmented filamentous bacteria (SFB) that regulate gut immunity, thus triggering gut dysbiosis, immune cell migration, increased intestinal inflammation, loss of barrier integrity and caudo-rostral progression of aSyn. Additionally, BMAA induced in vitro and in vivo mitochondrial dysfunction with cardiolipin exposure and consequent activation of neuronal innate immunity. These events primed neuroinflammation, dopaminergic neuronal loss and motor deficits. CONCLUSION: Taken together, our results demonstrate that chronic exposure to dietary BMAA can trigger a chain of events that recapitulate the evolution of the PD pathology from the gut to the brain, which is consistent with 'gut-first' PD.

Preclinical assessment of an anti-HTLV-1 heterologous DNA/MVA vaccine protocol expressing a multiepitope HBZ protein.

BACKGROUND: Human T-lymphotropic virus 1 (HTLV-1) is associated with the development of several pathologies and chronic infection in humans. The inefficiency of the available treatments and the challenge in developing a protective vaccine highlight the need to produce effective immunotherapeutic tools. The HTLV-1 basic leucine zipper (bZIP) factor (HBZ) plays an important role in the HTLV-1 persistence, conferring a survival advantage to infected cells by reducing the HTLV-1 proteins expression, allowing infected cells to evade immune surveillance, and enhancing cell proliferation leading to increased proviral load. METHODS: We have generated a recombinant Modified Virus Vaccinia Ankara (MVA-HBZ) and a plasmid DNA (pcDNA3.1(+)-HBZ) expressing a multiepitope protein based on peptides of HBZ to study the immunogenic potential of this viral-derived protein in BALB/c mice model. Mice were immunized in a prime-boost heterologous protocol and their splenocytes (T CD4+ and T CD8+) were immunophenotyped by flow cytometry and the humoral response was evaluated by ELISA using HBZ protein produced in prokaryotic vector as antigen. RESULTS: T CD4+ and T CD8+ lymphocytes cells stimulated by HBZ-peptides (HBZ42-50 and HBZ157-176) showed polyfunctional double positive responses for TNF-α/IFN-γ, and TNF-α/IL-2. Moreover, T CD8+ cells presented a tendency in the activation of effector memory cells producing granzyme B (CD44+High/CD62L-Low), and the activation of Cytotoxic T Lymphocytes (CTLs) and cytotoxic responses in immunized mice were inferred through the production of granzyme B by effector memory T cells and the expression of CD107a by CD8+ T cells. The overall data is consistent with a directive and effector recall response, which may be able to operate actively in the elimination of HTLV-1-infected cells and, consequently, in the reduction of the proviral load. Sera from immunized mice, differently from those of control animals, showed IgG-anti-HBZ production by ELISA. CONCLUSIONS: Our results highlight the potential of the HBZ multiepitope protein expressed from plasmid DNA and a poxviral vector as candidates for therapeutic vaccine.

Malnutrition and nutritional deficiencies in children with cerebral palsy: a systematic review and meta-analysis.

OBJECTIVES: This systematic review study and meta-analysis sought to estimate the prevalence of malnutrition and nutritional deficiencies in children with cerebral palsy (CP). STUDY DESIGN: This is a systematic review and meta-analysis. METHODS: The systematic review was conducted according to the PRISMA guidelines. The articles were chosen using the PubMed, Embase, Scopus, Web of Science, Cochrane Library, SciELO, and Lilacs databases and the bibliographical reference lists of the articles. No limitations were placed on the time of publication, but the articles had to include children from 0 to 18 years old with CP who presented the prevalence of malnutrition and nutritional deficiencies. The methodological quality of the articles was assessed using the verification list for analytical cross-sectional studies, the Newcastle-Ottawa scale, and the Cochrane Collaboration tool for randomized studies. The meta-analysis of proportions was conducted based on the prevalence data for malnutrition or nutritional deficiencies. The study is registered in PROSPERO under CRD number 42020175068. RESULTS: Sixty-seven articles (N = 453,804) published between 1986 and 2019 were included. Most of the articles presented a low risk of bias and no publication was excluded for quality reasons. The most widely used anthropometric index for diagnosing nutritional status was weight-to-age and the estimated prevalence of malnutrition was 40% (95% CI = 28.0-53.0). Nutrient deficiency was investigated by nine publications, with hypocalcemia and reduced serum concentrations of zinc, copper, and vitamin D being reported the most. CONCLUSIONS: We found a high rate of malnutrition in the population in this review, moreover, we suggest that some nutritional deficiencies are associated with food deficit and that the socio-economic and age factors of these children may relate with the poor nutritional outcome. This makes monitoring and personalized nutritional management necessary, in accordance with the characteristics and particularities of children with CP.

Incidence of inflammatory bowel disease and phenotype at diagnosis in 2011: results of the Epi-IBD 2011 study in the Vigo area.

OBJECTIVE: to validate the incidence of inflammatory bowel disease (IBD) reported in Vigo in 2010 within the Epi-IBD study, which was the highest incidence reported so far in Spain. METHODS: an epidemiological, prospective, population-based inception cohort study. All incident cases of IBD living in the Vigo area at diagnosis from January 1 to December 31, 2011 were included. RESULTS: one hundred patients were diagnosed (62 % men; median age, 43.27 years): 49 with ulcerative colitis (UC), 34 with Crohn's disease (CD), and 17 with IBD unclassified (IBDU). The incidence (per 100,000 inhabitants/year) was 17.56 (CD: 5.97; UC: 8.60; IBDU: 2.98), similar to that reported in 2010. The incidence in the non-pediatric population was 19.66 (CD: 6.89, UC: 9.52; IBDU: 3.04). CD and UC phenotype was similar in 2010 and 2011. CONCLUSION: this study supports the increased incidence of EII in the Vigo area reported in 2010.

Seroprevalence of anti-SARS-CoV-2 antibodies in COVID-19 patients and healthy volunteers up to 6 months post disease onset.

SARS-CoV-2 has emerged as a human pathogen, causing clinical signs, from fever to pneumonia-COVID-19-but may remain mild or asymptomatic. To understand the continuing spread of the virus, to detect those who are and were infected, and to follow the immune response longitudinally, reliable and robust assays for SARS-CoV-2 detection and immunological monitoring are needed. We quantified IgM, IgG, and IgA antibodies recognizing the SARS-CoV-2 receptor-binding domain (RBD) or the Spike (S) protein over a period of 6 months following COVID-19 onset. We report the detailed setup to monitor the humoral immune response from over 300 COVID-19 hospital patients and healthcare workers, 2500 University staff, and 198 post-COVID-19 volunteers. Anti-SARS-CoV-2 antibody responses follow a classic pattern with a rapid increase within the first three weeks after symptoms. Although titres reduce subsequently, the ability to detect anti-SARS-CoV-2 IgG antibodies remained robust with confirmed neutralization activity for up to 6 months in a large proportion of previously virus-positive screened subjects. Our work provides detailed information for the assays used, facilitating further and longitudinal analysis of protective immunity to SARS-CoV-2. Importantly, it highlights a continued level of circulating neutralising antibodies in most people with confirmed SARS-CoV-2.

Blood biomarkers associated with inflammation predict poor prognosis in cerebral venous thrombosis:: a multicenter prospective observational study.

BACKGROUND AND PURPOSE: Experimental studies suggest inflammation can contribute to blood barrier disruption and brain injury in cerebral venous thrombosis (CVT). We aimed to determine whether blood biomarkers of inflammation were associated with the evolution of brain lesions, persistent venous occlusion or functional outcome in patients with CVT. METHODS: Pathophysiology of Venous Infarction-Prediction of Infarction and Recanalization in CVT (PRIORITy-CVT) was a multicenter prospective cohort study of patients with newly diagnosed CVT. Evaluation of neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) concentrations in peripheral blood samples was performed at admission in 62 patients. Additional quantification of interleukin (IL)-6 was performed at day 1, 3 and 8 in 35 patients and 22 healthy controls. Standardized magnetic resonance imaging was performed at day 1, 8 and 90. Primary outcomes were early evolution of brain lesion, early recanalization and functional outcome at 90 days. RESULTS: Interleukin-6 levels were increased in patients with CVT with a peak at baseline. IL-6, NLR and CRP levels were not related with brain lesion outcomes or early recanalization but had a significant association with unfavourable functional outcome at 90 days (IL-6: OR = 1.28, 95% CI: 1.05-1.56, P = 0.046; NLR: OR = 1.39, 95% CI: 1.4-1.87, P = 0.014; CRP: OR = 1.756, 95% CI: 1.010-3.051, P = 0.029). Baseline IL-6 had the best discriminative capacity, with an area under the receiver operating characteristic curve to predict unfavourable functional outcome of 0.74 (P = 0.031). CONCLUSIONS: Increased baseline levels of NLR, CRP and IL-6 may serve as new predictive markers of worse functional prognosis at 90 days in patients with CVT. No association was found between inflammatory markers and early evolution of brain lesion or venous recanalization.

Molecular Profile of Sensitization to Dermatophagoides pteronyssinus Dust Mite in Portugal.

BACKGROUND AND OBJECTIVES: To analyze component-resolved diagnosis of sensitization to Dermatophagoides pteronyssinus (Der p) in patients with respiratory allergy and the association between diagnostic findings and clinical severity in different geographical areas. METHODS: The study population comprised 217 patients (mean age, 25.85 [12.7] years; 51.16% female) selected from 13 centers in Portugal (5 from the North, n=65). All had allergic rhinitis with or without asthma and positive skin prick test results to at least 1 dust mite. Specific IgE (sIgE) to Der p, Dermatophagoides farinae, Lepidoglyphus destructor, Der p 1, Der p 2, Der p 10, and Der p 23 was determined using ImmunoCAP. The Mann-Whitney test was applied for the following comparisons: rhinitis vs rhinitis and asthma; mild vs moderate-to-severe rhinitis; North vs South. RESULTS: The prevalence of sensitization was 98.2% for Der p, and 72.4%, 89.4%, 9.7%, and 77% for Der p 1, Der p 2, Der p 10, and Der p 23, respectively. The corresponding median sIgE levels were 8.56, 17.7, 0.01, and 3.95 kUA/L. sIgE to all allergens was higher in patients with moderate-to-severe rhinitis and rhinitis with asthma (nonsignficant). Concentrations of sIgE to Der p 2 were significantly higher in the South than in the North (P=.0496). CONCLUSION: The most common sensitization in Portugal was to Der p. The highest prevalence and median sIgE level were observed for Der p 2. All sIgE values for molecular components were higher in more symptomatic patients (nonsignificant). Concentrations of sIgE to Der p 2 were higher in the South, probably because of the warmer temperature and/or the larger sample size.

Obesity and overweight decreases the effect of vitamin D supplementation in adults: systematic review and meta-analysis of randomized controlled trials.

Overweight and obesity are associated with vitamin D deficiency (VitD), which are both important health problems. Reduced serum vitamin D levels has been registered in all phases of life and is commonly associated with the genesis of overweight and obesity. Thus, the objective of this review with meta-analysis was to investigate and evidence the efficacy of vitamin D supplementation in vitamin D. Interventional studies were searched for in 5 databases, without restriction of publication date or language. The absolute mean difference was used as a summary measure of the selected studies. A total of 2370 studies were identified, of which 18 descriptive articles were eligible - based on criteria and variables of selection and exclusion. Then the data were synthesized and submitted to meta-analysis. The results evidence that after supplementation individuals with obesity presented increased serum vitamin D 39.83 nmol/L (95% CI: 34.06-45.61) in relation to the control/placebo group. However, the obese state decreased serum vitamin D concentration by -38.17 nmol/L (95% CI: -59.90/-16.44) compared to the normal weight group. In addition, increasing the dose of VitD supplementation does not appear to contribute significantly to increased serum VitD levels. The study observed that obesity in adults reduced the effect of vitamin D supplementation. Therefore, research should be developed on the optimal dose of vitamin D supplementation for people with obesity.Systematic Review Registration: PROSPERO number CRD42018091.

Evolution of Api m10 Specific IgE and IgG4 After One Year of Bee Venom Immunotherapy.

Summary: Background. Bee-venom (BV) anaphylaxis can be life-threatening, requiring treatment with BV immunotherapy (bVIT). Different molecular profiles may be associated with different outcomes after bVIT. Methods. In 19 patients with BV anaphylaxis, sensitized both to Api m1 and Api m10, we evaluated sIgE and sIgG4 Api m1 and Api m10 levels before and after 1 year bVIT.Results.7 patients (37%) had higher baseline Api m10 than Api m1 sIgE levels (Api m10 predominant). bVIT reduced sIgE to both components but sIgG4 levels were increased only for Api m1. 5 patients (2 in the Api m10 predominant group) were re-stung without anaphylaxis. Conclusions. Although there was no increase in Api m10 sIgG4 levels after 1 year bVIT, we did not observe relevant differences in other outcomes between patients with predominant Api m1 or Api m10 sensitization.

Design, Synthesis, and In Vitro Evaluation of Hydroxybenzimidazole-Donepezil Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease.

A series of multi-target-directed ligands (MTDLs), obtained by attachment of a hydroxyphenylbenzimidazole (BIM) unit to donepezil (DNP) active mimetic moiety (benzyl-piperidine/-piperazine) was designed, synthesized, and evaluated as potential anti-Alzheimer's disease (AD) drugs in terms of biological activity (inhibition of acetylcholinesterase (AChE) and ß-amyloid (Aß) aggregation), metal chelation, and neuroprotection capacity. Among the DNP-BIM hybrids studied herein, the structural isomerization did not significantly improve the biological properties, while some substitutions, namely fluorine atom in each moiety or the methoxy group in the benzyl ring, evidenced higher cholinergic AChE activity. All the compounds are able to chelate Cu and Zn metal ions through their bidentate BIM moieties, but compound 5, containing a three-dentate chelating unit, is the strongest Cu(II) chelator. Concerning the viability on neuroblastoma cells, compounds 9 and 10 displayed the highest reduction of Aß-induced cell toxicity. In silico calculations of some pharmacokinetic descriptors indicate that all the compounds but the nitro derivatives have good potential oral-bioavailability. Overall, it can be concluded that most of the studied DNP-BIM conjugates showed quite good anti-AD properties, therefore deserving to be considered in further studies with the aim of understanding and treating AD.

Morphometric evaluation of Japanese quail embryos and their extraembryonic vascular networks exposed to low-frequency magnetic field with two different intensities.

Animals developed or in an embryonic stage, are constantly subjected to magnetic pollution generated by electrical and electronic devices. Several researches have used the bird embryo as an experimental model to evaluate the action of magnetic field (MF) and electromagnetic field (EMF). This study proposed to perform a morphometric evaluation in the embryos and in the blood vascular network of the yolk sac membranes (YSM) of Japanese quail (Coturnix japonica) exposed to the 60 Hz MF with two different intensities (0.16 and 0.65 mT). A total of 30 eggs were used, 10 eggs were used for each assay. Each assay formed a group (control group, group submitted to the MF of 0.16 mT and 0.65 mT). The images of the skeletonized vascular network of YSM were evaluated by two methods of fractal dimension: box-counting dimension (Dbc) and information dimension (Dinf). The embryos were evaluated by body mass, percentage cephalic length and body area. The fractal dimensions revealed no difference among groups. There were no significant differences in relation to embryonic body mass among groups. However, the embryos exposed to 0.65 mT MF presented a smaller embryonic body development (body area and percentage cephalic length). In conclusion, 0.16 mT and 0.65 mT magnetic fields were not able to generate significant effects on vasculogenesis and angiogenesis. However, the embryos exposed to 6 h of magnetic field with 0.65 mT intensity and 60 Hz frequency showed a decrease in embryonic body development.

Epidemiology of vitamin D insufficiency and deficiency in a population in a sunny country: Geospatial meta-analysis in Brazil.

Studies conducted among populations of tropical countries have reported high prevalences of vitamin D deficiency and insufficiency. Information resulting from meta-analyses on the spatial distribution of vitamin D deficiency and insufficiency in tropical countries is still rare. The aim of this review was investigated the prevalence of vitamin D deficiency and insufficiency among the Brazilian population. Observational studies were searched in eight electronically databases. Additionally, theses and dissertations and abstracts were screened. Details on study design, methods, population, mean and data on serum concentrations of vitamin D in different age groups in Brazil were extracted. Data were pooled using a random-effects model and choropleth maps were created based on the geopolitical regions of the country. 72 published paper met the inclusion criteria. The mean vitamin D concentration among the Brazilian population between 2000 and 2017 of 67.65 nmol/L (95% CI: 65.91, 69.38 nmol/L).The prevalences of vitamin D deficiency and insufficiency were 28.16% (95% CI: 23.90, 32.40) and 45.26% (95% CI: 35.82, 54.71), respectively, for the Brazilian population. The highest prevalence of deficiency were observed in the southern and southeastern regions and the highest occurrence of vitamin D insufficiency was among the populations of the southeastern and northeastern regions. Finally, there are high prevalence of inadequate vitamin D concentrations among the population, regardless of age group in Brazil. The development of vitamin D food fortification policies in needs to be cautious and carefully planned.

Influence of vitamin D serum concentration, prenatal care and social determinants on birth weight: a northeastern Brazilian cohort study.

The relationship among social determinants, vitamin D serum concentration and the health and nutrition conditions is an important issue in the healthcare of pregnant women and newborns. Thus, the present study analyses how vitamin D, prenatal monitoring and social determinants are associated with birth weight. The cohort comprised 329 pregnant women, up to 34 weeks gestational age at the time of admission, who were receiving care through the prenatal services of Family Health Units. Structural equation modelling was used in the statistical analysis. The mean birth weight was 3340 (sd 0·545) g. Each nmol increase in maternal vitamin D serum concentration was associated with an increase in birth weight of 3·06 g. Prenatal healthcare with fewer appointments (ß -41·49 g, 95 % CI -79·27, -3·71) and late onset of care in the second trimester or third trimester (ß -39·24 g, 95 % CI -73·31, -5·16) favoured decreased birth weight. In addition, low socio-economic class and the practice of Afro-Brazilian religions showed a direct association with high vitamin D serum concentrations and an indirect association with high birth weight, respectively. High gestational BMI (ß 23·84, 95 % CI 4·37, 43·31), maternal education level (ß 24·52 g, 95 % CI 1·82, 47·23) and length of gestation (ß 79·71, 95 % CI 52·81; 106·6) resulted in high birth weight. In conclusion, maternal vitamin D serum concentration, social determinants and prenatal care, evaluated in the context of primary healthcare, directly determined birth weight.

Polymorphism in the vitamin D receptor gene is associated with maternal vitamin D concentration and neonatal outcomes: A Brazilian cohort study.

OBJECTIVES: This study evaluated the associations between single-nucleotide polymorphisms (SNPs) of the vitamin D receptor (VDR) gene, maternal vitamin D concentration, and gestational outcomes. METHODS: The cohort consisted of 270 pregnant women who received prenatal services at basic public healthcare centers in the city of Santo Antônio de Jesus, Bahia, Brazil. For statistical analysis, multiple linear regression was used. RESULTS: A mean of 72.62 (SD = 31.51) nmol/L for 25-hydroxyvitamin D (25(OH)D) concentrations was found. The mean birth weight was 3.340 g (SD = 0.545 g), and the mean duration of gestation was 38.66 (SD = 1.83) weeks. Pregnant women who were homozygous for the low-frequency allele GG of SNP TaqI had a higher concentration of vitamin D during gestation (ß = 14.09 nmol/L; 95% CI = 0.85, 27.34) than the higher frequency homozygotes AA (ß = 3.33 nmol/L; 95% CI = -4.37, 11.05). The children of heterozygous women for the ApaI SNP (GA) were born with a lower weight (ß = -131.99 g, 95% CI = -258.50, -5.47, P = .04). The heterozygote genotype of the SNP TaqI (CA) decreased the risk of short duration of gestation (ß = 0.54 weeks, 95% CI = 0.09, 0.99, P = .01), and the homozygote for the lower frequency allele in the SNP ApaI (CC) showed a negative effect, decreasing the duration of gestation (ß = -0.69 weeks, 95% CI = -1.35, -0.26, P = .04). CONCLUSIONS: The VDR gene is an important genetic predictor of a higher concentration of vitamin D during gestation, low birth weight, and decreasing duration of gestation.

Venom Immunotherapy: a 20-year experience with an ultra-rush protocol (210-min).

SUMMARY: Background. Ultra-rush (UR) are induction protocols used in venom immunotherapy (VIT). Objectives: To evaluate the adverse reactions during a 210-minutes UR and determine possible risk factors. Methods: Retrospective study of 129 patients submitted to UR with VIT in the last 20 years. Results: In 114 (88.4%) patients the 101.1 µg maintenance dose was reached in 210 minutes. Systemic reactions (SR) occurred in 22% of patients (71% mild). There were no severe SR, late reactions or fatalities. Adrenaline was administered in 10% of all UR. The SR were more frequent with honey bee VIT and had greater severity in the patients with a previous severe systemic sting reaction. No significant difference in the risk of SR was found with other demographic, clinical or laboratory factors. There were 5% of large local reactions (LLR), these being more frequent in females. Conclusion: Most SR during UR were mild with no need for adrenaline treatment. The honey bee venom and the severity of the anaphylaxis during the field sting were the only SR´s risk factors for systemic adverse reactions during the UR.

Amphotericin B-Loaded Emulgel: Effect of Chemical Enhancers on the Release Profile and Antileishmanial Activity In Vitro.

Cutaneous leishmaniasis is a neglected parasitic disease. Treatment is preferably performed with pentavalent antimony associated or not with amphotericin B (AmB). This study aimed to develop an emulgel with different chemical enhancers of cutaneous release. Initially, AmB emulsions were obtained with the chemical promoters, oleic acid and geraniol and without promoter, then for the evaluation of the formulations, a preliminary stability study was carried out where the formulations were submitted to centrifugation, before and after the freeze-thaw cycle and analyzed appearance, color, pH, spreadability, viscosity, conductivity, droplet size, assay, in vitro release study, in vitro antileishmania activity in Leishmania major promastigotes, and macrophage toxicity in the MTT test. The emulsions were yellowish, with no signs of instability after the centrifugation test. The pH range corresponded to that of the skin, which is 4.6 to 5.8, before and after the freeze-thaw cycle, the formulations had good spreadability and did not present significant viscosity differences before and after the freeze-thaw cycle, presenting a non-Newtonian characteristic. AmB content was within the kinetic model of zero order release, the formulation of 3% AmB and 5% oleic acid (formulation 1) was chosen to proceed with the antileishmania activity test and showed potential activity against the in vitro parasite with significant reduction of cytotoxicity on murine macrophages, indicating that the formulation is promising for the treatment of cutaneous leishmaniasis.