Lipocalin-2 regulates adult neurogenesis and contextual discriminative behaviours.

In the adult mammalian brain, newborn granule cells are continuously integrated into hippocampal circuits, and the fine-tuning of this process is important for hippocampal function. Thus, the identification of factors that control adult neural stem cells (NSCs) maintenance, differentiation and integration is essential. Here we show that the deletion of the iron trafficking protein lipocalin-2 (LCN2) induces deficits in NSCs proliferation and commitment, with impact on the hippocampal-dependent contextual fear discriminative task. Mice deficient in LCN2 present an increase in the NSCs population, as a consequence of a G0/G1 cell cycle arrest induced by increased endogenous oxidative stress. Of notice, supplementation with the iron-chelating agent deferoxamine rescues NSCs oxidative stress, promotes cell cycle progression and improves contextual fear conditioning. LCN2 is, therefore, a novel key modulator of neurogenesis that, through iron, controls NSCs cell cycle progression and death, self-renewal, proliferation and differentiation and, ultimately, hippocampal function.

The dynamics of stress: a longitudinal MRI study of rat brain structure and connectome.

Stress is a well-established trigger for a number of neuropsychiatric disorders, as it alters both structure and function of several brain regions and its networks. Herein, we conduct a longitudinal neuroimaging study to assess how a chronic unpredictable stress protocol impacts the structure of the rat brain and its functional connectome in both high and low responders to stress. Our results reveal the changes that stress triggers in the brain, with structural atrophy affecting key regions such as the prelimbic, cingulate, insular and retrosplenial, somatosensory, motor, auditory and perirhinal/entorhinal cortices, the hippocampus, the dorsomedial striatum, nucleus accumbens, the septum, the bed nucleus of the stria terminalis, the thalamus and several brain stem nuclei. These structural changes are associated with increasing functional connectivity within a network composed by these regions. Moreover, using a clustering based on endocrine and behavioural outcomes, animals were classified as high and low responders to stress. We reveal that susceptible animals (high responders) develop local atrophy of the ventral tegmental area and an increase in functional connectivity between this area and the thalamus, further spreading to other areas that link the cognitive system with the fight-or-flight system. Through a longitudinal approach we were able to establish two distinct patterns, with functional changes occurring during the exposure to stress, but with an inflection point after the first week of stress when more prominent changes were seen. Finally, our study revealed differences in functional connectivity in a brainstem-limbic network that distinguishes resistant and susceptible responders before any exposure to stress, providing the first potential imaging-based predictive biomarkers of an individual's resilience/vulnerability to stressful conditions.

Inhibitory Effect of 5-Aminoimidazole-4-Carbohydrazonamides Derivatives Against Candida spp. Biofilm on Nanohydroxyapatite Substrate.

Candida can adhere and form biofilm on biomaterials commonly used in medical devices which is a key attribute that enhances its ability to cause infections in humans. Furthermore, biomaterial-related infections represent a major therapeutic challenge since Candida biofilms are implicated in antifungal therapies failure. The goals of the present work were to investigate the effect of three 5-aminoimidazole-4-carbohydrazonamides, namely (Z)-5-amino-1-methyl-N'-aryl-1H-imidazole-4-carbohydrazonamides [aryl = phenyl (1a), 4-fluorophenyl (1b), 3-fluorophenyl (1c)], on Candida albicans and Candida krusei biofilm on nanohydroxyapatite substrate, a well-known bioactive ceramic material. To address these goals, both quantitative methods (by cultivable cell numbers) and qualitative evaluation (by scanning electron microscopy) were used. Compounds cytocompatibility towards osteoblast-like cells was also evaluated after 24 h of exposure, through resazurin assay. The three tested compounds displayed a strong inhibitory effect on biofilm development of both Candida species as potent in vitro activity against C. albicans sessile cells. Regarding cytocompatibility, a concentration-dependent effect was observed. Together, these findings indicated that the potent activity of imidazole derivatives on Candida spp. biofilms on nanohydroxyapatite substrate, in particular compound 1c, is worth further investigating.

Effect of Mercaptosuccinic Acid Stabilizer Agent on the Optical Properties of Colloidal CdTe Quantum Dots.

In the present work, we report on the positive effect of mercaptosuccinic acid (MSA) stabilizer agent on the optical features of colloidal CdTe quantum dots (QDs). With this aim, we performed some spectroscopic measurements such as steady-state absorption and fluorescence, fluorescence quantum yield and time-resolved photoluminescence for five MSA-capped CdTe QD samples with different synthesis times. The first general aspect to highlight is that the QDs' average size increased with synthesis time (from 30 to 150 min) while the size dispersion decreased due to the Ostwald ripening mechanism. Second, comparing the optical properties of CdTe QDs obtained from the same synthesis route, we show that MSA stabilizer agent enhanced the optical properties of CdTe QDs as compared with other widely used stabilizer agents such as GSH and TGA. We ascribe this outcome to reduction of the number of surface defects of the CdTe QDs because the MSA stabilizer agent decreases the growth rate of nanocrystals, causing an improvement in their surface quality. In the light of Fermi's golden rule, we observed that for longer synthesis time the optical properties of CdTe QDs increases due to the enhancement of the direct radiative recombination rate of electrons and holes and decrease in the decay rate for core states. Finally, we investigated the pH-dependent fluorescence and demonstrated the similar behaviour in acidic range between MSA-capped CdTe and mercaptocarboxylates-capped CdTe.

mySinusitisCoach: patient empowerment in chronic rhinosinusitis using mobile technology.

Mobile health technology is emerging to take a prominent position in the management of chronic diseases. These technologies aim at enhancing patient empowerment via education and self-management. To date, of all the different apps available for patients with sinus disease, none were developed by medical experts dealing with chronic rhinosinusitis (CRS). The European Forum for Research and Education in Allergy and Airway diseases (EUFOREA) has undertaken a multi-stakeholder approach for designing, developing and implementing a tool to support CRS patients in monitoring their symptoms and to provide patients with a digital support platform containing reliable medical information about their disease and treatment options. mySinusitisCoach has been developed by medical experts dealing with CRS in close collaboration with patients, primary care physicians and community pharmacists, meeting the needs of both patients and health care providers. From a research perspective, the generation of real life data will help to validate clinical studies, patient stratification and improve understanding of the socio-economic impact of CRS, thereby paving the way for better treatment strategies.

Size-dependent bandgap and particle size distribution of colloidal semiconductor nanocrystals.

A new analytical expression for the size-dependent bandgap of colloidal semiconductor nanocrystals is proposed within the framework of the finite-depth square-well effective mass approximation in order to provide a quantitative description of the quantum confinement effect. This allows one to convert optical spectroscopic data (photoluminescence spectrum and absorbance edge) into accurate estimates for the particle size distributions of colloidal systems even if the traditional effective mass model is expected to fail, which occurs typically for very small particles belonging to the so-called strong confinement limit. By applying the reported theoretical methodologies to CdTe nanocrystals synthesized through wet chemical routes, size distributions are inferred and compared directly to those obtained from atomic force microscopy and transmission electron microscopy. This analysis can be used as a complementary tool for the characterization of nanocrystal samples of many other systems such as the II-VI and III-V semiconductor materials.

Evidence of autochthonous hepatitis E in a Portuguese pediatric cohort, 1992-1995.

Despite the growing importance of hepatitis E virus (HEV) in industrialized countries, minimal attention has been given to autochthonous HEV infection in children. The present study screened archived sera (N = 71) from a Portuguese pediatric cohort collected in 1992-1995 for the presence of antibodies against HEV, using enzyme immunoassays and immunodot. Anti-HEV IgG was detected in two children and anti-HEV IgM in one, suggesting an acute HEV infection. This shows that HEV was circulating in the paediatric population of Portugal in the early 1990s.

Post-resistance exercise hemodynamic and autonomic responses: Comparison between normotensive and hypertensive men.

To compare post-resistance exercise hypotension (PREH) and its mechanisms in normotensive and hypertensive individuals, 14 normotensives and 12 hypertensives underwent two experimental sessions: control (rest) and exercise (seven exercises, three sets, 50% of one repetition maximum). Hemodynamic and autonomic clinic measurements were taken before (Pre) and at two moments post-interventions (Post 1: between 30 and 60 min; Post 2: after 7 h). Ambulatory blood pressure (BP) was monitored for 24 h. At Post 1, exercise decreased systolic BP similarly in normotensives and hypertensives (-8 ± 2 vs -13 ± 2 mmHg, P > 0.05), whereas diastolic BP decreased more in hypertensives (-4 ± 1 vs -9 ± 1 mmHg, P < 0.05). Cardiac output and systemic vascular resistance did not change in normotensives and hypertensives (0.0 ± 0.3 vs 0.0 ± 0.3 L/min; -1 ± 1 vs -2 ± 2 U, P > 0.05). After exercise, heart rate (+13 ± 3 vs +13 ± 2 bpm) and its variability (low- to high-frequency components ratio, 1.9 ± 0.4 vs +1.4 ± 0.3) increased whereas stroke volume (-14 ± 5 vs -11 ± 5 mL) decreased similarly in normotensives and hypertensives (all, P > 0.05). At Post 2, all variables returned to pre-intervention, and ambulatory data were similar between sessions. Thus, a session of resistance exercise promoted PREH in normotensives and hypertensives. Although this PREH was greater in hypertensives, it did not last during the ambulatory period, which limits its clinical relevance. In addition, the mechanisms of PREH were similar in hypertensives and normotensives.

Case report of isochromosome 17q in acute myeloid leukemia with myelodysplasia-related changes after treatment with a hypomethylating agent.

Isochromosome 17q is a relatively common karyotypic abnormality in medulloblastoma, gastric, bladder, and breast cancers. In myeloid disorders, it is observed during disease progression and evolution to acute myeloid leukemia in Philadelphia-positive chronic myeloid leukemia. It has been reported in rare cases of myelodysplastic syndrome, with an incidence of 0.4-1.57%. Two new agents have been approved for treatment of myelodysplastic syndrome/chronic myelomonocytic leukemia. These are the hypomethylating agents, 5-azacytidine and decitabine, recommended by consensus guidelines for high-risk myelodysplastic syndrome patients not eligible for hematopoietic stem cell transplantation. We present a case of chronic myelomonocytic leukemia with normal cytogenetics at diagnosis treated with decitabine (with good response); however, the patient evolved to acute myeloid leukemia with i(17q) shortly after suspending treatment. To the best of our knowledge, this is the first report of acute myeloid leukemia with myelodysplasia-related changes with i(17q) after the use of a hypomethylating agent.

Performance assessment of 11 commercial serological tests for SARS-CoV-2 on hospitalised COVID-19 patients.

BACKGROUND: Commercial availability of serological tests to evaluate immunoglobulins (Ig) targeting severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has grown exponentially since the start of the coronavirus disease 2019 (COVID-19) outbreak. Thorough validation of these tests is important before use as epidemiological tools to infer seroprevalence in specific populations and as diagnostic tools to complement molecular approaches (e.g., quantitative reverse transcription-polymerase chain reaction). METHODS: Commercial serological tests from 11 suppliers were assayed side-by-side using 126 samples from SARS-CoV-2-infected inpatients and 36 from healthy and HIV-infected individuals. RESULTS: The majority of the tests assayed have >95% specificity. For the sensitivity calculation, samples were stratified by days since symptoms onset; sensitivity peaks at 16-21 days for IgM and IgA (maximum 91.2%, Euroimmun) and, dependant on the test, at 16-21 or >21 days for IgG (maximum 94.1%, Snibe). Data from semiquantitative tests show that patients with a severe clinical presentation have lower levels of Ig targeting SARS-CoV-2 at <10 days since symptoms onset and higher levels at >21 days, compared to patients with a non-severe presentation. CONCLUSIONS: This study highlights the heterogeneity of sensitivity and generally high specificity of the serological tests and establishes a basis for their usefulness to complement diagnostic techniques and population seroprevalence studies.

Ex vivo evaluation of the accuracy and coefficient of repeatability of three electronic apex locators using a simple mounting model: a preliminary report.

AIM: To compare ex vivo the accuracy and coefficient of repeatability of three electronic apex locators in locating the apical constriction. METHODOLOGY: Thirty-one single-rooted teeth were used. The teeth were sectioned at the cement--enamel junction. A mounting model was used for the measurement of electronic length (EL). The Root ZX-II, the Mini Apex Locator and the Novapex were used for electronic measurements. Each electronic measurement was obtained and repeated. After the last measurement, the file was cemented in place, and the apical 4 mm of each root canal was exposed. The distance from the tip of the file to the apical constriction was determined by three investigators and compared with the corresponding ELs. RESULTS: The coefficient of repeatability of all devices was acceptable: Root ZX-II, 0.04 mm; Mini Apex Locator, 0.10 mm; and Novapex, 0.08 mm. There was little variation in inter-examiner agreement; the rho(C) (Lin) correlation coefficient was 0.83 for examiners 1 and 2, 0.88 for examiners 1 and 3 and 0.99 for examiners 2 and 3. Using the Root ZX-II, 13 of 31 electronic measurements were located at the apical constriction (42%). Otherwise, the tip of the file was not located at the apical constriction in any of the electronic measurements with the other two devices. The Wilcoxon signed rank test did not reveal any statistical difference between the Root ZX-II measurements and the actual length (P = 0.628), but there was a statistical difference between the Mini Apex Locator and Novapex measurements and the actual length position (P < 0.05). CONCLUSIONS: The devices tested in this study had a high coefficient of repeatability. The Root ZX-II was accurate, but the Mini Apex Locator and Novapex were not accurate in locating the apical constriction.

Respiratory medicine curriculum in Portuguese family medicine training: A Delphi study.

BACKGROUND: Respiratory diseases (RD) constitute a significant part of the workload of family physicians. There is no consensus on what family doctors should know in this area but established methods for achieving consensus may help to overcome this. OBJECTIVES: The purpose of the study was to obtain a national consensus on the required knowledge and skills in respiratory medicine for family medicine trainees after vocational training. METHODS: A Delphi study was conducted via e-mail with a diverse panel of experts. We developed a Learning Curriculum Framework (LCF) with 399 items adapted from the Royal Australasian College of Physicians - Respiratory Medicine Advanced Training Curriculum. The LCF was submitted to the experts in two rounds for consensus. Consensus was considered for items that had an agreement of 80% in the classifications above 4 on a scale of importance that ranged from 1 (not important) to 5 (very important). RESULTS: Consensus was obtained for 159 items (38.8%). These included structure and function of the respiratory tract (0.6%), presenting problems (21.4%), diagnosis (7.5%), interventions and prevention (11.3%), COPD-emphysema (12.6%), tumours (3.1%), infections (10.7%), tuberculosis (5.7%), HIV (1.3%), thromboembolic disease (2.5%), pleural-pulmonary disease (3.1%), pregnancy (0.6%) and sleep disorders (3.8%). Items on iatrogenic diseases and respiratory research did not reach consensus. CONCLUSIONS: Consensus on the respiratory medicine curriculum may contribute to further development of the vocational training curriculum in Portugal. This approach may help teachers in other countries in Europe to develop curricula for respiratory medicine and other areas of general practice.

Direct evidences of enhanced Ga interdiffusion in InAs vertically aligned free-standing nanowires.

Direct evidences of enhanced Ga interdiffusion in InAs free-standing nanowires grown at moderate temperatures by molecular beam epitaxy on GaAs (111)B are presented in this work. Scanning electron microscopy, energy dispersive X-ray spectroscopy and X-ray diffraction measurements in coplanar and grazing incidence geometries show that nominally grown InAs NWs are actually made of an In0.86Ga0.14As alloy. Unlike typical vapor-liquid-solid growth, these nanowires are formed by diffusion-induced growth combined with strong interdiffusion from substrate material. Based on the experimental results, a simple nanowire growth model accounting for the Ga interdiffusion is also presented. This growth model could be generally applicable to the molecular beam heteroepitaxy of III-V nanowires.

The SIGMA rat brain templates and atlases for multimodal MRI data analysis and visualization.

Preclinical imaging studies offer a unique access to the rat brain, allowing investigations that go beyond what is possible in human studies. Unfortunately, these techniques still suffer from a lack of dedicated and standardized neuroimaging tools, namely brain templates and descriptive atlases. Here, we present two rat brain MRI templates and their associated gray matter, white matter and cerebrospinal fluid probability maps, generated from ex vivo [Formula: see text]-weighted images (90 µm isotropic resolution) and in vivo T2-weighted images (150 µm isotropic resolution). In association with these templates, we also provide both anatomical and functional 3D brain atlases, respectively derived from the merging of the Waxholm and Tohoku atlases, and analysis of resting-state functional MRI data. Finally, we propose a complete set of preclinical MRI reference resources, compatible with common neuroimaging software, for the investigation of rat brain structures and functions.

Lithium blocks stress-induced changes in depressive-like behavior and hippocampal cell fate: the role of glycogen-synthase-kinase-3beta.

Mood disorders are the most common psychiatric disorders. Although the mechanisms implicated in the genesis of mood disorders are still unclear, stress is known to predispose to depression, and recently, studies have related hippocampal neurogenesis and apoptosis to depression. In the present study we first examined the balance between cell birth-death in the hippocampus and subventricular zone (SVZ) of pre-pubertal and adult rats subjected to chronic-mild-stress (CMS). CMS led to increased corticosterone secretion and induced depressive-like symptoms (assessed in the forced-swimming test); these endocrine and behavioral effects were paralleled by decreased hippocampal, but not SVZ, cell proliferation/differentiation and by increased apoptotic rate. In order to determine if lithium, a known mood stabilizer with antidepressant properties, could prevent the stress-induced events, we analyzed the same parameters in a group of rats treated with lithium during the stress exposure period (CMS+Li) and observed that the hormonal, behavioral and cell turnover effects of CMS were abrogated in these animals. Subsequently, to search for possible pathways through which CMS and lithium influence behavior, cell fate and synaptic plasticity, we analyzed the expression of glycogen-synthase-kinase-3beta (GSK-3beta), as well as some of its downstream targets (B-cell-CLL/lymphoma2-associated athanonege (BAG-1) and synapsin-I). CMS increased GSK-3beta and decreased synapsin-I and BAG-1 expression in the hippocampus. Interestingly, co-administration of lithium precluded the CMS-induced effects in GSK-3beta, synapsin-I and BAG-1 expression. Our observation that specific inhibition of this kinase with AR-A014418 blocked the effects of CMS in depressive-like behavior and in BAG-1 and synapsin-I expression confirmed the involvement of the GSK-3beta pathway in stress-induced effects. In summary, these results reveal that lithium, by regulating the activity of GSK-3beta, prevents the deleterious effects of stress on behavior and cellular functions.

The choroid plexus response to peripheral inflammatory stimulus.

Increased interest is being raised on the interaction between systemic inflammation and the brain. The choroid plexus (CP) constitutes a monolayer of epithelial cells located within the brain ventricles and is responsible for the production of cerebrospinal fluid (CSF). Despite the knowledge that the CP capillaries are fenestrated, allowing free passage of molecules and cells, the involvement of the vast blood-brain boundary represented by the CP/CSF barrier in brain inflammatory processes has seldom been considered. In the present study we investigate, in mice, how the expression of genes encoding major constitutively expressed CP proteins is influenced by a systemic inflammatory stimulus. Confirming that the CP responds to peripheral inflammation, the messenger RNA (mRNA) levels of the pro-inflammatory cytokines interleukin 1 beta and tumor necrosis factor alpha are rapidly induced. As for the constitutively expressed proteins, while the mRNA for genes encoding transthyretin and transferrin remain unaltered by the inflammatory challenge, that for prostaglandin D2 synthase (LPTGDS) is up-regulated at 6 h, and stays up-regulated up to 24 h after lipopolysacharide administration. Accordingly, LPTGDS CSF levels are also augmented. LPTGDS catalyzes the synthesis of the major prostanoid of the CNS and, being increased in the CSF, might mediate immune signaling into the brain. These observations emphasize that the CP must be considered a relevant mediator of immune signals between the periphery and the brain.

Effect of shear stress on growth, adhesion and biofilm formation of Pseudomonas aeruginosa with antibiotic-induced morphological changes.

The aim of this study was to investigate the effect of shear stress and antibiotic-induced morphological changes on the growth, adhesion and biofilm formation ability of Pseudomonas aeruginosa. A modified microtitre plate assay was used to quantify adhesion, biofilm formation and planktonic culture density of P. aeruginosa ATCC 27853 under the effect of 0.5x minimal inhibitory concentrations (MICs) of piperacillin/tazobactam, imipenem and meropenem. Hydrodynamic conditions were achieved by orbital shaking at 250 rpm with the presence of a glass bead in each microtitre well. These conditions decreased adhesion and biofilm formation abilities, increased planktonic culture density over 1h and decreased planktonic culture density over 16 h for bacteria with antibiotic-induced morphological changes in comparison with static conditions. Our results demonstrate the importance of using a high-throughput dynamic model to assess the adhesion and biofilm formation behaviour of P. aeruginosa with antibiotic-induced morphological changes and suggest the possible use of sub-MIC antibiotics in clinical applications to prevent infections acquired by haematogenous spread. This dynamic model provides a better simulation of in vivo conditions of adhesion and biofilm formation of P. aeruginosa with altered morphologies induced by beta-lactam antibiotics.

Nanohydroxyapatite microspheres as delivery system for antibiotics: release kinetics, antimicrobial activity, and interaction with osteoblasts.

Severe periodontitis treatment, where massive alveolar bone loss occurs, involves bone defect filling and intensive systemic log-term antibiotics administration. This study aims at developing novel injectable drug delivery systems (nanohydroxyapatite microspheres) with the drug releasing capability for periodontitis treatment and simultaneously initiating the osteointegration process. Materials were characterized by XRD, SEM, inverted stand optical microscope analysis, and mercury porosimetry method. Amoxicillin, amoxicillin + clavulanic acid, and erythromycin were the antibiotics used. Release properties during 28 days from the hydroxyapatite (HA) granules, and two types of nanoHA microspheres were investigated. Biocompatibility was assessed by cytotoxicity assays. HA granules were inadequate, releasing all antibiotic during the first hours. The concentration of antibiotics released in the first days from HA-2 was higher than from HA-1 microspheres, because of the increased porosity and surface area. The release profiles (fast initial release followed by long-term sustained release) of effective doses of antibiotics make these systems good alternatives for antibiotics delivery. Osteoblasts proliferated well on both types of microspheres, being cell growth enhanced in the presence of antibiotics. Erythromycin presented the most beneficial effect. Combining the sustained antibiotic release with the osteoconduction, resorbability, and potential use as injectable bone filling material of porous HA microspheres, these systems provided a forth fold beneficial effect.

Preparation and characterization of activated carbon from rice bran.

A study on the preparation of rice bran-based activated carbon was conducted, with and without an acid treatment step prior the activation process. The influence of the activation time on the structure of the activated carbons was evaluated. The acid treatment had a significant positive influence on sorption properties. The rice bran-activated carbon presented a BET surface area of 652m(2)g(-1) and a pore volume of 0.137cm(3)g(-1), with mesopores predominance (ca. 55%). These experimental results indicated the potential use of rice bran as a precursor in the activated carbon preparation process, thus representing an economically promising material.