Long-term developmental outcomes of children with congenital Zika syndrome.

BACKGROUND: Eight years after the epidemics in Brazil, children with congenital Zika syndrome (CZS) and their families confront ongoing health challenges. OBJECTIVE: This study aims to characterize how virally induced prenatal brain injury impacts development and functional outcomes among children diagnosed with CZS. METHODS: We performed a cross-sectional study of a consecutive series of children diagnosed with CZS. Using validated neurodevelopmental assessments, we evaluated gross motor function, manual ability, communication, eating and drinking, and visual function. RESULTS: Sixty children (29 males, and 31 females) met the inclusion criteria for the study. Comorbidities such as epilepsy (90.0%) and undernutrition (38.3%), along with clinical conditions including dysphagia (68.3%) and dependence on tube feeding (31.7%), were observed. Our results demonstrate a majority of children at level V - the most severe level within a five-tier system - in the Gross Motor Function (86.7%), Manual Ability (85.0%), Communication Function (68.3%), Eating and Drinking Ability (40.0%) Classification Systems, and level IV in the Visual Function Classification System (38.3%). CONCLUSION: CZS is associated with severe functional impairments and comorbidities, adversely impacting child development and quality of life. These findings reveal persistent challenges affecting the functioning of children with CZS, underscoring the need for continued support and specialized care. IMPACT: This study aimed to characterize the long-term clinical and functional characteristics of a subset of children with Congenital Zika Syndrome (CZS). We found that eight years after the Brazilian Zika epidemic, this subset of children with CZS continues to demonstrate major functional limitations impacting mobility, vision, and the ability to eat and drink. Our analysis documented a very high level of disability in several key functional classification systems. Notably, applying a new instrument for visual ability among children diagnosed with cerebral palsy, we found that more than 60% of the study group have poor or very poor visual function.

The selection of indicator species of birds and mammals for the monitoring of restoration areas in a highly fragmented forest landscape.

Indicator species are frequently used to monitor restoration areas. However, species of conservation concern are usually absent in highly fragmented landscapes, making the selection of indicator species a challenging task. Here, we select indicator species of birds and mammals to be used for the evaluation of restoration sites in a highly fragmented landscape, the Capivara-Taquaruçu Dams region located in north Paraná, Brazil. By using the Index of Biotic Integrity (IBI), we show that the Capivara-Taquaruçu Dams landscape has low IBI values and bird richness when compared with two other landscapes in the north of Paraná. Therefore, we used the Individual Indicate Value to identify birds and mammals associated with forest fragments in the Capivara-Taquaruçu Dams landscape. Six bird and four mammal species were selected as indicators of forest fragments, none of which were of conservation concern. However, monitoring of these species could help evaluate the recovery of restoration sites in the Capivara-Taquaruçu Dams region. Lastly, several species of birds and mammals were frequently recorded in the restoration sites, including vulnerable species such as the lowland tapir (Tapirus terrestris). This is indicative that restoration sites can be important habitats in highly fragmented landscapes despite the loss of biodiversity.

Neurodevelopmental outcomes in a cohort of children with congenital Zika syndrome at 12 and 24 months of age.

BACKGROUND: Early child development is a critical stage of life that influences social, educational and health outcomes worldwide. A few years after Zika epidemic, families of children born with congenital Zika syndrome (CZS) continue to face uncertainties when it comes to the development of their children. The present study sought to analyse the developmental trajectories of a subset of children born with CZS in the first 24 months of life. METHODS: Thirty-five children with CZS were assessed with the Bayley-III Scales at 12 and 24 months of age from November 2016 to December 2018 in a rehabilitation centre in Brazil. Inclusion criteria included children with established diagnosis of CZS. Exclusion criteria included the presence of arthrogryposis, prematurity, irregular follow-up, clinical complications or other causes of microcephaly. Children born with CZS who evolved with cerebral palsy (CP) were classified according to the Gross Motor Function Classification System (GMFCS) at 2 years of age. RESULTS: At 12 months of age mean composite scores on the Bayley cognitive, communication and motor scores were 57.71 (SD 7.11), 57.94 (SD 14.34) and 49.26 (7.20), respectively. At 24 months of age, composite scores were 57.43 (SD 7.11), 53.60 (SD 12.29) and 48.83 (7.76). In addition, 31 (88.57%) out of 34 children diagnosed with CP were classified as GMFCS levels IV and V. CONCLUSION: Zika virus congenital infection is a risk factor for functional impairments across all developmental domains having a direct and substantial negative impact in early child development.

The Effects of Stress on Hippocampal Neurogenesis and Behavior in the Absence of Lipocalin-2.

Lipocalin-2 (LCN2) is an acute phase protein able to bind iron when complexed with bacterial siderophores. The recent identification of a mammalian siderophore also suggested a physiological role for LCN2 in the regulation of iron levels and redox state. In the central nervous system, the deletion of LCN2 induces deficits in neural stem cells proliferation and commitment, with an impact on the hippocampal-dependent contextual fear discriminative task. Additionally, stress is a well-known regulator of cell genesis and is known to decrease adult hippocampal cell proliferation and neurogenesis. Although voluntary running, another well-known regulator of neurogenesis, is sufficient to rescue the defective hippocampal neurogenesis and behavior in LCN2-null mice by promoting stem cells' cell cycle progression and maturation, the relevance of LCN2-regulated hippocampal neurogenesis in response to stress has never been explored. Here, we show a lack of response by LCN2-null mice to the effects of chronic stress exposure at the cellular and behavioral levels. Together, these findings implicate LCN2 as a relevant mediator of neuronal plasticity and brain function in the adult mammalian brain.

Cell Uptake of Steroid-BODIPY Conjugates and Their Internalization Mechanisms: Cancer Theranostic Dyes.

Estradiol-BODIPY linked via an 8-carbon spacer chain and 19-nortestosterone- and testosterone-BODIPY linked via an ethynyl spacer group were evaluated for cell uptake in the breast cancer cell lines MCF-7 and MDA-MB-231 and prostate cancer cell lines PC-3 and LNCaP, as well as in normal dermal fibroblasts, using fluorescence microscopy. The highest level of internalization was observed with 11ß-OMe-estradiol-BODIPY 2 and 7α-Me-19-nortestosterone-BODIPY 4 towards cells expressing their specific receptors. Blocking experiments showed changes in non-specific cell uptake in the cancer and normal cells, which likely reflect differences in the lipophilicity of the conjugates. The internalization of the conjugates was shown to be an energy-dependent process that is likely mediated by clathrin- and caveolae-endocytosis. Studies using 2D co-cultures of cancer cells and normal fibroblasts showed that the conjugates are more selective towards cancer cells. Cell viability assays showed that the conjugates are non-toxic for cancer and/or normal cells. Visible light irradiation of cells incubated with estradiol-BODIPYs 1 and 2 and 7α-Me-19-nortestosterone-BODIPY 4 induced cell death, suggesting their potential for use as PDT agents.

Bridging the Chemical Profile and Biological Activities of a New Variety of Agastache foeniculum (Pursh) Kuntze Extracts and Essential Oil.

This study investigated the phytochemical content of alcoholic extracts and essential oil of a new variety of medicinal plants, Agastache foeniculum (Pursh), which Kuntze adapted for cultivation in Romania, namely "Aromat de Buzau". The essential oil was investigated by GC-MS, while the identification and quantification of various compounds from alcoholic extracts were performed by HPLC-DAD. The total phenol and flavonoid contents of the extracts were evaluated by using standard phytochemical methods. The antioxidant activities of ethanol, methanol extracts, and essential oil of the plant were also assessed against 2,2'-diphenyl-1-picrylhydrazyl (DPPH•), 2,2'-azino-bis-(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS•+), and by ferric reducing power (FRAP) using spectroscopic methods. Cyclic voltammetry was used to evaluate the antioxidant capacity of the essential oil. The concentrations of phenolic compounds were higher in methanolic extract compared to ethanolic extract. A significant correlation was found between total phenol and total flavonoid contents (r = 0.9087). Significant high correlations were also found between the total phenolic compounds and the antioxidant activities of the extracts (r ≥ 0.8600, p < 0.05). In addition, the extracts and essential oil showed good antioxidant and xanthine oxidase inhibitory activities. Estragole was detected as the major constituent of the essential oil (94.89%). The cytotoxic activity of the essential oil was evaluated by the MTT assay. At lower concentrations (1 µg/mL) high cytotoxicity against MCF-7 breast cancer cells was observed but not on the non-tumoral dermal fibroblasts (HDF) which indicated selectivity for cancer cells and suggests the presence of biologically active components that contribute to the observed high cytotoxic effect. Findings from the present study offer new perspectives on the use of A. foeniculum as a potential source of bioactive compounds and a good candidate for pharmaceutical plant-based products.

Cone-beam computed tomography study of mandibular morphology and tooth compensation in asymmetrical patients.

INTRODUCTION: This study evaluated mandibular morphology and transverse dental compensation between symmetrical and asymmetrical subjects, allocated according to sagittal skeletal patterns. In addition, the hypothesis that mandibular morphology and dental compensations differed between symmetrical/asymmetrical groups and also among the different types of sagittal skeletal patterns was tested. METHODS: Cone-beam computed tomography images of 96 patients were included in this study and were divided into 2 groups according to the degree of menton deviation: a symmetrical group with deviation up to 2.0 mm (n = 48; mean age, 15 ± 6 years), and an asymmetrical group with deviation from 3.5 mm (n = 48; mean age, 16 ± 8 years). The 2 groups were divided in accordance with the ANB angle: Class I, II, and III. Skeletal and dental measurements were performed. Intergroup and intragroup analyses were carried out, using a 2-way analysis of variance to assess the interaction of factors: symmetry and sagittal skeletal pattern; and the Student t test for differences between deviated (Dv) and nondeviated (NDv) sides. RESULTS: Symmetrical/asymmetrical groups and Class I, II, and III groups were similar in relation to demographic aspects (P = 0.412 and P = 0.357 for sex and age, respectively). Asymmetrical patients had higher values for body length and mandibular ramus and condyle height on the NDv side (P = 0.011, P = 0.024, and P = 0.001, respectively). When comparing the different skeletal patterns, patients with a Class III relationship demonstrated higher values for mandibular ramus height. Intergroup analysis showed no differences in dental parameters. In the comparison between the sides, the asymmetrical group showed a significant difference in canine inclination (P = 0.008), mandibular ramus height (P = 0.004), condyle height (P = 0.010) and gonion to midsagittal plane distance (P = 0.018). CONCLUSIONS: Asymmetrical subjects showed higher values for canine inclination and mandibular body, ramus and condylar height on the NDv side. The hypothesis was partially confirmed that mandibular morphology and dental compensations are different between symmetrical/asymmetrical groups and among different sagittal skeletal patterns.

Comparative effectiveness of preventive treatment with dimethyl fumarate-loaded solid lipid nanoparticles and oral dimethyl fumarate in a mouse model of multiple sclerosis.

BACKGROUND: Orally administered dimethyl fumarate (DMF) presents gastrointestinal adverse effects, such as pain and diarrhea, in addition to flushing and lymphopenia. OBJECTIVE: Solid lipid nanoparticles (SLNs) with DMF were developed for subcutaneous administration. METHODS: DMF-incorporated SLNs and free DMF were tested in mice induced with experimental autoimmune encephalomyelitis (EAE). RESULTS: Preventive treatment of free or incorporated DMF were able to reduce the EAE clinical scores, increase the weight of the animals, reduce the lesion area (demyelination and infiltration), reduce microglial fluorescence intensity and reduce the number of microglial cells and astrocytes, when compared to untreated EAE animals. Groups that received DMF had reduced numbers of T cells, B cells and natural killer (NK) cells in the blood, when compared to the non-induced group. CONCLUSIONS: DMF incorporated in SLNs was as effective as free DMF in reducing the clinical scores of the animals, but with reduced administrations when given subcutaneously. In addition, SLN-DMF preventive treatment partially prevented a reduction in the percentages of T and B cells, in the blood, when compared to preventive treatment with free DMF (oral), which suggests reduction of lymphopenia.

Copper(II) and oxidovanadium(IV) complexes of chromone Schiff bases as potential anticancer agents.

We report the synthesis, characterization and biological screening of new chromone Schiff bases derived from the condensation of three 6-substituted-3-formyl-chromones with pyridoxal (HL1-3) and its Cu(II) complexes [Cu(L1-3)Cl], 1-3. For the 6-methyl derivative, HL2, the VIVO-complex [VO(L2)Cl] (5), as well as ternary Cu and VIVO complexes with 1,10-phenanthroline (phen), [Cu(L2)(phen)Cl] (4) and [VO(L2)(phen)Cl] (6), were also prepared and evaluated. Their stability in aqueous medium and radical scavenging activity toward DPPH are screened, with [Cu(L2)(phen)Cl] (4) showing hydrolytic stability and [VO(L2)(phen)Cl] (6) high radical scavenging activity. Spectroscopic studies establish bovine serum albumin (BSA), a model for HSA, as a potential reversible carrier of [Cu(L2)(phen)Cl] in blood with KBC ≈ 105 M-1. The cytotoxic activity of a group of compounds is evaluated against a panel of human cancer cell lines of different origin (ovary, cervix, brain and breast) and compared to normal cells. Our results indicate that Cu complexes are more cytotoxic than the ligands but not selective towards cancer cells. The most potent complexes (4 and 6) are further evaluated for their apoptotic potential, induction of reactive oxygen species (ROS) and genotoxicity. Both complexes efficiently triggered cell death through apoptosis as evaluated by DNA morphology and TUNEL assay, increased ROS formation as determined by DCFDA (2',7'-dichlorodihydrofluorescein diacetate) analysis, and induced genotoxic damage as visualized via COMET assay in all cancer cells under study. Therefore, 4 and 6 may be potential precursor anticancer molecules, yet they need to be targeted toward cancer cells.

Exploring the Physical and Biological Aspects of BNCT with a Carboranylmethylbenzo[b]acridone Compound in U87 Glioblastoma Cells.

Boron neutron capture therapy (BNCT) is a re-emerging technique for selectively killing tumor cells. Briefly, the mechanism can be described as follows: after the uptake of boron into cells, the thermal neutrons trigger the fission of the boron atoms, releasing the α-particles and recoiling lithium particles and high-energy photons that damage the cells. We performed a detailed study of the reactor dosimetry, cellular dose assessment, and radiobiological effects induced by BNCT in glioblastoma (GBM) cells. At maximum reactor power, neutron fluence rates were ϕ0 = 6.6 × 107 cm−2 s−1 (thermal) and θ = 2.4 × 104 cm−2 s−1 with a photon dose rate of 150 mGy·h−1. These values agreed with simulations to within 85% (thermal neutrons), 78% (epithermal neutrons), and 95% (photons), thereby validating the MCNPX model. The GEANT4 simulations, based on a realistic cell model and measured boron concentrations, showed that >95% of the dose in cells was due to the BNC reaction. Carboranylmethylbenzo[b]acridone (CMBA) is among the different proposed boron delivery agents that has shown promising properties due to its lower toxicity and important cellular uptake in U87 glioblastoma cells. In particular, the results obtained for CBMA reinforce radiobiological effects demonstrating that damage is mostly induced by the incorporated boron with negligible contribution from the culture medium and adjacent cells, evidencing extranuclear cell radiosensitivity.

Dose Rate Effects on the Selective Radiosensitization of Prostate Cells by GRPR-Targeted Gold Nanoparticles.

For a while, gold nanoparticles (AuNPs) have been recognized as potential radiosensitizers in cancer radiation therapy, mainly due to their physical properties, making them appealing for medical applications. Nevertheless, the performance of AuNPs as radiosensitizers still raises important questions that need further investigation. Searching for selective prostate (PCa) radiosensitizing agents, we studied the radiosensitization capability of the target-specific AuNP-BBN in cancer versus non-cancerous prostate cells, including the evaluation of dose rate effects in comparison with non-targeted counterparts (AuNP-TDOTA). PCa cells were found to exhibit increased AuNP uptake when compared to non-tumoral ones, leading to a significant loss of cellular proliferation ability and complex DNA damage, evidenced by the occurrence of multiple micronucleus per binucleated cell, in the case of PC3 cells irradiated with 2 Gy of γ-rays, after incubation with AuNP-BBN. Remarkably, the treatment of the PC3 cells with AuNP-BBN led to a much stronger influence of the dose rate on the cellular survival upon γ-photon irradiation, as well as on their genomic instability. Overall, AuNP-BBN emerged in this study as a very promising nanotool for the efficient and selective radiosensitization of human prostate cancer PC3 cells, therefore deserving further preclinical evaluation in adequate animal models for prostate cancer radiotherapy.

Radiolabeled Gold Nanoseeds Decorated with Substance P Peptides: Synthesis, Characterization and In Vitro Evaluation in Glioblastoma Cellular Models.

Despite some progress, the overall survival of patients with glioblastoma (GBM) remains extremely poor. In this context, there is a pressing need to develop innovative therapy strategies for GBM, namely those based on nanomedicine approaches. Towards this goal, we have focused on nanoparticles (AuNP-SP and AuNP-SPTyr8) with a small gold core (ca. 4 nm), carrying DOTA chelators and substance P (SP) peptides. These new SP-containing AuNPs were characterized by a variety of analytical techniques, including TEM and DLS measurements and UV-vis and CD spectroscopy, which proved their high in vitro stability and poor tendency to interact with plasma proteins. Their labeling with diagnostic and therapeutic radionuclides was efficiently performed by DOTA complexation with the trivalent radiometals 67Ga and 177Lu or by electrophilic radioiodination with 125I of the tyrosyl residue in AuNP-SPTyr8. Cellular studies of the resulting radiolabeled AuNPs in NKR1-positive GBM cells (U87, T98G and U373) have shown that the presence of the SP peptides has a crucial and positive impact on their internalization by the tumor cells. Consistently, 177Lu-AuNP-SPTyr8 showed more pronounced radiobiological effects in U373 cells when compared with the non-targeted congener 177Lu-AuNP-TDOTA, as assessed by cell viability and clonogenic assays and corroborated by Monte Carlo microdosimetry simulations.

Broad Spectrum Functional Activity of Structurally Related Monoanionic Au(III) Bis(Dithiolene) Complexes.

The biological properties of sixteen structurally related monoanionic gold (III) bis(dithiolene/ diselenolene) complexes were evaluated. The complexes differ in the nature of the heteroatom connected to the gold atom (AuS for dithiolene, AuSe for diselenolene), the substituent on the nitrogen atom of the thiazoline ring (Me, Et, Pr, iPr and Bu), the nature of the exocyclic atom or group of atoms (O, S, Se, C(CN)2) and the counter-ion (Ph4P+ or Et4N+). The anticancer and antimicrobial activities of all the complexes were investigated, while the anti-HIV activity was evaluated only for selected complexes. Most complexes showed relevant anticancer activities against Cisplatin-sensitive and Cisplatin-resistant ovarian cancer cells A2780 and OVCAR8, respectively. After 48 h of incubation, the IC50 values ranged from 0.1-8 µM (A2780) and 0.8-29 µM (OVCAR8). The complexes with the Ph4P+ ([P]) counter-ion are in general more active than their Et4N+ ([N]) analogues, presenting IC50 values in the same order of magnitude or even lower than Auranofin. Studies in the zebrafish embryo model further showed that, despite their marked anticancer effect, the complexes with [P] counter-ion exhibited low in vivo toxicity. In general, the exocyclic exchange of sulfur by oxygen or ylidenemalononitrile (C(CN)2) enhanced the compounds toxicity. Most complexes containing the [P] counter ion exhibited exceptional antiplasmodial activity against the Plasmodium berghei parasite liver stages, with submicromolar IC50 values ranging from 400-700 nM. In contrast, antibacterial/fungi activities were highest for most complexes with the [N] counter-ion. Auranofin and two selected complexes [P][AuSBu(=S)] and [P][AuSEt(=S)] did not present anti-HIV activity in TZM-bl cells. Mechanistic studies for selected complexes support the idea that thioredoxin reductase, but not DNA, is a possible target for some of these complexes. The complexes [P] [AuSBu(=S)], [P] [AuSEt(=S)], [P] [AuSEt(=Se)] and [P] [AuSeiPr(=S)] displayed a strong quenching of the fluorescence intensity of human serum albumin (HSA), which indicates a strong interaction with this protein. Overall, the results highlight the promising biological activities of these complexes, warranting their further evaluation as future drug candidates with clinical applicability.

Infants' and toddlers' digital media use and mothers' mental health: A comparative study before and during the COVID-19 pandemic.

This study compared children's and mothers' digital media use and mothers' mental health in two samples: one accessed before (Group 1; N = 257; M = 33.18 years; SD = 4.79) and the other accessed during (Group 2; N = 256; M = 33.51 years; SD = 4.96) the COVID-19 pandemic in Brazil. Mothers of children up to 3 years old (Group 1: M = 17.95 months, SD = 9.85; Group 2: M = 16.48 months, SD = 10.15) answered an online survey. Bivariate analysis, factorial ANOVA tests, and multiple linear regression were performed. Results suggest that mothers' and children's media use duration was higher during the pandemic only among children over 12 months. Mothers' media use duration (ß = .18) and mothers' intention to offer media (ß = .23) contributed to the explanation of children's media use duration (F(4, 474) = 16.81; p < .001; R2  = .12; R2 adjusted = .117). Higher mothers' common mental disorders symptoms were also positively correlated to mothers' intention to offer media to children both before and during the pandemic. Results suggest that interventions focusing on infants and toddlers screen time reduction should target maternal aspects such as mental health, maternal screen time, and intention to offer media, taking into account the mothers' needs when planning these actions.

Este estudio comparó el uso de los medios digitales por parte de los niños y las madres con la salud mental de las madres en dos grupos muestra: uno al cual se tuvo acceso antes (Grupo 1: N = 257; M = 33.18 años; SD = 4.79) y el otro al cual se tuvo acceso durante (Grupo 2; N = 256; M = 33.51 años; SD = 4.96) la pandemia del COVID-19 en Brasil. Las madres de niños de hasta tres años (Grupo 1: M = 17.95 meses, SD = 9.85; Grupo 2: M = 16.48 meses, SD = 10.15) respondieron una encuesta electrónica. Los análisis bivariados los exámenes factoriales ANOVA, así como múltiples regresiones lineales se llevaron a cabo. Los resultados indican que la duración de uso de los medios por parte de las madres y los niños fue más alta durante la pandemia sólo entre niños de más de 12 meses. La duración de uso de los medios por parte de las madres (ß = 0.18) y la intención de las madres de ofrecer los medios (ß = 0.23) contribuyeron a explicar la duración de uso de los medios por parte de los niños (F(4,474) = 16,81; p < .001; R2 = .12; R2 ajustado = .117). Más altos síntomas de trastornos mentales comunes en las madres se correlacionaron también positivamente con la intención de las madres de ofrecer los medios a los niños tanto antes como durante la pandemia. Los resultados indican que las intervenciones enfocadas en reducir el tiempo frente a la pantalla de infantes y niños pequeñitos deben dirigirse a los aspectos maternos como la salud mental, el tiempo de la madre frente a la pantalla, así como la intención de ofrecer los medios, tomando en cuenta las necesidades de las madres cuando se planeen estas acciones.

Cette étude a comparé l'utilisation des médias numériques des enfants et des mères et la santé mentale des mères chez deux échantillons: l'un accédé avant la pandémie du Covid-19 (Groupe 1; N = 257; M = 33,18 ans; SD = 4,79) et l'autre accédé durant la pandémie du covid-19 (Groupe 2; N = 256; M = 33,51 ans; SD = 4,96) au Brésil. Les mères d'enfants jusqu'à l'âge de trois ans (Groupe 1: M = 17,95 mois, SD = 9,85; Groupe 2: M = 16,48 mois, SD = 10,15) ont répondu à un questionnaire en ligne. Une analyse à deux variables, des tests ANOVA factoriels, et une régression linéaire multiple ont été faits. Les résultats suggèrent que la durée de l'utilisation média des mères et des enfants a été plus élevée durant la pandémie uniquement pour les enfants de plus de 12 mois. La durée de l'utilisation média des mères (ß = 0,18) et l'intention des mères à offrir le média (ß = 0,23) a contribué à l'explication de la durée de l'utilisation média des enfants (F(4, 474) = 16,81; p <,001; R2 = ,12; R2 adjusté = ,117). Plus de symptômes communs de troubles mentaux des mères était aussi lié de manière positive à l'intention des mères d'offrir le média à la fois avant et durant la pandémie. Les résultats suggèrent que les interventions s'attachant à la réduction du temps d'écran des bébés et des petits enfants devraient cibler des aspects maternels comme la santé mentale, le temps d'écran maternel, et l'intention d'offrir le média, prenant en compte les besoins des mères en planifiant ces actions.

Altered astrocytic function in experimental neuroinflammation and multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that affects about 2.5 million people worldwide. In MS, the patients' immune system starts to attack the myelin sheath, leading to demyelination, neurodegeneration, and, ultimately, loss of vital neurological functions such as walking. There is currently no cure for MS and the available treatments only slow the initial phases of the disease. The later-disease mechanisms are poorly understood and do not directly correlate with the activity of immune system cells, the main target of the available treatments. Instead, evidence suggests that disease progression and disability are better correlated with the maintenance of a persistent low-grade inflammation inside the CNS, driven by local glial cells, like astrocytes and microglia. Depending on the context, astrocytes can (a) exacerbate inflammation or (b) promote immunosuppression and tissue repair. In this review, we will address the present knowledge that exists regarding the role of astrocytes in MS and experimental animal models of the disease.

Cytotoxic oxidovanadium(IV) complexes of tridentate halogen-substituted Schiff bases: First dinuclear V(IV) complexes with O → VIV = O → VIV = O core.

The reaction of potentially N,N,O-tridentate Schiff base ligands, Cl-LH, Br-LH, BrCl-LH and H-LH, with [VIVO(acac)2] in 2:1 ratio in methanol gave the corresponding mononuclear and dinuclear oxidovanadium(IV) complexes, VO(Cl-L)2 (1), VO(Br-L)2 (2), [(BrCl-L)2(H2O)V(µ-O)VO(BrCl-L)2] (3) and [(H-L)2(H2O)V(µ -O)VO(H-L)2] (4), in good yields. The ligands and complexes were fully characterized by elemental analysis and FT-IR spectroscopy. The ligands were also characterized by 1H NMR spectroscopy. The oxidation state of V(IV)O with d1 configuration in all synthesized complexes was confirmed by EPR. Moreover, the structures of 2 and 3 were determined by X-ray diffraction (XRD) analysis which revealed them as mono- and dinuclear vanadium(IV) complexes, respectively, with the ligands coordinated as bidentate chelates. The structure of 3 represents the first example of dinuclear V(IV) complex with O â†’ VIV = O â†’ VIV = O core (Cambridge Structural Database (CSD)​, version 5.42, update of May 2021). The cytotoxicity of ligands and complexes was evaluated towards ovarian (A2780), breast (MCF7) and prostate (PC3) cancer cells at 48 h. While ligands showed modest IC50 values (>42 µM), all complexes turned out to be effective in the range 3.9-17.2 µM. In particular, A2780 and MCF7 cell lines were the most sensitive to the newly synthesized V(IV)O complexes.

Half-Sandwich Ru(p-cymene) Compounds with Diphosphanes: In Vitro and In Vivo Evaluation As Potential Anticancer Metallodrugs.

Ruthenium(II) complexes are currently considered attractive alternatives to the widely used platinum-based drugs. We present herein the synthesis and characterization of half-sandwich ruthenium compounds formulated as [Ru(p-cymene)(L)Cl][CF3SO3] (L = 1,1-bis(methylenediphenylphosphano)ethylene, 1; L = 1,1-bis(diphenylphosphano)ethylene, 2), which were characterized by elemental analysis, mass spectrometry, 1H and 31P{1H} NMR, UV-vis and IR spectroscopy, conductivity measurements and cyclic voltammetry. The molecular structures for both complexes were determined by single-crystal X-ray diffraction. Their cytotoxic activity was evaluated using the MTT assay against human tumor cells, namely ovarian (A2780) and breast (MCF7 and MDA-MB-231). Both complexes were active against breast adenocarcinoma cells, with complex 1 exhibiting a quite remarkable cytotoxicity in the submicromolar range. Interestingly, at concentrations equivalent to the IC50 values in the MCF7 cancer cells, complexes 1 and 2 presented lower cytotoxicity in normal human primary fibroblasts. The antiproliferative effects of 1 and 2 in MCF7 cells might be associated with the induction of reactive oxygen species (ROS), leading to a combined cell death mechanism via apoptosis and autophagy. Despite the fact that in vitro a partial intercalation between complexes and DNA was observed, no MCF7 cell cycle delay or arrest was observed, indicating that DNA might not be a direct target. Complexes 1 and 2 both exhibited a moderate to strong interaction with human serum albumin, suggesting that protein targets may be involved in their mode of action. Their acute toxicity was evaluated in the zebrafish model. Complex 1 (the most toxic of the two) exhibited a lethal toxicity LC50 value about 1 order of magnitude higher than any IC50 concentrations found for the cancer cell models used, highlighting its therapeutic relevance as a drug candidate in cancer chemotherapy.

Elevated levels of neutrophil gelatinase-associated lipocalin among OCD patients: an exploratory study.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disease that is characterized by its clinical heterogeneity and complex pathophysiology. This complexity comes from the diversity of pathophysiological factors that have been proposed to be involved in the natural history of the disorder. Many theories on OCD pathology support inflammation as a pathophysiological factor, although studies are not consistent on the presence of a pro-inflammatory state among OCD patients. However, some pre-clinical animal studies suggest lipocalin-2 (LCN2), an analogous form of the acute-phase pro-inflammatory protein neutrophil gelatinase-associated lipocalin (NGAL), may be involved in in the regulation of the stress response, which is thought to be disrupted in OCD. METHODS: Twenty-one OCD patients and 19 healthy subjects participated in this exploratory study. Levels of NGAL were assessed in the peripherous blood of all participants. Severity of disease was assessed using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). RESULTS: OCD patients exhibited significantly higher levels of NGAL when compared to healthy control subjects. No correlation was found between elevated levels of NGAL and severity of symptoms. CONCLUSIONS: This is the first study to report elevated levels of NGAL among OCD patients, adding evidence for a possible role of immune dysregulation in the pathophysiology of OCD.

Are temporomandibular disorders associated with facial asymmetry? A systematic review and meta-analysis.

OBJECTIVE: To assess scientific evidence of the association between temporomandibular joint (TMJ) disorders and facial asymmetry (FA). METHODS: A systematic review was performed in accordance with the PRISMA checklist. A search strategy was developed in electronic databases including MEDLINE, Scopus, Web of Science, Virtual Health Library and Cochrane Library until January 2020. Eligibility criteria included observational studies that investigated the occurrence of FA among patients with and without signs and symptoms of TMJ disorders. Risk of bias of individual studies was analysed after study selection and data collection processes according to Fowkes and Fulton guidelines. Four meta-analyses (MA) were performed to evaluate the association between TMJ disorders and linear/angular menton deviation, subgrouping the studies into unilateral and bilateral cases. The evidence was certainty-tested using the GRADE approach. RESULTS: The search retrieved 2371 studies, 31 of which were eligible for full-text reading. Seven cross-sectional clinical studies met the eligibility criteria and were included in the qualitative synthesis, comprising a total of 621 subjects (345 with TMJ disease and 276 in control group), four of which were classified as being methodologically sound. Five studies were eligible for quantitative synthesis. Linear and angular menton deviation was greater in individuals with unilateral TMJ disorders than controls (MD = 2.41 [0.33, 4.50] P = .02; I2  = 86% and MD = 2.68 [0.99, 4.38] P = .002; I2  = 0%, respectively). CONCLUSIONS: Despite the low certainty in evidence, the present study indicated that unilateral TMJ disorders are associated with FA. However, longitudinal studies with greater certainty of evidence should be conducted to achieve a stronger estimate of this association.

Evaluation of photobiomodulation therapy to accelerate bone formation in the mid palatal suture after rapid palatal expansion: a randomized clinical trial.

To evaluate the efficiency of photobiomodulation therapy (PBMT) in the midpalatal suture (MPS) and pain sensation in patients undergoing rapid palatal expansion (RPE). Thirty-four individuals with the diagnosis of skeletal maxillary hypoplasia were divided in two groups: laser (n = 18) and control (n = 16). Treatment plan consisted of the use of the Hyrax expander in all patients. Subjects in the laser group were irradiated with diode laser (980 nm, 0.3 W) in six spots bilaterally distributed along the MPS for 10 s during the active phase of treatment and after overcorrection (passive phase of RPE). Control group received sham irradiations with the laser in standby mode to characterize the placebo effect. Digital occlusal radiographs were performed at different time-points for bone formation evaluation in both groups. The effects of laser irradiation on pain were assessed by the visual analog scale (Wong-Baker Faces Pain Scale). Bone formation between groups was not significantly different (p = 0.2273). At 3 months, bone formation was not yet complete in both groups. Pain sensation was similar between groups (p = 0.3940). However, pain was significantly higher for the first 7 days of treatment compared with the 14th day. PBMT did not accelerate bone regeneration in the MPS and pain sensation was similar.