Neonatal estrogen induces male-like expression of astroglial markers of maturation and plasticity in the neocortex of female mice.

Astroglia play a crucial role in various aspects of neurodevelopment including building, maintaining, and modulating neuronal circuits that underly complex behaviours in the neocortex. Telencephalic regions exhibit sex differences in neuronal networks that arise early in development. Astroglia express receptors for gonadal hormones responsible for the organization of sex differences, such as estrogen, placing them in a key position to modulate sex differences in the development of neuronal networks. Astroglial cells express specific proteins related to their morphology, function, and maturation. We have previously shown that P7-P14 is a key transition period for neocortical astroglial maturation and that males reach a mature phenotype earlier than females, at P7. In this study, we investigated whether administration of perinatal estradiol to female mice is sufficient to masculinize astroglial protein and gene expression related to maturation that we previously observed at P7. We found that canonical astroglial markers like glial fibrillary acidic protein and glutamine synthetase are not affected by perinatal estrogen, but markers of astroglial maturation, Vimentin, Aldh1a1, Dio2, and the number of actively dividing astroglia are masculinized by perinatal estradiol administration. These findings suggest that sex differences in neocortical astroglial maturation are at least in-part due to the role of perinatal estrogen. Given the higher prevalence of neurodevelopmental disorders in males compared to females and the involvement of astroglia in virtually all neurodevelopmental disorders, further research is needed to determine other contributions to sex differences in neocortical astroglial cells.

Comparison of knowledge between Italian and Spanish parents about the oral health of their preschool children.

AIM: To evaluate and compare baseline knowledge between Italian and Spanish parents with regards to the oral and dental health of their preschool children. METHODS: Study design epidemiological descriptive observational cross-sectional study. The research data was collected through an anonymous bilingual survey, generated through Google Forms and distributed either in paper form or through several digital channels together with a QR code to drive the participants to the questionnaire. In order to assess the differences between Italy and Spain, t-Student (with confidence interval) or Mann-Whitney tests were used to compare the independent numerical variables, and the Chi-Square test was used to compare the independent categorical variables. CONCLUSION: Independently of the differences identified among the two countries, the results show that parents from both nationalities have limited knowledge about their preschool children's oral health and are not fully informed about child's oral hygiene practices.

The inhibition of microtubule dynamics instability alters lipid homeostasis in TM4 Sertoli cells.

Sertoli cells (SC) structurally support and transport nutrients to germ cells during spermatogenesis facilitated by an active cytoskeleton. Chemical perturbation of SC microtubule (MT) dynamics instability leads to premature germ cell exfoliation demonstrating that this process is essential for male fertility, yet the effects of MT damaging drugs on SC lipid metabolism have been less explored. The aim of this study was to advance our understanding of how adequate SC MT dynamicity is needed to finely tune lipid homeostasis. To elucidate the role of MT dynamics instability on the latter, we suppressed MT dynamicity by long-term exposures to 10 nM of nocodazole (NCZ) on TM4-SC cultures. Inhibition of MT dynamics instability affected the distribution of [3H] arachidonate on TM4-SC. Triacylglycerols (TAG) exhibited a higher proportion of the [3H] label, with significantly lower percentages in the mitochondrial phospholipid cardiolipin, and notably, also in phosphatidylethanolamine. A noteworthy and progressive accumulation of lipid droplets during the period of exposure to NCZ was accompanied by increased TAG levels but not cholesterol levels in TM4-SC. NCZ-exposed cells reduced their mitochondrial membrane potential and increased ROS production without triggering apoptosis, had a compromised autophagic flux, and lost their transferrin expression. Although SC morphology was preserved, the NCZ-exposed cells displayed alteration of the normal organization of microfilaments (f-actin) and intermediate filaments (vimentin). Our findings suggest that a preserved MT dynamicity is essential in the maintenance of lipid and fatty acids homeostasis in SC, and thus highlights a novel target in these cells for drugs that impair MT dynamicity.

Collective strong coupling in a plasmonic nanocavity.

Quantum plasmonics extends cavity quantum electrodynamics (cQED) concepts to the nanoscale, benefiting from the strongly subwavelength confinement of the plasmon modes supported by metal nanostructures. In this work, we describe in detail collective strong coupling to a plasmonic nanocavity. Similarities and differences to cQED are emphasized. We notably observe that the Rabi splitting can strongly deviate from the standard NeΔΩ1 law, where Ne is the number of emitters and ΔΩ1 is the Rabi splitting for a single emitter. In addition, we discuss the collective Lamb shift and the role of quantum corrections to the emission spectra.

Antioxidant treatment ameliorates prefrontal hypomyelination and cognitive deficits in a rat model of schizophrenia.

Cognitive dysfunction in schizophrenia (SZ) is thought to arise from neurodevelopmental abnormalities that include interneuron hypomyelination in the prefrontal cortex (PFC). Here we report that RNA-sequencing of the medial (m)PFC of the APO-SUS rat model with SZ-relevant cognitive inflexibility revealed antioxidant metabolism as the most-enriched differentially expressed pathway. Antioxidant-related gene expression was altered throughout postnatal development and preceded hypomyelination. Furthermore, reduced glutathione levels and increased mitochondria numbers were observed in the mPFC. Strikingly, chronic treatment with the glutathione precursor N-acetylcysteine (NAC) from postnatal days 5-90 restored not only antioxidant-related mRNA expression and mitochondria numbers, but also myelin-related mRNA expression and mPFC-dependent cognitive dysfunction, while blood glutathione levels remained unaffected. The promyelinating effect of NAC was at least partly due to a positive effect on oligodendrocyte lineage progression. Together, our findings highlight that oxidative stress may contribute to cognitive symptoms in the APO-SUS rat model of SZ and encourage antioxidant therapy in early phases of SZ.

Co-expression analysis of pancreatic cancer proteome reveals biology and prognostic biomarkers.

PURPOSE: Despite extensive biological and clinical studies, including comprehensive genomic and transcriptomic profiling efforts, pancreatic ductal adenocarcinoma (PDAC) remains a devastating disease, with a poor survival and limited therapeutic options. The goal of this study was to assess co-expressed PDAC proteins and their associations with biological pathways and clinical parameters. METHODS: Correlation network analysis is emerging as a powerful approach to infer tumor biology from omics data and to prioritize candidate genes as biomarkers or drug targets. In this study, we applied a weighted gene co-expression network analysis (WGCNA) to the proteome of 20 surgically resected PDAC specimens (PXD015744) and confirmed its clinical value in 82 independent primary cases. RESULTS: Using WGCNA, we obtained twelve co-expressed clusters with a distinct biology. Notably, we found that one module enriched for metabolic processes and epithelial-mesenchymal-transition (EMT) was significantly associated with overall survival (p = 0.01) and disease-free survival (p = 0.03). The prognostic value of three proteins (SPTBN1, KHSRP and PYGL) belonging to this module was confirmed using immunohistochemistry in a cohort of 82 independent resected patients. Risk score evaluation of the prognostic signature confirmed its association with overall survival in multivariate analyses. Finally, immunofluorescence analysis confirmed co-expression of SPTBN1 and KHSRP in Hs766t PDAC cells. CONCLUSIONS: Our WGCNA analysis revealed a PDAC module enriched for metabolic and EMT-associated processes. In addition, we found that three of the proteins involved were associated with PDAC survival.

Oxidative stress, prefrontal cortex hypomyelination and cognitive symptoms in schizophrenia.

Schizophrenia (SZ) is a neurodevelopmental disorder with a broad symptomatology, including cognitive symptoms that are thought to arise from the prefrontal cortex (PFC). The neurobiological aetiology of these symptoms remains elusive, yet both impaired redox control and PFC dysconnectivity have been recently implicated. PFC dysconnectivity has been linked to white matter, oligodendrocyte (OL) and myelin abnormalities in SZ patients. Myelin is produced by mature OLs, and OL precursor cells (OPCs) are exceptionally susceptible to oxidative stress. Here we propose a hypothesis for the aetiology of cognitive symptomatology in SZ: the redox-induced prefrontal OPC-dysfunctioning hypothesis. We pose that the combination of genetic and environmental factors causes oxidative stress marked by a build-up of reactive oxygen species that, during late adolescence, impair OPC signal transduction processes that are necessary for OPC proliferation and differentiation, and involve AMP-activated protein kinase, Akt-mTOR-P70S6K and peroxisome proliferator receptor alpha signalling. OPC dysfunctioning coincides with the relatively late onset of PFC myelination, causing hypomyelination and disruption of connectivity in this brain area. The resulting cognitive deficits arise in parallel with SZ onset. Hence, our hypothesis provides a novel neurobiological framework for the aetiology of SZ cognitive symptoms. Future research addressing our hypothesis could have important implications for the development of new (combined) antioxidant- and promyelination-based strategies to treat the cognitive symptoms in SZ.

[Decolonization for Staphylococcus aureus carriers in arthroplasty surgery after hip fracture]. / Descolonización de pacientes portadores de Staphylococcus aureus en cirugía de artroplastia por fractura de cadera.

OBJECTIVE: Staphylococcus aureus is the main causative agent of joint prosthesis infections. The decolonization of the carriers is effective in the prevention of the infections of the elective arthroplasties. The aim of this study is to evaluate if it is also in arthroplasties after hip fracture. METHODS: Study in patients with hip fracture who underwent joint prosthesis from January 2011 to December 2015 with a protocol of S. aureus detection-decolonization with intranasal mupirocin and chlorhexidine baths. Patients between January 2009 and December 2010 were the comparison group. RESULTS: In the intervention period, the study of colonization of S. aureus was performed in 307 patients, of whom 87 were positive (28.3%). The study period was completed by 267 patients, of whom two developed S. aureus infection, compared to six of 138 in the control group (0.7% vs 4.3%, RR 0.1, p = 0.03). CONCLUSIONS: In our study, S. aureus decolonization in patients with hip fracture decreased the incidence of joint prosthesis infection by this microorganism.

[Prosthetic joint infection in patients with hip fracture. Differences from infection of elective prosthesis]. / Infección de prótesis articular en el paciente con fractura de cadera. Diferencias frente a la infección de prótesis electiva.

OBJECTIVE: Most publications about prosthetic joint infections (PJI) are referred to elective prosthesis and they exclude arthroplasties due to hip fracture. METHODS: We conducted a descriptive study about prosthetic joint infections after joint fracture in Alcalá de Henares Hospital (Madrid) between 2009 and 2014 and we compared with elective prosthetic infections in the same period. RESULTS: There were 30 PJI after hip fracture and 14 elective PJI. The incidence of infection was 4.7% in arthroplasties due to hip fracture from 1.3% in elective prosthesis (RR 3.8, p=0.005). The PJI after fracture affected older patients (82.5 years vs 71.5, p=0.006), with greater comorbidity (5.4 vs 3.6, p=0.003), higher anesthetic risk (ASA>2 70% vs 21.4%, p=0.004) and higher incidence of dementia (50% vs 0%, p=0.02). Staphylococcus aureus was the most common causative agent in both groups, but there was higher incidence of Gram negative-cases in PJI after fracture group (43.3% vs 21.4%, p no significance) and cefazolin-resistance (63.3% vs 28.6%, p=0.03). In logistic regression analysis the treatment had less chance of success in PJI after fracture than elective PJI (33.3% vs 78.6%, OR 0.09, p=0.06). CONCLUSIONS: The PJI after fracture are more frequent than elective PJI, affect older patients, with poor general condition, are produced by more resistant bacteria and have worst evolution than EPJI.

Role of brain transmigrating neutrophils in depression-like behavior during systemic infection.

Peripheral inflammation induces transmigration of interleukin (IL)-1ß-expressing neutrophils to the brain. We investigated the possibility that this presents a new route of immune-to-brain communication by assessing their role in sickness behaviors relevant for mood disorders. Mice treated with lipopolysaccharide (LPS) developed despair-like behavior, and administration of an anti-polymorphonuclear antibody abolished LPS-induced despair-like and asocial behaviors, which correlated with the levels of IL-1ß expression in the brain. These behavioral changes were directly mediated by the energy-regulating hormone, leptin. Increasing the concentration of endogenous leptin during obesity exacerbated, whereas its neutralization using a specific antiserum attenuated sickness behaviors and importantly the neutrophil transmigrating process. Our results indicate a role for peripheral neutrophils in conveying inflammatory signals to the brain, which appears to be dependent on the energy status of the organism. This constitutes a novel mechanism of immune-to-brain communication relevant to mood disorders.

Generation of polarization-entangled photon pairs in a Bragg reflection waveguide.

We demonstrate experimentally that spontaneous parametric down-conversion in an AlxGa(1-x)As semiconductor Bragg reflection waveguide can make for paired photons highly entangled in the polarization degree of freedom at the telecommunication wavelength of 1550 nm. The pairs of photons show visibility higher than 90% in several polarization bases and violate a Clauser-Horne-Shimony-Holt Bell-like inequality by more than 3 standard deviations. This represents a significant step toward the realization of efficient and versatile self pumped sources of entangled photon pairs on-chip.

Fluoxetine administration to pregnant rats increases anxiety-related behavior in the offspring.

RATIONALE: Fluoxetine (Prozac®) is the most frequently prescribed drug to battle depression in pregnant women, but its safety in the unborn child has not yet been established. Fluoxetine, a selective serotonin reuptake inhibitor, crosses the placenta, leading to increased extracellular serotonin levels and potentially neurodevelopmental changes in the fetus. OBJECTIVES: The purpose of this study was to elucidate the long-term consequences of prenatal fluoxetine in rats. METHODS: Pregnant rats were injected daily with 12 mg/kg fluoxetine or vehicle from gestational day 11 until birth, and the behavior of the offspring was monitored. RESULTS: Plasma fluoxetine transfer from mother to pup was 83%, and high levels of fluoxetine (13.0 µg/g) were detected in the pup brain 5 h after the last injection. Fluoxetine-treated dams gave birth to litters 15% smaller than usual and to pups of reduced weight (until postnatal day 7). Furthermore, prenatal fluoxetine exposure significantly increased anxiety in the novelty-suppressed feeding test, the footshock-induced conditioned place aversion test, and the elevated plus maze test (following footshock pre-exposure) during adulthood, and also significantly decreased components of social play behavior at 4 weeks of age, and a strong tendency for increased self-grooming and making less contact in adults. Behavioral despair, anhedonia, and sexual behavior were not different between treatment groups. Finally, the hypothermic response to the 5-HT(1A) agonist flesinoxan was observed at a lower dose in prenatally fluoxetine-exposed rats than in controls. CONCLUSIONS: Prenatal fluoxetine exposure in rats leads to detrimental behavioral outcomes in later life, which may partly be due to altered 5-HT(1A) receptor signaling.

The anticonvulsive drug lamotrigine blocks neuronal {alpha}4{beta}2 nicotinic acetylcholine receptors.

Lamotrigine (LTG), an anticonvulsive drug, is often used for the treatment of a variety of epilepsies. In addition to block of sodium channels, LTG may act on other targets to exert its antiepileptic effect. In the present study, we evaluated the effects of LTG on neuronal nicotinic acetylcholine receptors (nAChRs) using the patch-clamp technique on human α4ß2-nAChRs heterologously expressed in the SH-EP1 cell line and on native α4ß2-nAChRs in dopaminergic (DA) neurons in rat ventral tegmental area (VTA). In SH-EP1 cells, LTG diminished the peak and steady-state components of the inward α4ß2-nAChR-mediated currents. This effect exhibited concentration-, voltage- and use-dependent behavior. Nicotine dose-response curves showed that in the presence of LTG, the nicotine-induced maximal current was reduced, suggesting a noncompetitive inhibition. These findings suggest that LTG inhibits human neuronal α4ß2-nAChR function through an open-channel blocking mechanism. LTG-induced inhibition in α4ß2-nAChRs was more profound when preceded by a 2-min pretreatment, after which the nicotine-induced current was reduced even without coapplication of LTG, suggesting that LTG is also able to inhibit α4ß2-nAChRs without channel activation. In freshly dissociated VTA DA neurons, LTG inhibited α4ß2-nAChR-mediated currents but did not affect glutamate- or GABA-induced currents, indicating that LTG selectively inhibits nAChR function. Collectively, our data suggest that the neuronal α4ß2-nAChR is likely an important target for mediating the anticonvulsive effect of LTG and the blockade of α4ß2-nAChR possibly underlying the mechanism through which LTG effectively controls some types of epilepsy, such as autosomal dominant nocturnal frontal lobe epilepsy or juvenile myoclonic epilepsy.

Boundary lipids in the nicotinic acetylcholine receptor microenvironment.

The structural and functional properties of the nicotinic acetylcholine receptor (AChR), the archetype molecule in the superfamily of Cys-looped ligand-gated ion channels, are strongly dependent on the lipids in the vicinal microenvironment. The influence on receptor properties is mainly exerted by the AChR-vicinal ("shell" or "annular") lipids, which occur in the liquid-ordered phase as opposed to the more disordered and "fluid" bulk membrane lipids. Fluorescence studies from our laboratory have identified discrete sites for fatty acids, phospholipids, and cholesterol on the AChR protein, and electron-spin resonance spectroscopy has enabled the establishment of the stoichiometry and selectivity of the shell lipid for the AChR and the disclosure of lipid sites in the AChR transmembrane region. Experimental evidence supports the notion that the interface between the protein moiety and the adjacent lipid shell is the locus of a variety of pharmacologically relevant processes, including the action of steroids and other lipids. I surmise that the outermost ring of M4 helices constitutes the boundary interface, most suitable to convey the signals from the lipid microenvironment to the rest of the transmembrane region, and to the channel inner ring in particular.

[Comparative study of sentinel node biopsy in patients with multifocal breast carcinoma versus in those with unifocal breast carcinoma.]. / Estudio comparativo de la técnica del ganglio centinela entre los casos de carcinoma de mama multifocal y unifocal.

OBJECTIVE: To evaluate the results for sentinel node biopsy (SNB) in patients with multifocal breast cancer (MBC) in comparison to in those with unifocal breast cancer (UBC). PATIENTS AND METHODS: A total of 1535 prospective SNB (174 on patients with MBC) were performed at 9 hospitals. In most patients, Tc-99m albumin colloids were injected intraparenchymally into each tumoral focus for SNB. RESULTS: The overall identification rate was 93.8%; no differences between groups were observed (94.8% in MBC vs 93.4% in UBC). The mean number of sentinel nodes detected was 1.46, being higher in the MBC group than in the UBC group (1.58 vs 1.45; p=0.036). Extra-axillary sentinel nodes were found in 19.6%; extra-axillary sentinel nodes were more common in the MBC group (23.4% vs 18.9%, ns) and in the internal mammary chain and in level III axillary lymph nodes. The incidence of sentinel node metastasis was 27.3% (29.1% MBC vs 26.7% UBC, ns), and the mean number of positive sentinel nodes was 0.42 in the MBC group vs 0.32 in the UBC group (p=ns). Axillary dissection identified the same rate of positive additional nodes (29.7%) in both groups. CONCLUSIONS: The diagnostic yield of SNB seems similar in MBC and UBC. In MBC, there appears to be a specific pattern of lymphatic drainage, with a higher number of sentinel nodes detected and probably a higher number of extra-axillary sentinel nodes.

Amygdala kindling differentially regulates the expression of the elements involved in TRH transmission.

Subthreshold electrical stimulation of the amygdala (kindling) activates neuronal pathways increasing the expression of several neuropeptides including thyrotropin releasing-hormone (TRH). Partial kindling enhances TRH expression and the activity or its inactivating ectoenzyme; once kindling is established (stage V), TRH and its mRNA levels are further increased but TRH-binding and pyroglutamyl aminopeptidase II (PPII) activity decreased in epileptogenic areas. To determine whether variations in TRH receptor binding or PPII activity are due to regulation of their synthesis, mRNA levels of TRH receptors (R1, R2) and PPII were semi-quantified by RT-PCR in amygdala, frontal cortex and hippocampus of kindled rats sacrificed at stage II or V. Increased mRNA levels of PPII were found at stage II in amygdala and frontal cortex, and of pro-TRH and TRH-R2, in amygdala and hippocampus. At stage V, pro-TRH mRNA levels increased and those of PPII, decreased in the three regions; TRH-R2 mRNA levels diminished in amygdala and frontal cortex and of TRH-R1 only in amygdala. In situ hybridization analyses revealed, at stage II, enhanced TRH-R1 mRNA levels in dentate gyrus and amygdala while decreased in piriform cortex; those of TRH-R2 increased in amygdala, CA2, dentate gyrus, piriform cortex, thalamus and subiculum and of PPII, in CAs and piriform cortex. In contrast, at stage V decreased expression of TRH-R1 occurred in amygdala, CA2/3, dentate gyrus and piriform cortex; of TRH-R2 in CA2, thalamus and piriform cortex, and of PPII in CA2, and amygdala. The magnitude of changes differed between ipsi and contralateral side. These results support a trans-synaptic modulation of all elements involved in TRH transmission in conditions that stimulate the activity of TRHergic neurons. They show that reported changes in PPII activity or TRH-binding caused by kindling relate to regulation of the expression of TRH receptors and degrading enzyme.

[Cyst and pseudocyst lesions of the floor of the mouth with submental affectation]. / Lesiones quísticas y pseudoquísticas del suelo de la boca con afectación submentoniana. Diagnóstico diferencial y tratamiento.

There are several lesions which can present as a cyst or pseudocyst of the floor of the mouth with submental repercussion. The aim of this paper is to review the diagnosis methods which can help us to differentiate these lesions such as the surgical peculiarities of every tumour. We are reporting two cases of cystic/pseudocystic lesions of the floor of the mouth with submental repercussion. Both of them were epidermoid cysts. Ranulas, lipomas and lymphangiomas should be considered in the differential diagnosis. Imaging diagnosis, fine needle aspiration and adequate treatment in all of the tumours are reviewed. Both cases were operated via intraoral. They are now free of disease after at least one year. Differential diagnosis of cystic lesions of the floor of the mouth is important because the recommended surgery technique is not exactly the same in all of them. The firmness of the wall of dermoid cysts let their exeresis via intraoral even when they are of a big size. Exeresis of sublingual gland is recommended by most authors to treat ranulas, although it is followed by an important percentage of morbidity.

Long-term effects of a single exposure to immobilization on the hypothalamic-pituitary-adrenal axis: neurobiologic mechanisms.

In apparent contrast to previous results from other labs, we have found that a single exposure to a severe stressor such as immobilization (IMO) caused a long-term desensitization of the hypothalamic-pituitary-adrenal (HPA) response to the homotypic stressor. Because such HPA desensitization was not found in response to heterotypic stressors, it seemed at first that we were describing a habituation process already observed after a single experience with the stressor. However, a more detailed analysis revealed two main properties incompatible with the interpretation of the results in terms of habituation: (1) The intensity of desensitization increases over the course of days to weeks with no additional exposures to the stressor, and (2) the degree of desensitization was greater with more severe stressors. The long-term effects were also observed after a single exposure to a high dose of a systemic stressor such as endotoxin but not after insulin-induced hypoglycemia, suggesting that not all severe systemic stressors can induce such long-term desensitization. Because systemic stressors are known to be processed in specific brain areas and because we have found changes in c-fos mRNA response to the homotypic stressor in some brain areas as a consequence of previous experience with IMO, we hypothesize that some severe stressors do not induce long-term desensitization because they are not processed in brain areas sensitive to previous experience with the stressor. The neurochemical mechanisms involved in the induction of long-term effects on the HPA axis are in process, but our results suggest only a partial role of glucocorticoids and NMDA receptors.

A single lipopolysaccharide administration is sufficient to induce a long-term desensitization of the hypothalamic-pituitary-adrenal axis.

We have previously shown that a single exposure of adult rats to a severe emotional stressor such as immobilization is able to exert a long-term desensitization of the response of the hypothalamic-pituitary-adrenal (HPA) axis to the same stimulus when applied days to weeks later. Surprisingly, the intensity of the effect increased with time elapsed between the two exposures, suggesting that we are dealing with a new type of stress-associated phenomenon. Taking into account the clinical importance of tolerance to endotoxin, in the present study we assessed whether a single exposure to an immunological stressor such as lipopolysaccharide can induce effects similar to those of immobilization. Rats injected with lipopolysaccharide (1 mg/kg) showed a reduction of the response of the corticotropin-releasing factor mRNA in the paraventricular nucleus of the hypothalamus after a new lipopolysaccharide injection 4, but not 2 weeks later. In an additional experiment using a different blood sampling procedure, adrenocorticotropin hormone, corticosterone and tumor necrosis factor-alpha responses were reduced approximately to the same extent by previous experience with lipopolysaccharide either 1 or 4 weeks before. Our data suggest that a previous single exposure to lipopolysaccharide induces a long-lasting tolerance of the HPA axis that likely involves some kind of learning-like brain plasticity.