Early-life stress elicits peripheral and brain immune activation differently in wild type and 5xFAD mice in a sex-specific manner.

BACKGROUND: The risk of developing Alzheimer's disease (AD) is modulated by genetic and environmental factors. Early-life stress (ELS) exposure during critical periods of brain development can impact later brain function and health, including increasing the risk of developing AD. Microglial dysfunction and neuroinflammation have been implicated as playing a role in AD pathology and may be modulated by ELS. To complicate matters further, sex-specific effects have been noted in response to ELS and in the incidence and progression of AD. METHODS: Here, we subjected male and female mice with either a wild type or 5xFAD familial AD-model background to maternal separation (MS) from postnatal day 2 to 14 to induce ELS. RESULTS: We detected hippocampal neuroinflammatory alterations already at postnatal day 15. By 4 months of age, MS mice presented increased immobility time in the forced swim test and a lower discrimination index in the novel object recognition memory test compared to controls. We found altered Bdnf and Arc expression in the hippocampus and increased microglial activation in the prefrontal cortex due to MS in a sex-dependent manner. In 5xFAD mice specifically, MS exacerbated amyloid-beta deposition, particularly in females. In the periphery, the immune cell population was altered by MS exposure. CONCLUSION: Overall, our results demonstrate that MS has both short- and long-term effects on brain regions related to memory and on the inflammatory system, both in the brain and periphery. These ELS-related effects that are detectable even in adulthood may exacerbate pathology and increase the risk of developing AD via sex-specific mechanisms.

Outcomes by sex following treatment initiation with darunavir/cobicistat in a large Spanish cohort of the CODAR study (GeSIDA 9316).

BACKGROUND: Few women have been included in darunavir/cobicistat clinical development studies, and hardly any of them were antiretroviral experienced or treated with anything other than triple-based therapies. OBJECTIVES: Our aim was to increase our knowledge about women living with HIV undergoing darunavir/cobicistat-based regimens. METHODS: A multicentre (21 hospitals), retrospective study including a centrally selected random sample of HIV-1 patients starting a darunavir/cobicistat-based regimen from June 2014 to March 2017 was planned. Baseline characteristics, 24 and 48 week viral load response (<50 copies/mL), CD4+ lymphocyte count increase, time to change darunavir/cobicistat and adverse event occurrence were all compared by sex. The study was approved by each of the 21 ethics committees, and patients signed informed consent. RESULTS: Out of 761 participants, 193 were women. Similar characteristics were found for both sexes, except that the women had a longer duration of HIV infection (P = 0.001), and were less frequently pre-treated with darunavir/cobicistat in their previous regimen (P = 0.02). The main reason for using a darunavir/cobicistat-based regimen was simplification, without differences by sex, while monotherapy seems to be more frequently prescribed in women than in men (P = 0.067). The main outcomes, HIV viral load response, CD4+ lymphocyte count increase at 24 or 48 weeks, occurrence of adverse events, main reasons for changing and time to the modify darunavir/cobicistat regimen, did not show differences between the sexes. CONCLUSIONS: No sex disparities were found in the main study outcomes. These results support the use of a darunavir/cobicistat-based regimen in long-term pre-treated women. Clinical Trial.gov No. NCT03042390.

Impact of Vitiligo on Quality of Life. / Impacto del vitíligo en la calidad de vida.

INTRODUCTION AND OBJECTIVE: Vitiligo is a chronic autoimmune skin disease caused by the destruction of melanocytes. Although quality of life (QOL) in vitiligo has been studied in different countries, it has not yet been investigated in Mexico. The aim of this study was to assess the QOL of Mexican patients with vitiligo. MATERIAL AND METHOD: We conducted a cross-sectional study at the research unit of Centro Dermatológico Dr. Ladislao de la Pascua in Mexico City. We included adults with vitiligo and excluded those with other pigmentation disorders or a neurological or psychiatric disorder. Patients on psychoactive medications were also excluded. All the patients were administered the Dermatology Life Quality Index (DLQI), a vitiligo-specific quality of life instrument (the VitiQoL), and the Beck Depression and Anxiety Inventories. RESULTS: We studied 150 patients with vitiligo (103 women [68.7%] and 47 men [31.3%]). The median (interquartile range) age was 38 (20) years. The mean (SD) scores on the DLQI and VitiQoL were 5.2 (5.4) and 32.1 (22.7) out of total possible scores of 30 and 90, respectively. The correlation between questionnaire scores was 0.675 (P<.001). Patients with genital involvement scored significantly worse on the VitiQoL than those without lesions in this area (43.95 [28.4]) vs. 28.98 [20.08], P<.001). The prevalence of depression and anxiety was 34% and 60%, respectively. CONCLUSION: Vitiligo has a minimal impact on the QOL of our patients. QOL was worse in patients with genital lesions.

SPARC (secreted protein acidic and rich in cysteine) knockdown protects mice from acute liver injury by reducing vascular endothelial cell damage.

Secreted protein, acidic and rich in cysteine (SPARC) is involved in many biological process including liver fibrogenesis, but its role in acute liver damage is unknown. To examine the role of SPARC in acute liver injury, we used SPARC knock-out (SPARC(-/-)) mice. Two models of acute liver damage were used: concanavalin A (Con A) and the agonistic anti-CD95 antibody Jo2. SPARC expression levels were analyzed in liver samples from patients with acute-on-chronic alcoholic hepatitis (AH). SPARC expression is increased on acute-on-chronic AH patients. Knockdown of SPARC decreased hepatic damage in the two models of liver injury. SPARC(-/-) mice showed a marked reduction in Con A-induced necroinflammation. Infiltration by CD4+ T cells, expression of tumor necrosis factor-α and interleukin-6 and apoptosis were attenuated in SPARC(-/-) mice. Sinusoidal endothelial cell monolayer was preserved and was less activated in Con A-treated SPARC(-/-) mice. SPARC knockdown reduced Con A-induced autophagy of cultured human microvascular endothelial cells (HMEC-1). Hepatic transcriptome analysis revealed several gene networks that may have a role in the attenuated liver damaged found in Con A-treated SPARC(-/-) mice. SPARC has a significant role in the development of Con A-induced severe liver injury. These results suggest that SPARC could represent a therapeutic target in acute liver injury.

Understanding arsenic-ulexite interactions in evaporite environments: Evidence from XRPD, micro-XRF, micro-FT-IR, and XPS studies.

World-class borate deposits often form from As-rich waters, this study addresses the understudied association of arsenic (As) species with evaporite borates, focusing on the Puna region's borate deposits (Central Andes of Argentina). The research aims to characterize the association between borate minerals and high As concentrations in brines and thermal waters. To achieve this, five borate samples were collected from the Olaroz salt flat nucleus and thermal springs, alongside associated water samples. Comprehensive analytical techniques, including ICP-MS, ICP-OES, synchrotron-based micro-XRF, XRPD, Rietveld analysis, micro-FT-IR, and XPS, were employed to determine bulk and surface chemical compositions, mineral identification, and solid speciation of As and boron. The study reveals that under oxidizing conditions and in absence of organic matter, aqueous arsenic species interact with ulexite through a stepwise process involving charge neutralization, cationic bridge formation, and surface complex formation with polyborate and As(V) oxyanions. However, in environments associated with microbial mats or organic-rich sediments, the dissolved As(V) is reduced to As(III), which forms complexes with functional groups of organic matter. The coexistence of As(III) and As(V) in specific layers suggests potential remediation strategies targeting organic matter for the removal of the more toxic As(III) in similar geological settings.

Maternal separation differentially modulates early pathology by sex in 5xFAD Alzheimer's disease-transgenic mice.

Alzheimer's disease (AD) is the most common neurodegenerative disease. Most cases of AD are considered idiopathic and likely due to a combination of genetic, environmental, and lifestyle-related risk factors. Despite occurring decades before the typical age of an AD diagnosis, early-life stress (ELS) has been suggested to have long-lasting effects that may contribute to AD risk and pathogenesis. Still, the mechanisms that underlie the role of ELS on AD risk remain largely unknown. Here, we used 5xFAD transgenic mice to study relatively short-term alterations related to ELS in an AD-like susceptible mouse model at 6 weeks of age. To model ELS, we separated pups from their dams for 3 h per day from postnatal day 2-14. Around 6 weeks of age, we found that maternally separated (MS) 5xFAD mice, particularly female mice, displayed increased amyloid-ß-immunoreactivity in the anterior cingulate cortex (ACC) and basolateral amygdala (BLA). In anterior cingulate cortex, we also noted significantly increased intraneuronal amyloid-ß-immunoreactivity associated with MS but only in female mice. Moreover, IBA1-positive DAPI density was significantly increased in relation to MS in ACC and BLA, and microglia in BLA of MS mice had significantly different morphology compared to microglia in non-MS 5xFAD mice. Cytokine analysis showed that male MS mice, specifically, had increased levels of neuroinflammatory markers CXCL1 and IL-10 in hippocampal extracts compared to non-MS counterparts. Additionally, hippocampal extracts from both male and female MS 5xFAD mice had decreased levels of synapse- and activity-related markers Bdnf, 5htr6, Cox2, and Syp in hippocampus. Lastly, we performed behavioral tests to evaluate anxiety- and depressive-like behavior and working memory but could not detect any significant differences between groups. Overall, we detected several sex-specific molecular and cellular alterations in 6-week-old adolescent 5xFAD mice associated with MS that may help explain the connection between ELS and AD risk.

[Quality of healthcare in oncological patients from health personnel's perspective]. / Calidad de la atención en pacientes oncológicos desde la perspectiva del personal de salud.

INTRODUCTION: The quality of care in health institutions is a constant challenge, mainly in oncology. The literature shows it has partially evaluated in contrast to it proposed by Donabedian; in addition, health personnel's perspective, who has direct contact with the patient, knows and executes the care process, has not been considered. The objective of the present study was to establish a framework to evaluate the quality of healthcare provided to patients with colorectal or ovarian cancer from health personnel's perspective. MATERIAL AND METHODS: Cross-sectional study that included health personnel belonging to nine services of a cancer hospital. A questionnaire was applied to evaluate the quality of healthcare through amenities, the interpersonal and scientific-technical dimension (Donabedian's model). The variables were standardized, compliance with them among services was compared using non-parametric tests (Kruskal-Wallis test and Mann-Whitney U test), and 40 indicators were evaluated. RESULTS: Health personnel's 181 members participated, the evaluated oncology hospital presented regular compliance to the quality of healthcare (bad ≤82, regular 83-109, good ≥110). When comparing this in the nine services, differences were detected between surgery and radiotherapy (higher compliance scores, 132 and 126 respectively) versus the other services P<.05. Both services had more than 25 indicators with compliance ≥80%. CONCLUSIONS: It is shown that the established framework is useful for evaluating the quality of healthcare from health personnel's perspective (an approach not used so far for this type of evaluation), by detecting differences in its compliance, specific problems and its causes by service.

Natural and anthropogenic sources of solutes in the wet precipitation of a densely populated city of Southern South America.

The chemistry of rainwater is controlled by the interaction among water, airborne particles and gas sources, whether natural or human-made. This article analyzes the chemical composition dynamics of individual rainfall events collected over a three-year period in the densely populated city of Córdoba (Argentina). The main purpose is to identify the natural and/or anthropogenic sources, and the extent to which they determine the seasonal chemical signature exhibited by wet precipitation in the heart of the South Eastern South America. The results reveal that, despite geogenic components are only minor constituents of the airborne particles in downtown Córdoba, they appear to be the main source of solutes in rainwaters, also responsible for the alkaline water pH that predominates most of the year. This fraction mostly corresponds to wind-blown soil particles transported either from local or distant sources, with rare earth elements (REE) patterns similar to those of rainwaters produced during the dry season. Anthropogenic contributions are only evident during the wet season, when rainwater shows REE patterns similar to those of industrial emissions and exhibits moderate enrichment of heavy metals such as Cu and Zn, derived from soluble compounds used in agricultural activities (e.g, sowing, fertilizing). With the exception of these two metals, the remaining heavy metals are depleted in rainwater suggesting that the airborne conveying compounds (mostly anthropogenic) are barely soluble.

The role of efflorescent salts associated with sulfide-rich mine wastes in the short-term cycling of arsenic: Insights from XRD, XAS, and µ-XRF studies.

The evaporation of As-rich leachates generated by the weathering of sulfide-rich mine wastes accumulated in abandoned tailing dams of the La Concordia mine, triggers the widespread precipitation of saline crusts and efflorescences. Because these salts are highly soluble, they may release high concentrations of arsenic after rainfall events. Thus, the goal of this work is to assess the solid speciation of As in these efflorescences, which may help to understand the short-term cycling of As in the site. The results reveal that As is present only as As(V), while its capacity to be retained in the salts highly depends on their mineralogical composition. Hydrous sulfates, such as gypsum and epsomite show a very low capacity to scavenge As, while copiapite retains the highest concentrations of this element. The spectroscopic evidences suggest that in this mineral, As(V) is included within the lattice, substituting sulfate in the tetrahedral sites. Because copiapite is highly soluble, it may be considered as one of the most important transient reservoirs of As in the site that can release high concentrations of this hazardous pollutant during the occasional rainfall events produced during the wet season.

Drug-facilitated sexual assault and other crimes: A systematic review by countries.

Drug-facilitated sexual assault (DFSA) and drug-facilitated crime (DFC) constitute a mode of violence that is generally unknown to the population and may go unnoticed by health professionals. The aim of this systematic review was to analyze the victims of DFC, compiling their sociodemographic characteristics, the toxic substances used and their biological matrices and modes of action, in order to identify the substances that are commonly put to criminal use. The aim would be to establish political and health strategies that inform and warn people about possible criminal social behaviors consequent danger to health. This systematic review was conducted following the PRISMA guidelines. Alcohol, benzodiazepines and cocaine were among the most commonly detected substances. In most of the hospitals, immunoassays, liquid chromatography (LC-MS), or gas chromatography-mass spectrometry (GC-MS) analyses were used to identify the substances, while the most frequently used biological matrices were blood and urine. From a judicial point of view, the instrumental protocols and techniques followed for the detection of toxics in different biological matrices must guarantee the reliability and validity of the results for use in a court of law. The recommendations of international organizations should be followed and must be called upon to strengthen their respective national laws against this chemical submission (CS) phenomenon.

SARS-CoV-2 induces mitochondrial dysfunction and cell death by oxidative stress/inflammation in leukocytes of COVID-19 patients.

The inflammation and activation of the immune system induced by SARS-CoV-2 are mediated by a pro-oxidant microenvironment that can induce cytotoxic effects that enhance tissue damage, favoring organic deterioration. We investigated whether the induction of oxidative stress and inflammation by COVID-19 infection could inhibit mitochondrial function and cause cellular damage in leukocytes. We evaluated levels of oxidative/inflammation markers and their correlation with mitochondrial function and leukocyte cell death in COVID-19 patients at two moments: viremia and severe sepsis with multi-organ failure. COVID-19 induces increased oxidative stress and inflammation markers that activate cellular damage processes. In the viremia stage, an increase in peroxide, nitric oxide, carbonylated proteins, and IL-6 was observed, which was correlated with a marked inhibition of mitochondrial function, decreased cell viability, early apoptosis, necrosis, and leukocytes-reactivity. The severe sepsis stage with multi-organ failure also showed a further increase in levels of peroxide, carbonylated proteins, and IL-6, with a slight decrease in nitric oxide. This oxidative process and inflammation were correlated with less inhibition of mitochondrial function, decreased cell viability and an increase in late apoptosis, and morphology changes evidencing damage in the leukocytes. SARS-CoV-2 induced damage promotes levels of oxidative stress and inflammation markers and mitochondrial dysfunction that potentiate morphological changes and cell death in leukocytes. These processes explain the rapid changes in the immune system, and that present an initial over-activation and early massive death due to SARS-CoV-2 infection, promoting endothelial-alveolar damage that would cause multi-organ failure, sustained by oxidative stress and inflammation.

Mesenchymal stem cells as therapeutic tools and gene carriers in liver fibrosis and hepatocellular carcinoma.

Mesenchymal stem (stromal) cells (MSCs) are a source of circulating progenitors that are able to generate cells of all mesenchymal lineages and to cover cellular demands of injured tissues. The extent of their transdifferentiation plasticity remains controversial. Cells with MSC properties have been obtained from diverse tissues after purification and expansion in vitro. These cellular populations are heterogeneous and under certain conditions show pluripotent-like properties. MSCs present immunosuppressive and anti-inflammatory features and high migratory capacity toward inflamed or remodeling tissues. In this study we review available data regarding factors and signaling axes involved in the chemoattraction and engraftment of MSCs to an injured tissue or to a tissue undergoing active remodeling. Moreover, experimental evidence in support of uses of MSCs as vehicles of therapeutic genes is discussed. Because of its regenerative capacity and its particular immune properties, the liver is a good model to analyze the potential of MSC-based therapies. Finally, the potential application of MSCs and genetically modified MSCs in liver fibrosis and hepatocellular carcinoma (HCC) is proposed in view of available evidence.

Murine abortion is associated with enhanced hyaluronan expression and abnormal localization at the fetomaternal interface.

The remodelling of the endometrial architecture is fundamental to create a suitable environment for the establishment of pregnancy. During this process, substantial alterations in the composition of maternal extracellular matrix play an important role by providing a prosperous medium for implantation as well as modulating trophoblast invasion leading to the formation of a functional placental unit. Hyaluronan is a conspicuous component of the extracellular matrix, particularly in remodelling tissues undergoing regeneration and repair. During gestation, changes in HA deposition and distribution indicate that this molecule may participate in preparation of the endometrial stroma for reception and implantation of the embryo. However, little is known about the role of hyaluronan at the fetomaternal interface, specially regarding its influence in pregnancy outcome. In the present study we show increased decidual hyaluronan levels in spontaneous abortion compared with normal pregnancy mice on gestation day 7.5. Both in normal and pathologic pregnancies, high molecular size hyaluronan was found at the fetomaternal unit. However, hyaluronan metabolism (which results from the activity of hyaluronan synthases and hyaluronidases) seems to be altered in spontaneous abortion as shown by a decrease in Hyal-3 expression as well as by differences in hyaluronan molecular size spectrum. This alteration in hyaluronan metabolism in spontaneous abortion could explain its increased concentration observed in decidua and the abnormal distribution of hyaluronan around the embryo implantation crypt. Thus, increased decidual hyaluronan levels resulting from abnormal deposition and turn over may contribute to the pathogenesis of pregnancy failure.

Abnormal adenosine and dopamine receptor expression in lymphocytes of Lesch-Nyhan patients.

Self-injurious behavior is the most outstanding feature of Lesch-Nyhan syndrome and has recently been ascribed to an obsessive-compulsive behavior. Lesch-Nyhan syndrome results from the complete enzyme deficiency of hypoxanthine-guanine phosphoribosyl transferase (HPRT) but the link between abnormal purine metabolism and its neurological and behavioral manifestations remains largely unknown. Previous studies led us to hypothesize that adenosine and dopamine receptor expression could be altered in HPRT-deficient cells. To test this hypothesis, we examined mRNA expressions of adenosine (ADORA2A and ADORA2B) and dopamine receptors (DRD1 and DRD2 like), and dopamine transporter (DAT1) in peripheral blood lymphocytes (PBLs) from Lesch-Nyhan patients. We also examined the influence of hypoxanthine in these expressions. As compared to normal PBLs, both ADORA2A and DRD5 expression were abnormal in PBLs from Lesch-Nyhan patients. In contrast, DAT1 expression was similar to control values in HPRT deficient PBLs. These results indicate an abnormal adenosine and dopamine receptor expression in HPRT-deficient cells and suggest disrupted adenosine and dopamine neurotransmission may have a significant role in the pathogenesis of the neurological manifestations of Lesch-Nyhan syndrome.

Synchrotron XAS study on the As transformations during the weathering of sulfide-rich mine wastes.

This paper describes the weathering processes that occurred across two tailing dumps in the Concordia mine (Puna of Argentina) with the purpose of evaluating the formation of secondary As-bearing minerals due to arsenopyrite alteration. After 30 years of exposure, the gradual oxidation of the wastes produced a number of secondary mineral phases containing As in different chemical arrangements. Synchrotron-based X-ray absorption spectroscopy was used to determine both, As and Fe solid speciation and to identify the formed As-bearing minerals. The results reveal that in the first stages of oxidation, As released from arsenopyrite is adsorbed/substituted in the jarosite structure partially inhibiting its dissolution. When pH values in the system slightly increase As-jarosite transforms into schwertmannite, where the released As could be re-adsorbed or co-precipitated. When the available adsorption sites become oversaturated with As, the precipitation of amorphous ferric arsenates may occur. The latter, likely constitute the more labile As fractions in the sediments and are therefore the main phases contributing As to the nearby environments. These amorphous and labile phases are more abundant in the uppermost layers of the profiles, where oxidation has taken place for a more prolonged time-lapse. The described transformations are enhanced by the acidic pH, the absence of minerals attenuating the acidity and the high sulfate and As concentrations in pore water.

X-chromosome data for 12 STRs: Towards an Argentinian database of forensic haplotype frequencies.

The analysis of X-chromosome STRs is useful in certain kinship cases for which autosomal markers provide insufficient statistical power. Particularly, powerful results are achieved in paternity cases with a daughter, when the alleged father is not accessible for analysis, contrarily to his unquestioned mother or daughter. However, representative haplotype frequencies for this type of markers are not available for some populations, as is the case of Argentina, which prevents the quantification of the proof in routine forensic analyses. In this work we present haplotype frequencies for the 12 X-chromosome STRs included in the Investigator Argus X-12 kit, as well as segregation data, obtained from the analysis of the genetic profiles of 457 father-daughter duos, which gave us information on 914 (unrelated) haplotypes from residents of all Argentinian provinces.

Correction: Porous monoliths synthesized via polymerization of styrene and divinyl benzene in nonaqueous deep-eutectic solvent-based HIPEs.

[This corrects the article DOI: 10.1039/C5RA02374B.].

Hydrogeochemical and isotopic signature of surface and groundwater in a highly industrialized sector of the Rio de la Plata coastal plain (Argentina).

The coastal plain of the middle estuary of the Río de la Plata is a highly industrialized area and is densely populated by sectors. The main human activity in the sector encompassed between the cities of Ensenada and Berisso is associated with the petrochemical industry. In this work, hydrogeochemical and isotopic characteristics of surface and groundwater in the impacted area are analyzed and the results are contrasted with those obtained in an undisturbed protected area. Major and trace elements were determined using standardized methods while the stable isotopes δ18O y δ2H were analyzed by mass spectroscopy. Human impact is evidenced by the occurrence of large variations in the major chemical composition of water, and also by the elevated concentrations of some trace elements that are not contributed from natural sources. These results may contribute to the understanding of chemical processes and pollutants distribution in highly industrialized coastal plain areas.

Extended vs. brief intermittent access to palatable food differently promote binge-like intake, rejection of less preferred food, and weight cycling in female rats.

BACKGROUND: Palatable food access promotes obesity leading some to diet. Here, we modeled the roles of duration, intermittency and choice of access in bingeing, escalation of daily intake, and underacceptance of alternatives. METHOD: Female rats with ("Choice") or without continuous chow access, received chow or continuous (Chocolate), intermittent (MWF) long (24h, Int-Long), or intermittent short (30min, Int-Short) access to a sucrose-rich, chocolate-flavored diet (CHOC). RESULTS: Int-Long rats showed cycling body weight; they overate CHOC, had increased feed efficiency on access days and underate chow and lost weight on non-access days, the latter correlating with their reduced brown fat. Int-Short rats had the greatest 30-min intake upon CHOC access, but did not underaccept chow or weight cycle. Individual vulnerability for intermittent access-induced feeding adaptations was seen. Continuous access rats gained fat disproportionate, but in direct relation, to their normalized energy intake and persistently underaccepted chow despite abstinence and return to normal weight. Abstinence reduced the binge-like CHOC intake of Int-Short rats and increased that of continuous access rats, but not to levels associated with intermittent access history. Choice increased daily CHOC intake under Continuous access and binge-like intake under Int-Short access. CONCLUSIONS: Intermittency and duration of past access to palatable food have dissociable, individually-vulnerable influences on its intake and that of alternatives. With extended access, daily intake reflects the palatability of available food, rather than metabolic need. Ongoing restrictedness of access or a history of intermittency each drive binge-like intake. Aspects of palatable food availability, similar and different to drug availability, promote disordered eating.