Search

Brain mechanisms of sexual attraction toward reproductive partners develop from a systematic interrelationship between biology (nature) and learning (nurture). However, the causes of attraction toward non-reproductive partners are poorly understood. Here, we explored the role of Pavlovian learning under dopaminergic agonism on the development of sexual preference and brain activation for young male rats. During conditioning, adult sexually naïve males received either Saline (Saline-Paired) or the D2-receptor agonist quinpirole (QNP-Paired) and cohabited in contingency, or out of contingency (QNP-Unpaired) during 24 h with an almond-scented prepubertal juvenile male (PD25). Conditioning occurred every 4 days for three trials. Social and sexual responses were assessed four days after the last conditioning trial in a drug-free test, and males chose freely between a scented young male (PD37) and a novel receptive female. Four days later, males were exposed to the conditioned odor only and brain Fos-IR and serum testosterone were analyzed. Saline-Paired and QNP-Unpaired males displayed more non-contact erections (NCEs) and genital investigations for females, whereas QNP-Paired males expressed more NCEs and genital investigations for young males. In the QNP-Paired group, exposure to the young male-paired odor evoked more Fos-IR in limbic, hypothalamic and cortical areas, but no differences in serum testosterone were observed. Cohabitation with juvenile males during enhanced D2 agonism results in atypical appetitive sexual responses and a higher pattern of brain response for the young male-paired odor, with no changes in serum testosterone. We discuss the potential implications for the development of pedophilic disorder and perhaps other paraphilias.

Introduction Spinal cord stimulation (SCS) is a commonly utilized therapy for the treatment of neuropathic pain conditions. The Neurostimulation Appropriateness Consensus Committee (NACC) has recommended that the placement of percutaneous SCS leads be performed in an awake patient capable of providing feedback. It is not currently known how commonly this recommendation is adhered to by physicians in clinical practice. This article presents the findings of a survey designed to answer this important question. Methods We conducted a survey of the active membership of the American Society of Regional Anesthesia and Pain Medicine (ASRA) and the Spine Intervention Society (SIS) regarding practice patterns with SCS therapy. We analyzed the percent of respondents who indicated that they use deep sedation and general anesthesia during SCS placement as well as any reported complications. Results Many practitioners frequently utilize deep sedation as well as general anesthesia when performing SCS implants. Our findings demonstrate that 77% of physicians reported that they utilize deep sedation for permanent SCS implants at times, and 45% of physicians reported the use of general anesthesia for 10 kHz implants. Additionally, 94% of physicians reported that they have never had a complication related to the use of general anesthesia for a spinal cord stimulator placement. Conclusions This survey provides initial data on SCS practices among a large cohort of clinicians who utilize SCS. SCS lead placement under deep sedation and general anesthesia appears to be common practice for many physicians who perform implants. This survey should stimulate further research on this topic, given that the current safety guidelines and the rate of physicians reporting the use of deep sedation and general anesthesia for spinal cord stimulator placement remain at odds.

Background. The influence of HLA class I and II loci on the susceptibility to melanoma remains an area of intense debate. This study aimed to examine whether the HLA system was related to melanoma susceptibility and prognosis in a southern Spanish population. Methods. In this study, HLA class I and class II genotyping were performed using polymerase chain reaction sequence-specific oligonucleotides (PCR-SSO) in 237 Spanish melanoma patients and 636 ethnically matched controls. Data were analyzed according to the clinical characteristics of the defined subgroups. Results. Compared to the control group, DRB1 ∗ 16:01 (4% vs. 1.3%, p = 0.001 , Pc = 0.035, OR = 3.28) and DQB1 ∗ 05:02 (4.9% vs. 2%, p = 0.001 , Pc = 0.017, OR = 2.54) were positivity associated with the susceptibility to melanoma. Both DRB1 ∗ 16:01 (5.4% vs. 1.3%, p = 0.001 , Pc = 0.035, OR = 4.46) and DQB1 ∗ 05:02 (6.5% vs. 2%, p = 0.001 , Pc = 0.017, OR = 3.44) also showed a positive correlation with Breslow thickness >1.5 mm, most notably at an early age of diagnosis (≤58 years), DRB1 ∗ 16:01 (4.2% vs. 1.3%, p = 0.001 , Pc = 0.035, OR = 3.41) and DQB1 ∗ 05:02 (5.4% vs. 2%, p = 0.002 , Pc = 0.034, OR = 2.86). Conclusion. These findings established HLA-DRB1 ∗ 16:01 and HLA-DQB1 ∗ 05:02 loci as melanoma risk factors in the southern Spanish population.

Cerebral oedema develops after anoxic brain injury. In two models of asphyxial and asystolic cardiac arrest without resuscitation, we found that oedema develops shortly after anoxia secondary to terminal depolarizations and the abnormal entry of CSF. Oedema severity correlated with the availability of CSF with the age-dependent increase in CSF volume worsening the severity of oedema. Oedema was identified primarily in brain regions bordering CSF compartments in mice and humans. The degree of ex vivo tissue swelling was predicted by an osmotic model suggesting that anoxic brain tissue possesses a high intrinsic osmotic potential. This osmotic process was temperature-dependent, proposing an additional mechanism for the beneficial effect of therapeutic hypothermia. These observations show that CSF is a primary source of oedema fluid in anoxic brain. This novel insight offers a mechanistic basis for the future development of alternative strategies to prevent cerebral oedema formation after cardiac arrest.

We report that the neurotrophin receptor p75 contributes to sensory neuron survival through the regulation of cholesterol metabolism in Schwann cells. Selective deletion of p75 in mouse Schwann cells of either sex resulted in a 30% loss of dorsal root ganglia (DRG) neurons and diminished thermal sensitivity. P75 regulates Schwann cell cholesterol biosynthesis in response to BDNF, forming a co-receptor complex with ErbB2 and activating ErbB2-mediated stimulation of sterol regulatory element binding protein 2 (SREBP2), a master regulator of cholesterol synthesis. Schwann cells lacking p75 exhibited decreased activation of SREBP2 and a reduction in 7-dehydrocholesterol (7-DHC) reductase (DHCR7) expression, resulting in accumulation of the neurotoxic intermediate, 7-dehyrocholesterol in the sciatic nerve. Restoration of DHCR7 in p75 null Schwann cells in mice significantly attenuated DRG neuron loss. Together, these results reveal a mechanism by which the disruption of lipid metabolism in glial cells negatively influences sensory neuron survival, which has implications for a wide range of peripheral neuropathies.SIGNIFICANCE STATEMENTAlthough expressed in Schwann cells, the role of p75 in myelination has remained unresolved in part because of its dual expression in sensory neurons that Schwann cells myelinate. When p75 was deleted selectively among Schwann cells, myelination was minimally affected, while sensory neuron survival was reduced by 30%. The phenotype is mainly due to dysregulation of cholesterol biosynthesis in p75-deficient Schwann cells, leading to an accumulation of neurotoxic cholesterol precursor, 7-dehydrocholesterol (7-DHC). Mechanism-wise, we discovered that in response to BDNF, p75 recruits and activates ErbB2 independently of ErbB3, thereby stimulating the master regulator, sterol regulatory element binding protein 2 (SREBP2). These results together highlight a novel role of p75 in Schwann cells in regulating DRG neuron survival by orchestrating proper cholesterol metabolism.

Acute Lymphoblastic Leukemia (ALL) is the most frequent cancer in pediatric population. Although the treatment has improved and almost 85% of the children are cured about 20% suffer relapse, therefore finding molecules that participate in the pathogenesis of the disease for the identification of relapse and patients at risk is an urgent unmet need. Class I myosins are molecular motors involved in membrane tension, endocytosis, phagocytosis and cell migration and recently they have been shown important for development and aggressiveness of diverse cancer types, however Myo1g an hematopoietic specific myosin has not been studied in cancer so far. We evaluated the expression of Myo1g by qRT-PCR, Immunocytochemistry and Immunofluorescence in a cohort of 133 ALL patients and correlated the expression at diagnosis and after treatment with clinical features and treatment outcomes. We found high expression levels of Myo1g in Peripheral Blood Mononuclear Cells (PBMCs) from patients with ALL at diagnosis and those levels decreased after complete remission; furthermore, we found an increase in Myo1g expression on patients with 9:22 translocation and those who relapse. This study show that Myo1g is over expressed in ALL and that may participate in the pathogenesis of the disease specially in high-risk patients.

Aim: We aimed to verify the frequency of CD8+ T cell subsets in patients with acute form and chronic form of paracoccidioidomycosis. Material & Methods: Mononuclear cells from paracoccidioidomycosis patients and healthy donors were isolated and phenotyped by flow cytometry. Dendritic cells were pulsed with Paracoccidioides brasiliensis yeast and co-cultures with lymphocytes. Cytokine production was measured by ELISA. Results: Acute form patients present a higher frequency of Tc1 and Tc10 cells, while chronic form patients have more Tc1 and Tc21 cells, compared with healthy controls. In vitro assays showed that P. brasiliensis induced polarization to the Tc17/Tc22 subsets. Conclusion: Our results suggest that CD8+ T cells can respond in a similar way to P. brasiliensis infection, regardless of the clinical presentation of the disease.

This systematic review and meta-analysis aimed to determine the effectiveness of brentuximab vedotin (BV) in relapsed/refractory classical Hodgkin lymphoma (R/R cHL) in the clinical practice setting using most recent results. A total of 32 observational studies reporting on treatment patterns, overall response rate (ORR), complete response (CR) rate, progression-free survival (PFS), overall survival (OS), and adverse events were found. After four cycles, a random-effect model yielded pooled ORR and CR rates of 62.6% (95% confidence interval (CI): 56.0-68.9; I-2 = 9.7%) and 32.9% (95% CI, 20.8-46.3, I-2 = 64.8%), respectively. Regarding survival, 1-year, 2-year, and 5-year PFS ranged from 52.1% to 63.2%, 45.2% to 56.2%, and 31.9% to 33.0%, respectively. OS rates were 68.2-82.7%, 58.0-81.9%, and 58.0-62.0%, respectively. Most common adverse events were hematological toxicities (neutropenia: 13.3-23%, anemia: 8.8-39.0%, and thrombocytopenia: 4-4.6%), and grade >= 3 peripheral neuropathy (3.3-7.3%). This study supports the effectiveness and safety of BV in R/R cHL patients in the real-world setting.

Background Extensive malaria control measures have been implemented on Bioko Island, Equatorial Guinea over the past 16 years, reducing parasite prevalence and malaria-related morbidity and mortality, but without achieving elimination. Malaria vaccines offer hope for reducing the burden to zero. Three phase 1/2 studies have been conducted successfully on Bioko Island to evaluate the safety and efficacy of whole Plasmodium falciparum (Pf) sporozoite (SPZ) malaria vaccines. A large, pivotal trial of the safety and efficacy of the radiation-attenuated Sanaria® PfSPZ Vaccine against P. falciparum is planned for 2022. This study assessed the incidence of malaria at the phase 3 study site and characterized the influence of socio-demographic factors on the burden of malaria to guide trial design. Methods A cohort of 240 randomly selected individuals aged 6 months to 45 years from selected areas of North Bioko Province, Bioko Island, was followed for 24 weeks after clearance of parasitaemia. Assessment of clinical presentation consistent with malaria and thick blood smears were performed every 2 weeks. Incidence of first and multiple malaria infections per person-time of follow-up was estimated, compared between age groups, and examined for associated socio-demographic risk factors. Results There were 58 malaria infection episodes observed during the follow up period, including 47 first and 11 repeat infections. The incidence of malaria was 0.25 [95% CI (0.19, 0.32)] and of first malaria was 0.23 [95% CI (0.17, 0.30)] per person per 24 weeks (0.22 in 6–59-month-olds, 0.26 in 5–17-year-olds, 0.20 in 18–45-year-olds). Incidence of first malaria with symptoms was 0.13 [95% CI (0.09, 0.19)] per person per 24 weeks (0.16 in 6–59-month-olds, 0.10 in 5–17-year-olds, 0.11 in 18–45-year-olds). Multivariate assessment showed that study area, gender, malaria positivity at screening, and household socioeconomic status independently predicted the observed incidence of malaria. Conclusion Despite intensive malaria control efforts on Bioko Island, local transmission remains and is spread evenly throughout age groups. These incidence rates indicate moderate malaria transmission which may be sufficient to support future larger trials of PfSPZ Vaccine. The long-term goal is to conduct mass vaccination programmes to halt transmission and eliminate P. falciparum malaria.

Recurrent pericarditis affects 15-30% of patients after acute pericarditis. A large number of the patients with recurrent pericarditis can become corticosteroid dependent, leading to disease chronicity and drug dependence, with additional morbidity from long-term steroid use. Recent randomized trials indicate the efficacy of the interleukin-1 inhibitors anakinra and rilonacept in recurrent pericarditis, including colchicine-resistant and corticosteroid-dependent cases. In particular, rilonacept was assessed in the RHAPSODY clinical trial and found to be a potential treatment option that would decrease recurrent episodes, enabling patients to be weaned off steroids. Additionally, new data indicate that rilonacept should be considered as an option for patients with recurrent pericarditis, as add-on therapy to colchicine and nonsteroidal anti-inflammatory drugs, in place of steroids. We review the current management options for recurrent pericarditis as well as rilonacept as a prospective new addition to our armamentarium.

Introduction: Multiple sclerosis (MS) is a chronic, demyelinating, autoimmune disease of the central nervous system causing neuroinflammation. Experimental autoimmune encephalitis (EAE) is a model of the disease. MS is classically treated with interferon beta (IFN-β) and glatiramer acetate (GA). Melatonin (MLT) has been reported to modulate immune system responses. The aim of the present study is to analyse the effects of MLT administration in comparison with the first-line treatments for MS (IFN-β and GA). Methods: EAE was induced in male Sprague-Dawley rats; the animals subsequently received either IFN-β, GA, or MLT. Cerebrospinal fluid (CSF) samples were analysed by multiplex assay to determine the levels of proinflammatory cytokines. The neurological evaluation of EAE was also recorded. Results: All immunised animals developed EAE. We evaluated the first relapse-remission cycle, observing that IFN-β and GA had better results than MLT in the clinical evaluation. Neither EAE nor any of the treatments administered modified CSF IL-1β and IL-12p70 concentrations. However, IFN-β and MLT did decrease CSF TNF-α concentrations. Conclusion: Further studies are needed to evaluate the molecular mechanisms involved in the behaviour of MLT in EAE, and to quantify other cytokines in different biological media in order for MLT to be considered an anti-inflammatory agent capable of regulating MS. Resumen: Introducción: La esclerosis múltiple (EM) es una enfermedad crónica desmielinizante autoinmune del sistema nervioso central (SNC) que produce neuroinflamación, un modelo es la encefalitis autoinmune experimental (EAE). La EM ha sido tratada con interferón beta (IFN-beta) y acetato de glatiramero (AG). Se ha descrito que la melatonina (MLT) modula la respuesta del sistema inmune. El objetivo de este estudio fue observar el efecto de la administración de melatonina contra los tratamientos de primera línea utilizados en la EM (IFN-β y AG). Métodos: A ratas macho Sprague Dawley se les indujo EAE y se administraron IFN-β, AG o MLT. Se colectó líquido cefalorraquídeo y se midieron citocinas proinflamatorias por multiplex, además del registro de la evaluación neurológica de la EAE. Resultados: Todos los animales inmunizados establecieron la EAE. Se evaluó el primer ciclo de recaída-remisión, observando que IFN-β y AG tienen mejores resultados que MLT en la evaluación clínica. La concentración en el LCR tanto de IL-1β e IL-12p70 no se vio modificada por el modelo o por los tratamientos administrados. EL TNF-α se vio disminuido en el LCR por el IFN-β y MLT bajo el modelo de MS. Conclusiones: Es necesario realizar estudios posteriores para evaluar los mecanismos moleculares involucrados en el comportamiento de la MLT en la EAE, así como la cuantificación de otras citocinas en diferentes matrices biológicas para poder considerar a la MLT como un agente antiinflamatorio regulador de la EM.

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, constituting 80% of all acute leukemias in minors. Despite the increase in the success of therapies, disease-free survival is over 80% in most cases. For the remaining 20% of patients, new strategies are needed to allow us to know and select those at greatest risk of relapse. We evaluated by immunohistochemistry the expression of the transcription factor YY1 and found that it is overexpressed in peripheral blood leukemia cells of pediatric patients with ALL with Pro-B and T phenotype compared to control samples. Over expression of YY1 was associated with a significantly lower chance of survival. We also evaluated by RT-PCR in bone marrow samples from ALL pediatric patients the association of YY1 expression with the percentage of blasts. High levels of YY1 were present in samples with higher percent of blasts in these patients. In addition, ALL pediatric patients with a poor response to therapy had higher levels at the nuclear level of YY1 than those who responded well to chemotherapy. In conclusion, our data suggest that YY1 could serve in pediatric ALL as markers of evolution and response for this disease, mainly in patients with pro-B and T immunophenotype. It is also suggested that YY1 is implicated in the expanse of blast in these patients.

This study compares outcomes of patients admitted for atrial fibrillation (AF) with and without coexisting systemic lupus erythematosus (SLE). The primary outcome was inpatient mortality. Hospital length of stay (LOS), total hospital charges, odds of undergoing ablation, pharmacologic cardioversion and electrical cardioversion were secondary outcomes of interest. Data were abstracted from the National Inpatient Sample (NIS) 2016 and 2017 database. The NIS was searched for adult hospitalizations with AF as principal diagnosis with and without SLE as secondary diagnosis using International Classification of Diseases, Tenth Revision, Clinical Modification codes. Multivariate logistic and linear regression analysis was used accordingly to adjust for confounders. There were over 71 million discharges included in the combined 2016 and 2017 NIS database. 821,630 hospitalizations were for adult patients, who had a principal diagnosis of AF, out of which, 2645 (0.3%) had SLE as secondary diagnosis. Hospitalizations for AF with SLE had similar inpatient mortality (1.5% vs 0.91%, adjusted OR (AOR): 1.0, 95% CI 0.47 to 2.14, p=0.991), LOS (4.2 vs 3.4 days, p=0.525), total hospital charges ($51,351 vs $39,121, p=0.056), odds of undergoing pharmacologic cardioversion (0.38% vs 0.38%, AOR: 0.90, 95% CI 0.22 to 3.69, p=0.880) and electrical cardioversion (12.9% vs 17.5%, AOR 0.87, 95% CI 0.66 to 1.15, p=0.324) compared with those without SLE. However, SLE group had increased odds of undergoing ablation (6.8% vs 4.2%, AOR: 1.9, 95% CI 1.3 to 2.7, p

Trazodone (TRZ) is a commonly prescribed antidepressant with significant off-label use for insomnia. A recent drug screening revealed that TRZ interferes with sterol biosynthesis, causing elevated levels of sterol precursor 7-dehydrocholesterol (7-DHC). Recognizing the well-documented, disruptive effect of 7-DHC on brain development, we designed a study to analyze TRZ effects during pregnancy. Utilizing an in vivo model and human biomaterial, our studies were designed to also account for drug interactions with maternal or offspring Dhcr7 genotype. In a maternal exposure model, we found that TRZ treatment increased 7-DHC and decreased desmosterol levels in brain tissue in newborn pups. We also observed interactions between Dhcr7 mutations and maternal TRZ exposure, giving rise to the most elevated toxic oxysterols in brains of Dhcr7+/− pups with maternal TRZ exposure, independently of the maternal Dhcr7 genotype. Therefore, TRZ use during pregnancy might be a risk factor for in utero development of a neurodevelopmental disorder, especially when the unborn child is of DHCR7+/− genotype. The effects of TRZ on 7-DHC was corroborated in human serum samples. We analyzed sterols and TRZ levels in individuals with TRZ prescriptions and found that circulating TRZ levels correlated highly with 7-DHC. The abundance of off-label use and high prescription rates of TRZ might represent a risk for the development of DHCR7 heterozygous fetuses. Thus, TRZ use during pregnancy is potentially a serious public health concern.

This paper examines the hydration/dehydration behaviour of geosynthetic clay liner (GCL) under polar conditions for four simulated conditions experienced at Australia's Casey Station in Antarctica: (a) hydration during summer, (b) dehydration during a winter-summer cycle, (c) hydration through a fine Antarctic soil, and (d) hydration through a coarse Antarctic soil. Hydration during the summer is found to occur if there is direct contact with the water table. In contrast, the low relative humidity of the environment tends to dehydrate the GCL along a path that depends on the field conditions the GCL is exposed to. Hydration from either fine or coarse Antarctica soil is function of the original gravimetric water content of the subgrade soil and its grain size distribution as well as the low relative humidity prevailing in Antarctica.

Plasmodium falciparum sporozoite (PfSPZ) Vaccine (radiation-attenuated, aseptic, purified, cryopreserved PfSPZ) and PfSPZ-CVac (infectious, aseptic, purified, cryopreserved PfSPZ administered to subjects taking weekly chloroquine chemoprophylaxis) have shown vaccine efficacies (VEs) of 100% against homologous controlled human malaria infection (CHMI) in nonimmune adults. Plasmodium falciparum sporozoite-CVac has never been assessed against CHMI in African vaccinees. We assessed the safety, immunogenicity, and VE against homologous CHMI of three doses of 2.7 × 106 PfSPZ of PfSPZ Vaccine at 8-week intervals and three doses of 1.0 × 105 PfSPZ of PfSPZ-CVac at 4-week intervals with each arm randomized, double-blind, placebo-controlled, and conducted in parallel. There were no differences in solicited adverse events between vaccinees and normal saline controls, or between PfSPZ Vaccine and PfSPZ-CVac recipients during the 6 days after administration of investigational product. However, from days 7–13, PfSPZ-CVac recipients had significantly more AEs, probably because of Pf parasitemia. Antibody responses were 2.9 times higher in PfSPZ Vaccine recipients than PfSPZ-CVac recipients at time of CHMI. Vaccine efficacy at a median of 14 weeks after last PfSPZ-CVac dose was 55% (8 of 13, P = 0.051) and at a median of 15 weeks after last PfSPZ Vaccine dose was 27% (5 of 15, P = 0.32). The higher VE in PfSPZ-CVac recipients of 55% with a 27-fold lower dose was likely a result of later stage parasite maturation in the liver, leading to induction of cellular immunity against a greater quantity and broader array of antigens.

Background Alcohol septal ablation (ASA) in patients with hypertrophic cardiomyopathy (HCM) can lead to heart rhythm disturbances including complete heart block (CHB) and atrial and ventricular arrhythmias. Objective We aimed to evaluate the utility of long-term arrhythmia monitoring with an implantable cardiac monitor (ICM) after ASA. Methods Between February 2014 and March 2019, 56 patients with HCM undergoing ASA were enrolled in a prospective study and underwent ICM implantation. Kaplan-Meier survival analysis was used to assess the rate of ICM-detected arrhythmic events. Results The mean age was 59 ± 11 years, and 20 (36%) were women. The median (25th, 75th percentile) resting left ventricular outflow tract gradient obtained by echocardiography was 43 (22, 81) mm Hg. Greater than 1 septal perforating artery was injected in 48 patients (86%). The Kaplan-Meier cumulative rate of ICM-detected arrhythmic events at 18 months of follow-up was 71%, with an event rate of 43% occurring within 3 months of ASA. The cumulative rate of the ICM-detected first atrial fibrillation event at 18 months was 37%, and the corresponding rate of CHB was 19%. All atrial fibrillation and CHB events were actionable, leading to the initiation of anticoagulation and pacemaker implantation, respectively. No baseline demographic or procedural variables were identified as independent predictors of an increased risk of developing ICM-detected arrhythmic events. Conclusion After ASA, ICM is effective in capturing clinically actionable arrhythmic events in patients with HCM regardless of patient's baseline risk factors.

Chikungunya virus (CHIKV) is a global emergent arthritogenic alphavirus transmitted by anthropophilic Stegomyia mosquitoes. Chikungunya fever may evolve to chronic arthralgia in 57–80% of infected patients. This study was developed to identify possibly fast, simple low-cost biomarkers to monitor chronic CHIKV-induced articular disease. Between 2017 and 2018, we analyzed clinical data of patients meeting the criteria established by standard protocols to define chronic chikungunya articular disease. Patients were classified according to the disease activity scores, inflammatory biomarkers (erythrocyte sedimentation rate [ESR], ferritin, and C-reactive protein [CRP] serum), positive rheumatoid factor, comorbidities, smoking, and previous use of corticosteroids determined before beginning therapy. Of 106 patients, 98 (92.5%) were women with mean age of 52 ± 13 years, 6.8 ± 4.4 months of illness duration at the first medical appointment, and 6.7 ± 4.5 affected joints. Mean ESR (26 ± 19), CRP (2.6 ± 3.6), and stratified ferritin (144 ± 115) levels were normal according to reference values. There was no significance in comparing the levels of inflammatory biomarkers and the additional variables analyzed in the presence of moderate chronic joint disease in the study population. However, we identified a negative correlation between disease activity measures and duration of disease at the first medical evaluation after initial infection (P < 0.001), corroborating data observed in the literature.

Prenatal insults during fetal development result in increased likelihood of developing chronic disease. Obesity, the biggest risk factor for the development of metabolic disease, is affected by several genetic and environmental factors. High-fat diet (HFD) consumption is usually linked with the development of obesity. The main goal of this study was to analyze the impact of the exposure to a HFD in prenatally stressed animals. For this purpose, we subjected pregnant BALB/c mice to restraint stress for 2 h a day between gestational day (GD) 14 and GD 21. Prenatally stressed and control offspring of both sexes were postnatally exposed to a HFD for 24 weeks. We found that prenatal stress (PS) per se produced disturbances in males such as increased total blood cholesterol and triglycerides, with a decrease in mRNA expression of sirtuin-1. When these animals were fed a HFD, we observed a rise in glucose and insulin levels and an increase in visceral adipose tissue gene expression of leptin, resistin, and interleukin-1 beta. Although females proved to be more resilient to PS consequences, when they were fed a HFD, they showed significant metabolic impairment. In addition to the changes observed in males, females also presented an increase in body weight and adiposity and a rise in cholesterol levels.

Purpose. Autonomic dysfunction is a common nonmotor feature and early manifestation of Parkinsons disease (PD). Autonomic dysfunction in PD is associated with a worse prognosis. We sought to characterize autonomic dysfunction and identify associated factors in patients with early PD. Methods. An observational, cross-sectional, descriptive, and analytical study was conducted to evaluate patients with early PD from the Parkinsons Progression Markers Initiative. We utilized the Scales for Outcomes in Parkinsons Disease-Autonomic dysfunction questionnaire to determine the prevalence and frequencies of autonomic symptomatology. The cohort was grouped into high and low dysautonomic scores. A regression model identified variables that independently explained dysautonomic scores in our early PD cohort. Results. 414 PD patients had a mean age of 61.1 (SD 9.7) years at diagnosis and mean disease duration of 6.7 (SD 6.6) months. Among all patients, 43.7% (181/414) had high dysautonomic scores. Urinary and gastrointestinal symptoms were the most prevalent and frequently reported dysautonomic symptoms. Patients with fatigue (beta = 4.28, p < 0.001 ), probable rapid eye movement sleep behavior disorder (beta = 2.71, p < 0.001 ), excessive daytime sleepiness (beta = 1.88, p = 0.039 ), impulsivity and compulsivity (beta = 2.42, p < 0.001 ), and increasing age (beta = 1.05, p < 0.001 ) were more likely to have high dysautonomic scores. Conclusion. Lower urinary tract and gastrointestinal symptoms are prevalent and frequent in early PD patients. Fatigue, sleep disorders, impulsivity and compulsivity, and age are predictors of autonomic dysfunction. Autonomic symptoms predominated in this group of early PD patients in the disease course and were associated with more severe disease.

Background Cognitive impairments are related to deficits in primary auditory and visual sensory processes in schizophrenia. These impairments can be remediated by neuroscience-informed computerized cognitive trainings that target auditory and visual processes. However, it is not clear which modality results in greater improvements in cognition, symptoms and quality of life. We aimed to investigate the impact of training auditory versus visual cognitive processes in global cognition in patients with schizophrenia. Methods Seventy-nine schizophrenia participants were randomly assigned to either 40 h of auditory or visual computerized training. Auditory and visual exercises were chosen to be dynamically equivalent and difficulties increased progressively during the training. We evaluated cognition, symptoms and quality of life before, after 20 h, and after 40 h of training. ClinicalTrials.gov (1R03TW009002-01). Results Participants who received the visual training showed significant improvements in global cognition compared to the auditory training group. The visual training significantly improved attention and reasoning and problem-solving, while the auditory training improved reasoning and problem-solving only. Schizophrenia symptoms improved after training in both groups, whereas quality of life remained unchanged. Interestingly, there was a significant and positive correlation between improvements in attention and symptoms in the visual training group. Conclusions We conclude that the visual training and the auditory training are differentially efficient at remediating cognitive deficits and symptoms of clinically stable schizophrenia patients. Ongoing follow-up of participants will evaluate the durability of training effects on cognition and symptoms, as well as the potential impact on quality of life over time.

Efficient communication between the glial cells and neurons is a bi-directional process that is essential for conserving normal functioning in the central nervous system (CNS). Neurons dynamically regulate other brain cells in the healthy brain, yet little is known about the first pathways involving oligodendrocytes and neurons. Oligodendrocytes are the myelin-forming cells in the CNS that are needed for the propagation of action potentials along axons and additionally serve to support neurons by neurotrophic factors (NFTs). In demyelinating diseases, like multiple sclerosis (MS), oligodendrocytes are thought to be the victims. Axonal damage begins early and remains silent for years, and neurological disability develops when a threshold of axonal loss is reached, and the compensatory mechanisms are depleted. Three hypotheses have been proposed to explain axonal damage: 1) the damage is caused by an inflammatory process; 2) there is an excessive accumulation of intra-axonal calcium levels; and, 3) demyelinated axons evolve to a degenerative process resulting from the lack of trophic support provided by myelin or myelin-forming cells. Although MS was traditionally considered to be a white matter disease, the demyelination process also occurs in the cerebral cortex. Recent data supports the notion that initial response is triggered by CNS injury. Thus, the understanding of the role of neuron-glial neurophysiology would help provide us with further explanations. We should take in account the suggestion that MS is in part an autoimmune disease that involves genetic and environmental factors, and the pathological response leads to demyelination, axonal loss and inflammatory infiltrates.

Cariprazine (CAR) is a strong inhibitor of the Dhcr7 enzyme, the last enzyme in the cholesterol biosynthesis pathway. We assessed the effects of CAR on maternally exposed Dhcr7+/− and wild-type mouse offspring, and tested the biochemical effects of CAR in human serum samples. Dhcr7+/− and wild-type time-pregnant mice were exposed to vehicle or 0.2 mg/kg CAR from E12 to E19. Levels of CAR, CAR metabolites, sterols, and oxysterols were measured in the brain of maternally exposed offspring at various time points using LC-MS/MS. Embryonic exposure to CAR significantly increased levels of 7-DHC in all organs of exposed embryos, with a particularly strong effect in the brain. Detectable levels of CAR and elevated 7-DHC were observed in the brain of newborn pups 14 days after drug exposure. In addition, CAR altered sterol metabolism in all animals analyzed, with the strongest effect on the brain of Dhcr7+/− pups born to Dhcr7+/− dams. Furthermore, CAR elevated toxic oxysterols in the brain of maternally exposed Dhcr7+/− offspring to levels approaching those seen in a mouse model of Smith–Lemli–Opitz syndrome. Finally, we observed that patients taking CAR have elevated 7-DHC in their serum. In summary, maternal DHCR7 heterozygosity, combined with offspring DHCR7 heterozygosity might represent a vulnerability factor to medications that interfere with sterol biosynthesis. Due to the conserved sterol biosynthesis between mice and humans, we suggest that the 1–3% of patient population with single-allele DHCR7 mutations might not be ideal candidates for CAR use, especially if they are nursing, pregnant or plan to become pregnant.

Introducción: La enfermedad de Parkinson (EP) es un trastorno neurodegenerativo, progresivo, caracterizado por diversos síntomas motores. El hallazgo patológico principal es la pérdida de neuronas productoras de dopamina en la sustancia nigra pars compacta. Los trastornos del sueño, apatía, ansiedad, deterioro cognitivo, demencia y depresión, son síntomas neuropsiquiátricos que también presentan los pacientes con EP. Debido a que las hormonas sexuales son factores importantes para la diferenciación estructural y funcional en el cerebro, existen diferencias entre géneros en los pacientes con EP. Objetivo: Analizar las diferencias en depresión y ansiedad entre géneros en pacientes con EP. Métodos: Se revisó la literatura en la base de datos de PubMed de enero 2000 a julio del 2019. Resultados: El 50% de los pacientes con EP cumplen con los criterios para depresión según la DSM-V y el 40% tiene síntomas consistentes con los trastornos de ansiedad. Las mujeres con EP tienen síntomas no motores más graves que los hombres. Conclusión: La EP y sus síntomas neuropsiquiátricos son de origen multifactorial pero parecen ser influenciados por el género, con una alta prevalencia en las mujeres.

Introduction: Accidental pediatric liquid paracetamol exposure is common. Most children do not require treatment with acetylcysteine and acute liver injury is rare.Case report: An otherwise well 3-...

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a wide range of clinical manifestations that may affect any organ. Polyarteritis nodosa (PAN) is defined as necrotizing inflammatory changes in the medium and small vessels, a rare form of systemic necrotizing vasculitis in childhood. This article discusses the case of a patient with a history of deep venous thrombosis of the left leg, who presented with erythematosus purple lesions in her right hand, associated with pain, intermittent claudication, progressive limping and generalized edema. While in hospital, she was diagnosed with SLE with renal involvement and medium vessel vasculitis mainly of the upper limbs. She also met the criteria for PAN, a rare association that is seldom described in the medical literature.

The objective of this study is to describe the characteristics of smokers admitted to different medical and surgical services in a university hospital and the perception of patients regarding the need for a specialized intervention. The sample comprises a total of 307 patients (mean age of 59.4 years), being 40% (n = 123) non-smokers, 42.7% (n = 131) ex-smokers, and 17.3% (n = 53) smokers. The average consumption of smokers was 22.2 cigarettes / day and the severity of nicotine dependence evaluated with the Fagerstrom test exceeded 5 points in more than half of the sample. On the other hand, 77.7% had made at least one previous attempt to quit tobacco use. Almost the entire sample (89.9 %) of smokers and ex-smokers considered it necessary to develop tobacco treatment programs during hospitalization. Finally, the importance of the hospital context is argued as an opportunity to address the cessation of smoking. The data obtained in this study will allow focusing more appropriately on the management of these patients and optimizing resources.

Magnetic resonance images from 197 patients with calcified neurocysticercosis (NCC), 38 with viable NCC and 197 NCC-free healthy rural villagers were evaluated to compare the frequency of hippocampal atrophy/sclerosis (HAS) across these populations. Scheltens’ medial temporal atrophy scale was used for hippocampal rating. The median age of the 432 study participants was 46 years (interquartile range, 29–62 years), and 58% were women. Hippocampal atrophy/sclerosis was disclosed in 26.9% patients with calcified NCC, compared with 7.9% in patients with viable NCC and 8.1% in healthy rural villagers. After adjusting for age, gender, and history of epilepsy, hippocampal atrophy/sclerosis was more frequent in patients with calcified NCC than in those with viable cysts (RR, 3.60; 95% CI, 1.18– 0.99; P = 0.025) and healthy rural villagers (RR, 3.43; 95% CI, 1.94–6.06; P

Urea cycle defects are inborn errors of metabolism produced by a defect in one of the enzymes responsible for the detoxification of ammonia, which generates its accumulation in the body. The clinical manifestations can present early, with high morbidity and mortality, or late onset. The heterogeneity of the symptoms and the lack of clinical suspicion in neonates leads to a wrong diagnosis, which can be confused with neonatal sepsis or cerebral hemorrhages. The increase in plasma ammonia in the biochemical examination orients his diagnosis towards a defect of the urea cycle. Argininosuccinic aciduria is the third most frequent defect of the urea cycle, and is caused by a argininosuccinate lyase deficiency. A neonatal onset case report is presented. The objective is to emphasize its diagnostic suspicion, and to propose early diagnostic tools such as its incorporation into the neonatal metabolic screening.

Carotenoids are antioxidant nutrients with the potential to provide protection against oxidative stress. Plasma carotenoid concentrations are lower in newborn infants compared to their mothers, however, limited information is available regarding how concentrations differ by gestational age. The objective of this research is to assess maternal and umbilical cord plasma carotenoid concentrations and maternal-umbilical cord plasma ratios across five groups of birth gestational age. Mother-infant dyads were enrolled at delivery for collection of maternal and umbilical cord blood. Plasma carotenoids were analyzed by HPLC and LC-MS/MS. Birth gestational age was categorized into five groups, and the Kruskal–Wallis test compared carotenoid concentrations and maternal-umbilical cord plasma ratios between these groups. A p-value of &lt, 0.05 was considered statistically significant. 370 mother-infant dyads were included, with most infants delivered at early term (20.3%) or term (64.6%). Though maternal plasma concentrations increased with birth gestational age, we observed less variability in umbilical cord plasma concentrations, thus the maternal-umbilical cord plasma ratio also increased with birth CGA groups for lutein + zeaxanthin (p = 0.008), β-cryptoxanthin (p = 0.027), α-carotene (p = 0.030), β-carotene approached significance (p = 0.056). Additional research is needed to determine if carotenoid concentrations were physiologic to varying gestational ages or if they were impacted by factors associated with preterm birth.

Sodium restriction is recommended for patients with heart failure (HF) despite the lack of solid clinical evidence from randomized controlled trials. Whether or not sodium restrictions provide beneficial cardiac effects is not known.The present study is a randomized, double-blind, controlled trial of stable HF patients with ejection fraction ≤ 40%. Patients were allocated to sodium restriction (2 g of sodium/day) vs. control (3 g of sodium/day). The primary outcome was change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) at 20 weeks. Secondary outcomes included quality of life and adverse safety events (HF readmission, blood pressure or electrolyte abnormalities).Seventy patients were enrolled. Median baseline sodium consumption was 3268 (2225-4537) mg/day. Adherence to the intervention based on 24-hour urinary sodium was 32%. NT-proBNP and quality of life did not significantly change between groups (p0.05 for both). Adverse safety events were not significantly different between the arms (p0.6 for all). In the per protocol analysis, patients who achieved a sodium intake2500 mg/day at the intervention conclusion showed improvements in NT-proBNP levels (between-group difference: -55%, 95% confidence interval -27 to -73%; p = 0.002) and quality of life (between-group difference -11 ± 5 points; p = 0.04). Blood pressure decreased in patients with lower sodium intake (between-group difference -9 ± 5 mmHg; p = 0.05) without significant differences in symptomatic hypotension or other safety events (p0.3 for all).Adherence assessed by 24-hour natriuresis and by the nutritionist was poor. The group allocated to sodium restriction did not show improvement in NT-proBNP. However, patients who achieved a sodium intake2500 mg/day appeared to have improvements in NT-proBNP and quality of life without any adverse safety signals. ClinicalTrials.gov Identifier: NCT03351283.

Objective: The objective was to infer the effect of the variables phenology (migration-non-migration), seasonal (rainfall-dry season), sex and forest condition on the abundances of birds (resident-migratory) in a semi-preserved and disturbed oak pine forest. Design/methodology/approach: It was carried out in Monte Tlaloc, State of Mexico, under two conditions of apparent disturbance, semi-preserved oak pine forest and disturbed oak pine forest. Ten bird samplings were carried out with "count on point" with a fixed radius of 25 m, covering the 4 seasons of the year and migratory periods. With the previous data, the Relative Abundance Index (RAI) was estimated. To infer the effect of the variables phenology, seasonality, sex and forest condition on the abundances of birds, generalized linear models were elaborated. Results: The IAR of the birds registered in the semi-considered pine forest indicates that the species with the lowest presence was Aphelocoma ultramarina (0.002) and with the highest frequency Empidonax sp. (0.13), unlike to that found in the disturbed pine forest where the lowest IAR corresponded to Colaptes auratus (0.003) and with the highest appearance was Ptiliogonys cinereus (0.23). The Generalized Linear Model suggested that forest condition and phenology are significantly related to the frequency of species. Limitations on study/implications: In this study it was found that the abundance of birds was affected by the condition of the forest and that the phenology (migration-non-migration), seasonal (rain-dry season), sex and condition of the forest were related to the abundance of birds. Four species classified as under Special Protection and two Threatened according to NOM-059 were registered as well as the presence of four endemic species which highlights the importance of conserving these ecosystems. Findings/conclusions: The fauna communities present in Monte Tláloc highlight the importance of conserving the pine-oak forests since this site is part of the Eje Neovolcanico Transversal.

INTRODUCTION: Acute spinal cord injury without tomographic evidence of vertebral fracture or dislocation in patients post trauma can represent a diagnostic challenge for the treating physician. The ossification of thoracic ligamentum flavum has been widely published as a cause of thoracic myelopathy, however its association with acute traumatic spinal cord injury is limited to isolated cases. CASE PRESENTATION: we report a Caucasian 37-year-old man who suffered a high-energy thoracolumbar spine trauma in a motorcycle accident with acute paraplegia. He presented ossification of the ligamentum flavum between the thoracic vertebrae T10 and T11 with a decrease in the diameter of the vertebral canal as the only pathological finding. We treated the patient with early surgical release before 72 h of trauma. We performed a posterior approach with hemilaminectomy and T10–T11 flavectomy. Arthrodesis was done with T10–T11 pedicle screws. Postoperative neurological status improved from ASIA Impairment Scale (AIS) A to C with severe functional dependence. DISCUSSION: Ossification of the ligamentum flavum should be considered in the differential diagnosis in patients presenting with acute traumatic spinal cord injury without tomographic evidence of trauma. A proper diagnosis in time is the key to decision making and treatment of spinal cord injury. Especially in adult patients, we must consider nontraumatic associated factors that could be involved in the spinal cord injury mechanism, such as ossification of the ligamentum flavum.

In men, 70% of circulating testosterone binds with high affinity to plasma sex hormone binding globulin (SHBG), which determines its bioavailability in their target cells. In recent years, a growing body of evidence has shown that circulating SHBG not only is a passive carrier for steroid hormones but also actively regulates testosterone signaling through putative plasma membrane receptors and by local expression of androgen-binding proteins apparently to reach local elevated testosterone concentrations in specific androgen target tissues. Circulating SHBG levels are influenced by metabolic and hormonal factors, and they are reduced in obesity and insulin resistance, suggesting that SHBG may have a broader clinical utility in assessing the risk for cardiovascular diseases. Importantly, plasma SHBG levels are strongly correlated with testosterone concentrations, and in men, low testosterone levels are associated with an adverse cardiometabolic profile. Although obesity and insulin resistance are associated with an increased incidence of cardiovascular disease, whether they lead to abnormal expression of circulating SHBG or its interaction with androgen signaling remains to be elucidated. SHBG is produced mainly in the liver, but it can also be expressed in several tissues including the brain, fat tissue, and myocardium. Expression of SHBG is controlled by peroxisome proliferator-activated receptor γ (PPARγ) and AMP-activated protein kinase (AMPK). AMPK/PPAR interaction is critical to regulate hepatocyte nuclear factor-4 (HNF4), a prerequisite for SHBG upregulation. In cardiomyocytes, testosterone activates AMPK and PPARs. Therefore, the description of local expression of cardiac SHBG and its circulating levels may shed new light to explain physiological and adverse cardiometabolic roles of androgens in different tissues. According to emerging clinical evidence, here, we will discuss the potential mechanisms with cardioprotective effects and SHBG levels to be used as an early metabolic and cardiovascular biomarker in men.

Epithelial cells lining the intestinal mucosa create a physical barrier that separates the luminal content from the interstitium. Epithelial barrier impairment has been associated with the development of various pathologies such as inflammatory bowel diseases (IBD). In the inflamed mucosa, superficial erosions or micro-erosions that corrupt epithelial monolayers correspond to sites of high permeability. Several mechanisms have been implicated in the formation of micro-erosions including cell shedding and apoptosis. These micro-erosions often represent microscopic epithelial gaps randomly distributed in the colon. Visualization and quantification of those epithelial gaps has emerged as an important tool to investigate intestinal epithelial barrier function. Here, we describe a new method to visualize the specific location of where transcellular and paracellular permeability is enhanced in the inflamed colonic mucosa. In this assay, we apply a 10 kDa fluorescent dye conjugated to a lysine fixable dextran to visualize high permeability regions (HPR) in the colonic mucosa. Additional use of cell death markers revealed that HPR encompass apoptotic foci where epithelial extrusion/shedding occurs. The protocol described here provides a simple but effective approach to visualize and quantify micro-erosions in the intestine, which is a very useful tool in disease models, in which the intestinal epithelial barrier is compromised.

Background: Diabetes mellitus (DM) is a multisystem metabolic disorder shown to have adverse effects on lung physiology, immune responses, and antimicrobial defenses. However, the impact of DM on the development of poor in-hospital outcomes in patients with Acute COPD exacerbation (AECOPD) is unclear. We aimed to assess this very impact in our study. Methods: A retrospective cohort study was conducted using the Nationwide Inpatient Sample from 2018. About 394,929 hospitalizations had AECOPD as a primary diagnosis and were stratified based on the presence of DM using ICD-10 codes. Multivariate regression analysis was used to adjust for confounders and analyze variables. The selection of covariates was done with a univariate screen and literature review. Results: Out of the 394,929 hospitalized patients with AECOPD, 123,425 patients had DM. In-hospital mortality in AECOPD patients with DM was lower than those without (0.78% vs. 1.17%, p Conclusion: DM in AECOPD did not have worse outcomes in terms of in-hospital mortality, LOS, and PC. DM patients had lower risk of MI, PE, and stroke, however, had higher risk of AKI. Further investigation is needed to understand the exact correlation between the paradoxical nature of outcomes in AECOPD in those with DM. Disclosure R. Atluri: None. M. Ramirez: None. H. Shaka: None. M. Murthi: None. C. D. Corpuz: None. S. Velagapudi: None. G. Velazquez: None.

Introduction: Diabetic ketoacidosis (DKA) is a medical emergency associated with significant patient mortality and morbidity. Studies have shown that the presence of Major Depressive Disorder (MDD) is associated with an increased incidence of DKA. We aimed to assess whether MDD was associated with increased risk of readmission following DKA. Methods: We utilized the National Readmission Database for 2016 to identify hospitalized adult patients with a principal diagnosis of DKA and a secondary diagnosis of MDD from January 1 to November 30, 2016. We excluded patients with elective and traumatic admissions. We utilized a multivariate cox regression model to identify independent predictors of readmission. Results: Of 15,981 patients with MDD and DKA who were discharged, 23.2%(n=3710) were readmitted within 30-days. The most common reason for readmission was DKA (63.9%, n=2371). In the multivariate cox regression model, MDD was associated with higher risk of readmission (HR: 1.17, 95% CI: 1.1 - 1.26, p=0.04) when adjusted for comorbidities and hospital characteristics. Of those MDD patients with DKA who were readmitted, type 1 DM (HR: 1.14, 95% CI: 1 - 1.3, p=0.04), CHF (HR: 1.40, 95% CI: 1.1 - 1.78, p=0.006), and CKD (HR: 1.44, 95% CI: 1.17 - 1.79, p=0.001) were associated with higher risk of readmission. Obesity (HR: 0.75, 95% CI: 0.59 - 0.97, p=0.025), private insurance (HR: 0.64, 95% CI: 0.53 - 0.79, p Conclusion: In this study, we found that patients with MDD admitted for DKA had a 17% increased risk of readmission within 30 days of discharge in comparison to those without MDD. This could be explained by their propensity for poor adherence to diet, exercise, and recommended pharmacological therapy. Further studies need to be done to assess and target the exact precipitants of readmission. Disclosure M. Ramirez: None. M. Murthi: None. B. Sharma: None. R. Atluri: None. H. Shaka: None. G. Velazquez: None.

In cutaneous T cell lymphoma (CTCL), a dominant Th2 profile associated with disease progression has been proposed. Moreover, although the production and regulation of IL-4 expression during the early stages of the disease may have important implications in later stages, these processes are poorly understood. Here, we demonstrate the presence of TOX+ CD4+ T cells that produce IL-4+ in early-stage skin lesions of CTCL patients and reveal a complex mechanism by which the NLRP3 receptor promotes a Th2 response by controlling IL-4 production. Unassembled NLRP3 is able to translocate to the nucleus of malignant CD4+ T cells, where it binds to the human il-4 promoter. Accordingly, IL-4 expression is decreased by knocking down and increased by promoting the nuclear localization of NLRP3. We describe a positive feedback loop in which IL-4 inhibits NLRP3 inflammasome assembly, thereby further increasing its production. IL-4 induced a potentially malignant phenotype measured based on TOX expression and proliferation. This mechanism of IL-4 regulation mediated by NLRP3 is amplified in late-stage CTCL associated with disease progression. These results indicate that NLRP3 might be a key regulator of IL-4 expression in TOX+ CD4+ T cells of CTCL patients and that this mechanism might have important implications in the progression of the disease.

Background Although esophagogastroduodenoscopy (EGD) is the standard procedure for the diagnosis of gastric cancer (GC), some GCs are missed. There are no published data on the missed rate of GC in Spain. Aims To determine the frequency and characteristics of missed GCs and assess the quality of the EGD in a specific population with GC. Methods Records of all patients diagnosed with gastric adenocarcinoma between 2012 and 2016 in a defined geographic area were reviewed. Missed GC was defined as a case with a prior negative EGD for cancer. Quality indicators from the prior EGDs were measured. Results From 212 cases of GC, 25 cases were excluded. Seventeen out of 187 patients had a prior EGD (9.1%). Twelve of those 17 missed GC had a prior EGD with some abnormal findings. In 6 of them, biopsies were taken. Survival was no different between patients with missed and non-missed GC. Quality indicators that failed to meet standards were recording time, image documentation, and a protocol of biopsies. Conclusions Missed GC in an EGD in a defined population in Spain is not uncommon (9.1%). The endoscopist is an important factor in missed GC due to lack of adequate detection and sampling error. Compliance with performance of quality indicators could reduce missed GC.

Cholesterol serves as a building material for cellular membranes and plays an important role in cellular metabolism. The brain relies on its own cholesterol biosynthesis, which starts during embryonic development. Cholesterol is synthesized from two immediate precursors, desmosterol and 7-dehydrocholesterol (7-DHC). Mutations in the DHCR24 enzyme, which converts desmosterol into cholesterol, lead to desmosterolosis, an autosomal recessive developmental disorder. In this study, we assessed the brain content of desmosterol, 7-DHC, and cholesterol from development to adulthood, and analyzed the biochemical, molecular, and anatomical consequences of Dhcr24 mutations on the sterol profile in a mouse model of desmosterolosis and heterozygous Dhcr24+/- carriers. Our HPLC-MS/MS studies revealed that by P0 desmosterol almost entirely replaced cholesterol in the Dhcr24-KO brain. The greatly elevated desmosterol levels were also present in the Dhcr24-Het brains irrespective of maternal genotype, persisting into adulthood. Furthermore, Dhcr24-KO mice brains showed complex changes in expression of lipid and sterol transcripts, nuclear receptors, and synaptic plasticity transcripts. Cultured Dhcr24-KO neurons showed increased arborization, which was also present in the Dhcr24-KO mouse brains. Finally, we observed a shared pathophysiological mechanism between the mouse models of desmosterolosis and Smith-Lemli-Opitz syndrome (a genetic disorder of conversion of 7-DHC to cholesterol).

Significance We have completed a screen of ∼106 small molecules to identify compounds that induce cell death in multipotent glioblastoma multiforme (GBM) cancer stem cells (CSCs). This resulted in the identification of a hit class (RIPGBM) that was found to induce apoptosis in GBM CSCs in a cell type-selective manner. Metabolite profiling experiments led to the identification of a proapoptotic derivative of RIPGBM (cRIPGBM), which was found to be selectively formed in GBM CSCs. Mechanistic studies revealed that cRIPGBM induces apoptosis by binding to receptor-interacting protein kinase 2 (RIPK2) in a mode that results in the formation of a proapoptotic RIPK2/caspase 1 complex. In a physiologically relevant orthotopic intracranial GBM CSC tumor xenograft mouse model, RIPGBM was found to significantly inhibit in vivo tumor formation., Glioblastoma multiforme (GBM; grade IV astrocytoma) is the most prevalent and aggressive form of primary brain cancer. A subpopulation of multipotent cells termed GBM cancer stem cells (CSCs) play a critical role in tumor initiation, tumor maintenance, metastasis, drug resistance, and recurrence following surgery. Here we report the identification of a small molecule, termed RIPGBM, from a cell-based chemical screen that selectively induces apoptosis in multiple primary patient-derived GBM CSC cultures. The cell type-dependent selectivity of this compound appears to arise at least in part from redox-dependent formation of a proapoptotic derivative, termed cRIPGBM, in GBM CSCs. cRIPGBM induces caspase 1-dependent apoptosis by binding to receptor-interacting protein kinase 2 (RIPK2) and acting as a molecular switch, which reduces the formation of a prosurvival RIPK2/TAK1 complex and increases the formation of a proapoptotic RIPK2/caspase 1 complex. In an orthotopic intracranial GBM CSC tumor xenograft mouse model, RIPGBM was found to significantly suppress tumor formation in vivo. Our chemical genetics-based approach has identified a drug candidate and a potential drug target that provide an approach to the development of treatments for this devastating disease.

Based on a set of two, semi-structured, individual interviews with 21 Japanese men aged between 25 and 57, from Tokyo and Osaka, this paper explores the rationale underneath their eating ha...

The ATP-binding cassette transporter A1 (ABCA1) promotes cellular cholesterol efflux, leading to cholesterol binding to the extracellular lipid-free apolipoprotein A-I. ABCA1 regulates lipid content, glucose tolerance and insulin sensitivity in adipose tissue. In skeletal muscle, most GLUT4-mediated glucose transport occurs in the transverse tubule, a system composed by specialized cholesterol-enriched invaginations of the plasma membrane. We have reported that insulin resistant mice have higher cholesterol levels in transverse tubule from adult skeletal muscle. These high levels correlate with decreased GLUT4 trafficking and glucose uptake; however, the role of ABCA1 on skeletal muscle insulin-dependent glucose metabolism remains largely unexplored. Here, we evaluated the functional role of the ABCA1 on insulin-dependent signaling pathways, glucose uptake and cellular cholesterol content in adult skeletal muscle. Male mice were fed for 8 weeks with normal chow diet (NCD) or high fat diet (HFD). Compared to NCD-fed mice, ABCA1 mRNA levels and protein content were lower in muscle homogenates from HFD-fed mice. In Flexor digitorum brevis muscle from NCD-fed mice, shABCA1-RFP in vivo electroporation resulted in 65% reduction of ABCA1 protein content, 1.6-fold increased fiber cholesterol levels, 74% reduction in insulin-dependent Akt (Ser473) phosphorylation, total suppression of insulin-dependent GLUT4 translocation and decreased 2-NBDG uptake compared to fibers electroporated with the scrambled plasmid. Pre-incubation with methyl-β cyclodextrin reestablished both GLUT4 translocation and 2-NBDG transport. Based on the present results, we suggest that decreased ABCA1 contributes to the anomalous cholesterol accumulation and decreased glucose transport displayed by skeletal muscle membranes in the insulin resistant condition.

Background: Autism spectrum disorder is an alteration of neurodevelopment with a conspicuous display of behaviors in children between 2 and 3 years of age. Basic behavioral manifestations are social isolation, language impairment, and motor problems. However, there are also manifestations related to sensory perception, although knowledge about tactile stimulation is yet poorly understood. Objective: We aimed to determine changes in the cutaneous sensitivity of autistic boys following a program of tactile and emotional stimulation. Methods: Sensory stimulation was applied as therapy to six autistic boys 5-12 years old. As stimuli, we used bubble paper and a skin massager twice a week for 1 year. During stimulation, kids were allowed to walk in socks during 2 min on a 2 × 2 m carpet made of bubble paper and asked to burst the bubbles. In addition, a handheld massager was used to stimulate the skin on the forearm and face cheek with level 2 of intensity for 2 min. Following stimulation, the cutaneous sensitivity threshold was obtained using von Frey fibers on the forearm and face cheek. Kids were asked to keep their eyes closed and to indicate their perception by pointing with a finger toward the stimulated area. Results: Our data indicate that kids were capable of perceiving smaller fibers with consecutive therapy sessions. Conclusion: Tactile and sensory stimulation to autistic children modifies cutaneous sensitivity, perhaps with an improved perception of the general environment and consequently social behavior. Antecedentes: El trastorno del espectro autista es una alteración del neurodesarrollo con manifestaciones conductuales particulares en niños entre los 2-3 años de edad. Las conductas básicas son el aislamiento social, alteraciones del lenguaje y problemas motores. Sin embargo, existen también modificaciones relacionadas con la percepción sensorial, aunque el conocimiento sobre ello es aún pobre. Objetivo: Tuvimos el propósito de determinar la sensibilidad cutánea de niños con autismo siguiendo un programa de estimulación táctil y emocional. Métodos: Aplicamos dos estímulos sensoriales a 6 niños con autismo de 5 a 12 años de edad. Los estímulos utilizados fueron papel burbuja y un masajeador, dos veces por semana durante un año. Un cuadro de 2 x 2 m de papel burbuja se colocó en el piso y la prueba consistió en que cada niño caminara en calcetas por dos minutos tratando de reventar las burbujas. Un masajeador manual fue utilizado para estimular la piel del antebrazo y la mejilla a un nivel 2 de intensidad por dos minutos. Después de los estímulos, el umbral a la sensibilidad cutánea se obtuvo usando fibras de von Fray sobre el antebrazo y la mejilla, pidiendo a los niños mantener los ojos cerrados y señalando la percepción con un dedo el área estimulada. Resultados: A medida que la terapia se aplicó continuamente, cada niño fue capaz de percibir fibras más pequeñas. Conclusiones: Una estimulación enriquecida táctil y sensorial de niños con autismo modifica la sensibilidad cutánea, probablemente con una percepción mejorada del ambiente en general y consecuentemente de la conducta social.

Background: The regulation of emotions and affective strategies have been shown to be relevant in the clinic of borderline personality disorder (BPD), however, the studies carried out are still not conclusive on the influencing role of these two variables on the course of the TLP. The need for empirical evidence on the relationship between the internal components of these manifestations is faced: cognitive reappraisal, expressive suppression, positive affect and negative affect. Result: The results indicate that the psychological variables studied present more dysfunctional values ​​in patients with BPD. The symptomatic of BPD does not moderate the relationship between cognitive reappraisal and negative affect; and cognitive reappraisal together with positive affect are associated with fewer BPD symptoms. Conclusion: The results obtained offer different clinical implications in the affective and emotional context of BPD, however, it would be necessary to use alternative measures of the emotional pattern, such as physiological methodologies to have more defining results.

A 27-year-old obese woman, a smoker, presented diplopia. She showed ptosis, impaired adduction, supraduction, and infraduction of the left eye with pupil-sparing (figure, A–C and video 1). Brain MRI showed restricted diffusion in the left midbrain, revealing ischemia (figure, D–F). Pupil-sparing third nerve palsy is usually associated with microvascular diabetic ischemia of central fibers in the cisternal segment, but is also related to partial fascicular lesions in brainstem stroke, ophthalmoplegic migraine, and, rarely, aneurysm. Although microvascular and brainstem ischemia have a better prognosis, regardless of pupillary involvement, the investigation is important for secondary stroke prevention, particularly in young patients, as in this case.1,2

Background: Extensive malaria control measures have been implemented on Bioko Island, Equatorial Guinea over the past 16 years, reducing parasite prevalence and malaria-related morbidity and mortality but without achieving elimination. Malaria vaccines offer hope for reducing the burden to zero. Three Phase 1/2 studies have been conducted successfully on Bioko Island to evaluate the safety and efficacy of whole Plasmodium falciparum (Pf) sporozoite (SPZ) malaria vaccines. A large, pivotal trial of the safety and efficacy of the radiation-attenuated Sanaria® PfSPZ Vaccine against Pf is planned for 2022. This study assessed the incidence of malaria at the Phase 3 study site and characterized the influence of socio-demographic factors on the burden of malaria to guide trial design. Methods: A cohort of 240 randomly selected individuals aged 6 months to 45 years from North Bioko Province, Bioko Island, was followed for 24 weeks after clearance of parasitemia. Assessment of clinical presentation consistent with malaria and thick blood smears were performed every two weeks. Incidence of first and multiple malaria infections per person-time of follow-up was estimated, compared between age groups, and examined for associated socio-demographic risk factors. Results: 58 malaria infection episodes (malaria) were observed during the follow up period, including 47 first and 11 repeat infections. The incidence of malaria was 0.25 [95% CI (0.19, 0.32)] and of first malaria was 0.23 [95% CI (0.17, 0.30)] per person per 24 weeks (0.22 in 6-59-month-olds, 0.26 in 5-17-year-olds, 0.20 in 18-45-year-olds). Incidence of first malaria with symptoms was 0.13 [95% CI (0.09, 0.19)] per person per 24 weeks (0.16 in 6-59-month-olds, 0.10 in 5-17-year-olds, 0.11 in 18-45-year-olds). Multivariate assessment showed that study area, gender, malaria positivity at screening, and household socioeconomic status independently predicted the observed incidence of malaria. Conclusion: Despite intensive malaria control efforts on Bioko Island, local transmission remains and is spread fairly evenly throughout age groups. These incidence rates are sufficient to support the planned future trial of PfSPZ Vaccine. The long-term goal is to conduct mass vaccination programs to halt transmission and eliminate Pf malaria.