New bands in the sleep stages of spider monkeys (Ateles geoffroyi): Electroencephalographic correlations and spatial distribution.

The study of electroencephalographic (EEG) signals in nonhuman primates has led to important discoveries in neurophysiology and sleep behavior. Several studies have analyzed digital EEG data from primate species with prehensile tails, like the spider monkey, and principal component analysis has led to the identification of new EEG bands and their spatial distribution during sleep and wakefulness in these monkeys. However, the spatial location of the EEG correlations of these new bands during the sleep-wake cycle in the spider monkey has not yet been explored. Thus, the objective of this study was to determine the spatial distribution of EEG correlations in the new bands during wakefulness, rapid eye movement (REM) sleep, and non-REM sleep in this species. EEG signals were obtained from the scalp of six monkeys housed in experimental conditions in a laboratory setting. Regarding the 1-21 Hz band, a significant correlation between left frontal and central regions was recorded during non-REM 2 sleep. In the REM sleep, a significant correlation between these cortical areas was seen in two bands: 1-3 and 3-13 Hz. This reflects a modification of the degree of coupling between the cortical areas studied, associated with the distinct stages of sleep. The intrahemispheric EEG correlation found between left perceptual and motor regions during sleep in the spider monkey could indicate activation of a neural circuit for the processing of environmental information that plays a critical role in monitoring the danger of nocturnal predation.

The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer.

The CD155/TIGIT axis can be co-opted during immune evasion in chronic viral infections and cancer. Pancreatic adenocarcinoma (PDAC) is a highly lethal malignancy, and immune-based strategies to combat this disease have been largely unsuccessful to date. We corroborate prior reports that a substantial portion of PDAC harbors predicted high-affinity MHC class I-restricted neoepitopes and extend these findings to advanced/metastatic disease. Using multiple preclinical models of neoantigen-expressing PDAC, we demonstrate that intratumoral neoantigen-specific CD8+ T cells adopt multiple states of dysfunction, resembling those in tumor-infiltrating lymphocytes of PDAC patients. Mechanistically, genetic and/or pharmacologic modulation of the CD155/TIGIT axis was sufficient to promote immune evasion in autochthonous neoantigen-expressing PDAC. Finally, we demonstrate that the CD155/TIGIT axis is critical in maintaining immune evasion in PDAC and uncover a combination immunotherapy (TIGIT/PD-1 co-blockade plus CD40 agonism) that elicits profound anti-tumor responses in preclinical models, now poised for clinical evaluation.

Canine mammary cancer tumour behaviour and patient survival time are associated with collagen fibre characteristics.

Precise diagnosis and prognosis are key in prevention and reduction of morbidity and mortality in all types of cancers. Here we show that changes in the collagen fibres in the main histological subtypes of canine mammary gland carcinomas are directly associated with the tumour behaviour and the animal survival time and could become a useful tool in helping with diagnosis. Imaging by second harmonic generation and multiphoton excited fluorescence microscopy were performed to evaluate the collagen and cellular segment parameters in cancer biopsies. We present a retrospective study of 45 cases of canine mammary cancer analysing 836 biopsies regions including normal mammary gland tissue, benign mixed tumours, carcinoma in mixed tumour, carcinosarcoma, micropapillary carcinoma and solid carcinoma. The image analyses and the comparison between the tumour types allowed to assess the collagen fibre changes during tumour progression. We demonstrate that the collagen parameters correlate with the clinical and pathological data, the results show that in neoplastic tissues, the collagen fibres are more aligned and shorter as compared to the normal tissues. There is a clear association of the mean fibre length with the dogs survival times, the carcinomas presenting shorter collagen fibres indicate a worse survival rate.

Methotrexate Triglutamate as a Determinant of Clinical Response in Mexican Patients With Rheumatoid Arthritis: Pharmacokinetics and Dose Recommendation.

Methotrexate is the gold standard treatment in rheumatoid arthritis. Once absorbed, it is internalized in cells, where glutamate residues are added to produce polyglutamated forms, which are responsible for the effect of methotrexate. The aim of the current study is to determine the relationship between methotrexate triglutamate concentrations and the clinical evolution in rheumatoid arthritis patients, as well as to characterize the variability in both features to propose strategies for low-dose methotrexate optimization. The quantification of methotrexate triglutamate concentration in red blood cells was performed through ultra-performance liquid chromatography coupled with mass spectrometry. Polymorphisms of genes involved in the formation of polyglutamates were determined by real-time polymerase chain reaction. A multivariate regression was performed to determine the covariates involved in the variability of methotrexate triglutamate concentrations and a population pharmacokinetics model was developed through nonlinear mixed-effects modeling. Disease activity score changed according to methotrexate triglutamate concentrations; patients with good response to treatment had higher concentrations than moderate or nonresponding patients. The methotrexate triglutamate concentrations were related to time under treatment, dose, red blood cells, and body mass index. A 1-compartment open model was selected to estimate the pharmacokinetic parameters; the typical total clearance (L/day) was determined as 1.45 * (body mass index/28 kg/m2 ) * (red blood cells/4.6 × 106 cells/µL) and the volume of distribution was 52.4 L, with an absorption rate of 0.0346/day and a fraction metabolized of 1.03%. Through the application of the model, the initial dose of methotrexate is proposed on the basis of stochastic simulations and considering methotrexate triglutamate concentrations found in responders patients.

Canine mammary cancer diagnosis from quantitative properties of nonlinear optical images.

We present nonlinear microscopy imaging results and analysis from canine mammary cancer biopsies. Second harmonic generation imaging allows information of the collagen structure in the extracellular matrix that together with the fluorescence of the cell regions of the biopsies form a base for comprehensive image analysis. We demonstrate an automated image analysis method to classify the histological type of canine mammary cancer using a range of parameters extracted from the images. The software developed for image processing and analysis allows for the extraction of the collagen fibre network and the cell regions of the images. Thus, the tissue properties are obtained after the segmentation of the image and the metrics are measured specifically for the collagen and the cell regions. A linear discriminant analysis including all the extracted metrics allowed to clearly separate between the healthy and cancerous tissue with a 91%-accuracy. Also, a 61%-accuracy was achieved for a comparison of healthy and three histological cancer subtypes studied.

Anthropometric and Genetic Factors Associated With the Exposure of Rifampicin and Isoniazid in Mexican Patients With Tuberculosis.

BACKGROUND: Tuberculosis (TB) remains a critical infectious, contagious disease worldwide with high prevalence and mortality rate. The directly observed treatment short-course therapy includes rifampicin (RMP) and isoniazid (INH) for at least 6 months. The purposes of this scheme are to interrupt the transmissibility of the Mycobacterium tuberculosis complex and to avoid secondary complications. Low plasma concentrations of these anti-TB drugs have been associated with extended treatment duration, therapeutic failure, and relapse. The determination of anthropometric, genetic, and clinical variables that may affect plasma concentrations of RMP and INH might facilitate the detection of patients at increased risk of therapeutic failure. METHODS: A prospective observational study was performed in patients with TB diagnosis. A fixed-dose combined formulation was administered following clinical guidelines, and 12 venous blood samples were collected within 24 hours after dose for the quantification of plasma levels of RMP and INH by high-performance liquid chromatography-ultraviolet. The plasma concentrations versus time for each drug in each patient were assessed by a noncompartmental approach to obtain Cmax, and the area under the concentration-time curve to the last observation point (AUC0-24 h) was calculated by the linear trapezoidal rule. Genetic polymorphisms of the enzyme involved in INH metabolism (NAT2) and proteins involved in RMP transport (glycoprotein-P and OATP1B1) were determined. RESULTS: A total of 34 patients aged between 18 and 72 years with the diagnosis of TB were included in the current study. A multivariate analysis was performed to determine the anthropometric and genetic characteristics that modified the Cmax and AUC0-24 h of RMP and INH. Results indicated that RMP Cmax and AUC0-24 h were affected by sex, dose/weight, and single nucleotide polymorphism of MDR1. In addition, age, body mass index, and NAT2 acetylator genotype were shown to determine the Cmax and AUC0-24 h for INH. CONCLUSIONS: Anthropometric, genetic, and dosage characteristics of Mexican patients with TB are an important source of risk for subtherapeutic plasma concentrations of anti-TB drugs. Factors such as lower-than-recommended RMP dose, male patients with TB, and MDR1 3435 genotype, in addition to age group, body mass index, and INH acetylator phenotype based on NAT2 genotype, should be considered during treatment.

Emotional facial expressions during REM sleep dreams.

Although motor activity is actively inhibited during rapid eye movement (REM) sleep, specific activations of the facial mimetic musculature have been observed during this stage, which may be associated with greater emotional dream mentation. Nevertheless, no specific biomarker of emotional valence or arousal related to dream content has been identified to date. In order to explore the electromyographic (EMG) activity (voltage, number, density and duration) of the corrugator and zygomaticus major muscles during REM sleep and its association with emotional dream mentation, this study performed a series of experimental awakenings after observing EMG facial activations during REM sleep. The study was performed with 12 healthy female participants using an 8-hr nighttime sleep recording. Emotional tone was evaluated by five blinded judges and final valence and intensity scores were obtained. Emotions were mentioned in 80.4% of dream reports. The voltage, number, density and duration of facial muscle contractions were greater for the corrugator muscle than for the zygomaticus muscle, whereas high positive emotions predicted the number (R2 0.601, p = 0.0001) and voltage (R2 0.332, p = 0.005) of the zygomaticus. Our findings suggest that zygomaticus events were predictive of the experience of positive affect during REM sleep in healthy women.

Ideal cardiovascular health score at the ELSA-Brasil baseline and its association with sociodemographic characteristics.

BACKGROUND: The American Heart Association's ideal cardiovascular health (ICH) define criteria for seven metrics, four classified as lifestyle factors (diet, physical activity, smoking and body-mass index) and four classified as health factors (smoking, blood pressure, fasting plasma glucose and total cholesterol). We aimed to analyze ICH scores at the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) baseline assessment and the associations with sociodemographic characteristics (age, sex, race, educational level, and family income). METHODS: We analyzed 13,356 ELSA-Brasil participants without cardiovascular disease using quasi-Poisson regression models to study the association between the ICH score and sociodemographic characteristics. RESULTS: Mean ICH scores were 2.5±1.3. Only 1047 (7.8%) participants had 5 or more ICH metrics. In adjusted models, age 65-74years was associated with lower ICH scores (-35.4%; 95% confidence interval [CI]: -37.6% to -33.1%) compared to age 35-44years. Women had higher ICH scores compared to men (+13.8%; 95%CI: +11.8% to +15.7%), mainly due to differences in the health factor ICH metrics. Participants of Black race had lower ICH scores compared to those of White race (-9.4%; 95%CI: -11.8% to -7.0%). Individuals with less than high school education had lower ICH scores than college-educated individuals (-17.2%; 95%CI: -20.0% to -14.2%). Low (<1245 USD) family income was also associated with lower ICH scores compared to those with high (≥3320 USD) family income (-4.4%, 95%CI: -7.2% to -1.6%). CONCLUSIONS: We found a low proportion of individuals with 5 or more ICH metrics. Age, sex, race, educational level and income were associated with ICH scores.

Expectativa de enfermeiros brasileiros acerca do acolhimento realizado na atenção primária em saúde / Expectation of Brazilian nurses about the reception held at the primary health care / Expectativa de las enfermeras brasileñas sobre la recepción celebrada en la atención primaria de salud

RESUMO Objetivo Conhecer as expectativas dos enfermeiros brasileiros em relação ao acolhimento realizado por eles na Atenção Primária em Saúde. Método Trata-se de um estudo qualitativo, orientado pela vertente da fenomenologia social de Alfred Schutz. Resultados Os enfermeiros relatam que o acolhimento é algo distante da realidade deles, dependente da política, da gestão, da população e da estrutura física do ambiente de trabalho. Conclusão Os achados deste estudo mostraram que a realidade do acolhimento realizado pelo enfermeiro na atenção primária à saúde é caracterizada por atendimentos destinados a avaliação de queixas agudas, e que a solução para o acolhimento ser ideal, proporcionar mudanças na relação entre ele e o usuário, eles necessitam de capacidades distantes de sua realidade, o que foi chamado neste estudo de saída mágica. Evidenciou-se que para os enfermeiros a reorganização do acolhimento e de seu processo de trabalho depende somente de fatores externos a suas ações, esquecendo-se do seu compromisso em oferecer um cuidado humanizado e baseado na aplicação de sua competência relacional.(AU)

ABSTRACT Objective To know the expectations of Brazilians nurses in relation to the reception held for them at the Primary Health Care. Method: This is a qualitative study based on the social phenomenology by Alfred Schutz. Results The nurses report that the host is something far from their reality, dependent on policy, management, population and physical structure of the workplace. Conclusion The findings of this study showed that the reality of care performed by nurses in primary health care is characterized by calls for the evaluation of acute complaints, and that the solution to the host be ideal, providing changes in the relationship between him and the user they require far capabilities of its reality, which was called in this study magic output. It was evident that for nurses the reorganization of the host and their work process depends only on external factors to their actions, forgetting its commitment to provide a humanized care and based on the application of its relational competence.(AU)

RESUMEN Objetivo Identificar las expectativas de los enfermeros brasileños en relación al acogimiento realizado por ellos en la Atención Primaria de Salud. Método Estudio cualitativo, con base en la fenomenología social de Alfred Schutz. Resultados Los enfermeros relatan que el acogimiento es algo lejano de la realidad de ellos, depende de la política, de la gestión, de la población y de la estructura física del ambiente de trabajo. Conclusión Los resultados de este estudio mostraron que la realidad del acogimiento realizado por el enfermeros en la atención primaria de salud se caracteriza por la atendencia destinados a la evaluación de quejas agudas, y la solución para que el acogimiento sea ideal, es proporcionar cambios en la relación entre él y el usuario, ellos necesitan de capacidades que están muy lejos de su realidad, que fue llamado en este estudio de salida de magia. Es cierto que para los enfermeros la reorganización del acogimiento y de su proceso de trabajo depende solamente de factores externos a sus acciones, olvidándose de su compromiso en ofrecer un cuidado humanizado y basado en la aplicación de su competencia relacional.(AU)

PTH/PTHrP Receptor Mediates Cachexia in Models of Kidney Failure and Cancer.

Cachexia is a wasting syndrome associated with elevated basal energy expenditure and loss of adipose and muscle tissues. It accompanies many chronic diseases including renal failure and cancer and is an important risk factor for mortality. Our recent work demonstrated that tumor-derived PTHrP drives adipose tissue browning and cachexia. Here, we show that PTH is involved in stimulating a thermogenic gene program in 5/6 nephrectomized mice that suffer from cachexia. Fat-specific knockout of PTHR blocked adipose browning and wasting. Surprisingly, loss of PTHR in fat tissue also preserved muscle mass and improved muscle strength. Similarly, PTHR knockout mice were resistant to cachexia driven by tumors. Our results demonstrate that PTHrP and PTH mediate wasting through a common mechanism involving PTHR, and there exists an unexpected crosstalk mechanism between wasting of fat tissue and skeletal muscle. Targeting the PTH/PTHrP pathway may have therapeutic uses in humans with cachexia.

[Expectation of Brazilian nurses about the reception held at the primary health care]. / Expectativa de enfermeiros brasileiros acerca do acolhimento realizado na atenção primária em saúde.

OBJECTIVE: To know the expectations of Brazilians nurses in relation to the reception held for them at the Primary Health Care. Method: This is a qualitative study based on the social phenomenology by Alfred Schutz. RESULTS: The nurses report that the host is something far from their reality, dependent on policy, management, population and physical structure of the workplace. CONCLUSION: The findings of this study showed that the reality of care performed by nurses in primary health care is characterized by calls for the evaluation of acute complaints, and that the solution to the host be ideal, providing changes in the relationship between him and the user they require far capabilities of its reality, which was called in this study magic output. It was evident that for nurses the reorganization of the host and their work process depends only on external factors to their actions, forgetting its commitment to provide a humanized care and based on the application of its relational competence.

Nicotinic α4 Receptor-Mediated Cholinergic Influences on Food Intake and Activity Patterns in Hypothalamic Circuits.

Nicotinic acetylcholine receptors (nAChRs) play an important role in regulating appetite and have been shown to do so by influencing neural activity in the hypothalamus. To shed light on the hypothalamic circuits governing acetylcholine's (ACh) regulation of appetite this study investigated the influence of hypothalamic nAChRs expressing the α4 subunit. We found that antagonizing the α4ß2 nAChR locally in the lateral hypothalamus with di-hydro-ß-erythroidine (DHßE), an α4 nAChR antagonist with moderate affinity, caused an increase in food intake following free access to food after a 12 hour fast, compared to saline-infused animals. Immunocytochemical analysis revealed that orexin/hypocretin (HO), oxytocin, and tyrosine hydroxylase (TH)-containing neurons in the A13 and A12 of the hypothalamus expressed the nAChR α4 subunit in varying amounts (34%, 42%, 50%, and 51%, respectively) whereas melanin concentrating hormone (MCH) neurons did not, suggesting that DHßE-mediated increases in food intake may be due to a direct activation of specific hypothalamic circuits. Systemic DHßE (2 mg/kg) administration similarly increased food intake following a 12 hour fast. In these animals a subpopulation of orexin/hypocretin neurons showed elevated activity compared to control animals and MCH neuronal activity was overall lower as measured by expression of the immediate early gene marker for neuronal activity cFos. However, oxytocin neurons in the paraventricular hypothalamus and TH-containing neurons in the A13 and A12 did not show differential activity patterns. These results indicate that various neurochemically distinct hypothalamic populations are under the influence of α4ß2 nAChRs and that cholinergic inputs to the lateral hypothalamus can affect satiety signals through activation of local α4ß2 nAChR-mediated transmission.

[Effect of partial and generalised epileptic seizures on sleep architecture in rats]. / Efecto de las crisis epilépticas parciales y generalizadas sobre la arquitectura del sueño en ratas.

INTRODUCTION: It is a well-known fact that epileptic seizures disrupt sleep, yet little information is available about sleep disorders according to the type of epileptic seizures. MATERIALS AND METHODS: The sleep architecture of rats was evaluated in polysomnography recordings 36 hours after inducing partial and generalised epileptic seizures in them. The epileptic seizures were induced by applying 50-100 IU of sodium G penicillin in the amygdala of the temporal lobe. RESULTS: Partial and generalised seizures triggered an increase in the latency of slow wave sleep (SWS) and rapid eye movement (REM) sleep. The number of episodes of the phases of wakefulness, SWS and REM sleep was reduced and the mean duration of the episodes of wakefulness and SWS increased, while that of REM sleep diminished. The total percentage of REM sleep diminished significantly. During the first period of light the partial and generalised seizures triggered an increase in wakefulness and a reduction in the phases of SWS and REM sleep. In the period of darkness, the SWS increased and wakefulness decreased, while there were no changes in REM sleep. In the second period of light, the percentages of the phases of wakefulness and SWS returned to control values and the percentage of REM sleep continued to be reduced. CONCLUSIONS: Changes in the structuring of sleep depend on the type of epileptic seizure that presents. Generalised epileptic seizures caused greater deterioration in REM sleep.

TITLE: Efecto de las crisis epilepticas parciales y generalizadas sobre la arquitectura del sueño en ratas.Introduccion. La alteracion del sueño producido por las crisis epilepticas se conoce; sin embargo, aun se tiene poca informacion de la alteracion en el sueño por el tipo de crisis epileptica. Materiales y metodos. Se evaluo la arquitectura del sueño de ratas en registros polisomnograficos de 36 horas tras inducirles crisis epilepticas parciales y generalizadas. Para la induccion de las crisis epilepticas se aplicaron in situ 50-100 UI de penicilina G sodica en la amigdala del lobulo temporal. Resultados. Las crisis parciales y generalizadas provocaron el aumento en la latencia del sueño de ondas lentas (SOL) y sueño de movimiento oculares rapidos (MOR). El numero de episodios de las fases de vigilia, SOL y sueño MOR disminuyo y la duracion media de los episodios de la vigilia y del SOL aumento, mientras que la del sueño MOR disminuyo. El porcentaje total del sueño MOR disminuyo significativamente. Durante el primer periodo de luz, las crisis parciales y generalizadas provocaron el incremento de la vigilia y la reduccion de las fases del SOL y sueño MOR. En el periodo de oscuridad, aumento el SOL, disminuyo la vigilia y no hubo cambios en el sueño MOR. En el segundo periodo de luz los porcentajes de las fases de vigilia y SOL regresaron a los valores control y el porcentaje del sueño MOR continuo disminuido. Conclusion. Los cambios en la organizacion del sueño dependen del tipo de crisis epileptica que se presenta. Las crisis epilepticas generalizadas provocaron mayor deterioro en el sueño MOR.

Melatonin role in experimental arthritis.

Our perception of the function of the pineal gland and its hormone melatonin has attained a new dimension during the last decade. Through melatonin, the pineal becomes a principal organ present in vertebrates involved in the control of rhythmic adaptations to daily and seasonal cycles. Melatonin is synthesized and secreted during the dark period of the light/dark cycle. The rhythmic nocturnal melatonin secretion is directly generated by the circadian clock and is entrained to a 24-hour period by the light-dark cycle. The periodic secretion of melatonin may be used as a circadian mediator to any system than can "read" the message. Melatonin acts as an arm of the circadian clock, giving a time-related signal to a number of body functions; one of them is the circadian organization of the immune response. This review discusses melatonin role in rheumatoid arthritis. Animal studies employing Freund's complete mycobacterial adjuvant (FCA) as a model of rheumatoid arthritis are described. Immune and neuroendocrine circadian rhythms were examined in FCA-injected rats, both in the preclinical phase of arthritis (2-3 days after FCA injection) as well as in the acute phase of the disease (18 days after FCA injection). In arthritic rats, the 24-h organization of immune and neuroendocrine responses becomes altered. Significant effects of immune response on diurnal rhythmicity of adenohypophysial and hypophysiotropic hormones occurred in arthritic rats. Melatonin treatment prevented alteration of 24-h rhythms of serum ACTH, prolactin and luteinizing hormone in rats injected with FCA. In addition, melatonin treatment prevented alteration of the 24-h variation in hypothalamic monoamine transmitter turnover during the preclinical phase of Freund's adjuvant arthritis in rats. A comparison between the inflammatory and immune responses elicited by physiological and pharmacological doses of melatonin in FCA arthritis is reported. Pinealectomized rats exhibited a significantly less pronounced inflammatory response, which was restored to normal by a low melatonin dose (0.3 microg/ml of drinking water), whereas a high melatonin dose (30 microg/ml) that resulted in a 50-60-fold increase in plasma melatonin, augmented the inflammatory and immune response. These results should be considered in the light of recent reports that rheumatoid arthritis patients have increased nocturnal plasma levels of melatonin and that their synovial macrophages respond to melatonin with an increased cytokine production.