Brief versus long maternal separation in lactating rats: Consequences on maternal behavior, emotionality, and brain oxytocin receptor binding

Maternal separation is a widely used animal model to study early life adversity in offspring. However, only a few studies have focused on the impact of disrupting the maternal bond from the mother's perspective. Such studies reveal alterations in behavior, whereas the underlying neuroendocrine mechanisms remain largely unknown. In this study, we compared the consequences of daily brief maternal separation (BMS; 15 min) versus long maternal separation (LMS; 180 min) during the first week postpartum with respect to behavioral and neuroendocrine changes in lactating Sprague–Dawley dams. Mothers were tested for their maternal care before and after separation, maternal motivation to retrieve pups, as well as anxiety-related and stress-coping behaviors. In addition, we analyzed their basal plasma corticosterone levels and oxytocin receptor binding in selected brain regions of the limbic system and maternal network. LMS dams showed higher levels of behavioral alterations compared to BMS and non-maternally separated (NMS) dams, including increased licking and grooming of the pups and decreased maternal motivation. Anxiety-related behavior was not affected by either separation paradigm, whereas passive stress-coping behavior tended to increase in the LMS group. Plasma corticosterone concentrations were not different between groups. Oxytocin receptor binding was higher in the medial preoptic area and tended to be higher in the prelimbic cortex of LMS dams, only. Our results demonstrate that especially daily prolonged maternal separation impacts on the mothers' behavior and oxytocin system, which suggests that enhanced oxytocin receptor binding could be a compensatory mechanism for potentially decreased central oxytocin release due to limited pup contact

Experimental approach for the study of SOFC cathodes

The suitability of impedance measurements in Solid Oxide Fuel Cells (SOFCs) is an important concern, especially in case of measuring separately the behaviour of one of the electrode when an overvoltage is applied. In this case a thin electrolyte-supported cell with the RE (Reference Electrode) coplanar with the WE (Working Electrode) is experimentally convenient, but many authors highlighted that incorrect results can be obtained if an inappropriate geometric configuration is used. In this work LSM cathodes ((La0.8Sr0.2)MnO3-x) were investigated in a Yttria-stabilised Zirconia (YSZ) electrolyte-supported cell, using an electrolyte 3 mm thick. Two types of cells were prepared: the first (Cell1) according to the geometric requirements suggested in literature: little WE (diameter 3 mm) aligned to the CE (Counter Electrode) and with equal Rpol(polarisation resistance) and time constant; RE co-planar around the WE and placed at a distance greater than three-electrolyte thicknesses from the WE; the second one (Cell2) equal to Cell1 but with a bigger WE (diameter 8 mm). Impedance measurements were carried out both in two- and three- electrode configuration, at OCV (Open Circuit Voltage) and under applied overpotentials. A preliminary comparison between the results extracted from Cell2 at two- and three- electrodes confirms that a thick electrolyte allows extracting suitable three-electrode impedance results in case of OCV and small overpotentials. On the other side, when an overpotential over 0.2 V is applied, a comparison between Cell1 and Cell2 gives quite different results. The investigation here presented considers also an experimental approach useful for the comprehension of the main phenomena governing the kinetic of the process

CRF binding protein activity in the hypothalamic paraventricular nucleus is essential for stress adaptations and normal maternal behaviour in lactating rats

To ensure the unrestricted expression of maternal behaviour peripartum, activity of the corticotropin-releasing factor (CRF) system needs to be minimised. CRF binding protein (CRF-BP) might be crucial for this adaptation, as its primary function is to sequester freely available CRF and urocortin1, thereby dampening CRF receptor (CRF-R) signalling. So far, the role of CRF-BP in the maternal brain has barely been studied, and a potential role in curtailing activation of the stress axis is unknown. We studied gene expression for CRF-BP and both CRF-R within the paraventricular nucleus (PVN) of the hypothalamus. In lactating rats, Crh-bp expression in the parvocellular PVN was significantly higher and Crh-r1 expression in the PVN significantly lower compared to virgin rats. Acute CRF-BP inhibition in the PVN with infusion of CRF(6–33) increased basal plasma corticosterone concentrations under unstressed conditions in dams. Furthermore, while acute intra-PVN infusion of CRF increased corticosterone secretion in virgin rats, it was ineffective in vehicle (VEH)-pre-treated lactating rats, probably due to a buffering effect of CRF-BP. Indeed, pre-treatment with CRF(6–33) reinstated a corticosterone response to CRF in lactating rats, highlighting the critical role of CRF-BP in maintaining attenuated stress reactivity in lactation. To our knowledge, this is the first study linking hypothalamic CRF-BP activity to hypothalamic-pituitary-adrenal axis regulation in lactation. In terms of behaviour, acute CRF-BP inhibition in the PVN under non-stress conditions reduced blanket nursing 60 min and licking/grooming 90 min after infusion compared to VEH-treated rats, while increasing maternal aggression towards an intruder. Lastly, chronic intra-PVN inhibition of CRF-BP strongly reduced maternal aggression, with modest effects on maternal motivation and care. Taken together, intact activity of the CRF-BP in the PVN during the postpartum period is essential for the dampened responsiveness of the stress axis, as well as for the full expression of appropriate maternal behaviour

GAA variants and phenotypes among 1,079 patients with Pompe disease: Data from the Pompe Registry

Identification of variants in the acid α-glucosidase (GAA) gene in Pompe disease provides valuable insights and systematic overviews are needed. We report on the number, nature, frequency, and geographic distribution of GAA sequence variants listed in the Pompe Regis

Epstein-Barr Virus and immune status imprint the immunogenomics of non-Hodgkin lymphomas occurring in immune-suppressed environments

Non-Hodgkin lymphomas (NHL) commonly occur in immune-deficient (ID) patients, both HIV-infected and transplanted, and are often EBV-driven with cerebral localization, raising the question of tumor immunogenicity, a critical issue for treatment responses. We investigated the immunogenomics of 68 lymphoproliferative disorders from 51 ID (34 posttransplant, 17 HIV+) and 17 immunocompetent patients. Overall, 72% were Large B Cells Lymphoma (LBCL) and 25% were primary central-nervous-system lymphoma (PCNSL) while 40% were EBV-positive. Tumor whole-exome and RNA sequencing, along with a bioinformatics pipeline allowed analysis of tumor mutational burden (TMB), tumor landscape and microenvironment (TME) and prediction of tumor neoepitopes. Both TMB (2.2 vs 3.4/Mb, p=0.001) and neoepitopes numbers (40 vs 200, p=0.00019) were lower in EBVpositive than in EBV-negative NHL, regardless of the immune status. In contrast both EBV and the immune status influenced the tumor mutational profile, with HNRNPF and STAT3 mutations exclusively observed in EBV-positive and ID NHL, respectively. Peripheral blood T-cell responses against tumor neoepitopes were detected in all EBV-negative cases but in only half EBV-positive ones, including responses against IgH-derived MHC-class-II restricted neoepitopes. The TME analysis showed higher CD8 T cell infiltrates in EBVpositive vs EBV-negative NHL, together with a more tolerogenic profile composed of Tregs, type-M2 macrophages and an increased expression of negative immune-regulators. Our results highlight that the immunogenomics of NHL in patients with immunodeficiency primarily relies on the tumor EBV status, while T cell recognition of tumor- and IgH-specific neoepitopes is conserved in EBV-negative patients, offering potential opportunities for future T cell-based immune therapies

Exploring productivity and collaboration in Australian Indigenous health research, 1995-2008

BACKGROUND Building research capacity in Indigenous health has been recognised as integral in efforts to reduce the significant health disparities between Indigenous and other Australian populations. The past few decades have seen substantial changes in funding policy for Australian Indigenous health research, including increases in overall expenditure and a greater focus on collaborative and priority-driven research. However, whether these policy shifts have resulted in any change to the structure of the research workforce in this field is unclear. We examine research publications in Australian Indigenous health from 1995–2008 to explore trends in publication output, key themes investigated, and research collaborations. METHODS A comprehensive literature search was undertaken to identify research publications about Australian Indigenous health from 1995–2008. Abstracts of all publications identified were reviewed by two investigators for relevance. Eligible publications were classified according to key themes. Social network analyses of co-authorship patterns were used to examine collaboration in the periods 1995–1999, 2000–2004 and 2005–2008. RESULTS Nine hundred and fifty three publications were identified. Over time, the number of publications per year increased, particularly after 2005, and there was a substantial increase in assessment of health service-related issues. Network analyses revealed a highly collaborative core group of authors responsible for the majority of outputs, in addition to a series of smaller separate groups. In the first two periods there was a small increase in the overall network size (from n = 583 to n = 642 authors) due to growth in collaborations around the core. In the last period, the network size increased considerably (n = 1,083), largely due to an increase in the number and size of separate groups. The general size of collaborations also increased in this period. CONCLUSIONS In the past few decades there has been substantial development of the research workforce in Indigenous health, characterised by an increase in authors and outputs, a greater focus on some identified priority areas and sustained growth in collaborations. This has occurred in conjunction with significant changes to funding policy for Indigenous health research, suggesting that both productivity and collaboration may be sensitive to reform, including the provision of dedicated funding.Alice R Rumbold, Joan Cunningham, Brydie Purbrick and Jenny M Lewi

Global Retinoblastoma Presentation and Analysis by National Income Level.

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs

Dysfunctions of brain oxytocin signaling: Implications for poor mothering

Good mothering has profound impact on both the mother's and the young's well-being. Consequently, experiencing inadequate maternal care - or even neglect - in the first stages of life is a major risk factor for the development of psychiatric disorders, and even for poor parenting towards the future offspring. Thus, understanding the neurobiological basis of maternal neglect becomes crucial. Along with other neurotransmitters and neuropeptides, oxytocin (OXT) has long been known as one of the main modulators of maternal behavior. In rodents, disruptions of central OXT transmission have been associated with poor maternal responses, like impaired onset of nursing behaviors, and reduced care and defense of the pups. Importantly, such behavioral and molecular deficits can be transmitted through generations, creating a vicious circle of low-quality maternal behavior. Similarly, evidence from human studies shows that OXT signaling is defective in conditions of inadequate mothering and child neglect. On those premises, this review aims at providing a comprehensive overview of animal and human studies linking perturbed OXT transmission to poor maternal behavior. Considering the important fallouts of inadequate maternal responses, we believe that unraveling the alterations in OXT transmission might provide useful insights for a better understanding of maternal neglect and, ultimately, for future intervention approaches

Anti-stress Properties of Atypical Antipsychotics

Stress exposure represents a major environmental risk factor for schizophrenia and other psychiatric disorders, as it plays a pivotal role in the etiology as well as in the manifestation of disease symptomatology. It may be inferred that pharmacological treatments must be able to modulate the behavioral, functional, and molecular alterations produced by stress exposure to achieve significant clinical outcomes. This review aims at examining existing clinical and preclinical evidence that supports the ability of atypical antipsychotic drugs (AAPDs) to modulate stress-related alterations. Indeed, while the pharmacodynamic differences between AAPDs have been extensively characterized, less is known on their ability to regulate downstream mechanisms that are critical for functional recovery and patient stabilization. We will discuss stress-related mechanisms, spanning from neuroendocrine function to inflammation and neuronal plasticity, which are relevant for the manifestation of schizophrenic symptomatology, and we will discuss if and how AAPDs may interfere with such mechanisms. Considering the impact of stress in everyday life, we believe that a better understanding of the potential effects of AAPDs on stress-related mechanisms may provide novel and important insights for improving therapeutic strategies aimed at promoting coping mechanisms and enhancing the quality of life of patients affected by psychiatric disorders

Assessing awareness of appropriate responses to symptoms of stroke

Objective: The study explored (1) the level of awareness, and associates of greater awareness, of the appropriate action to take in response to stroke symptoms; and (2) actions taken in response to potential stroke symptoms, among general practice patients. Methods: Patients attending general practice clinics in New South Wales, Australia completed a paper and pencil survey. Results: 308 participants returned the survey. 76% indicated they would call an ambulance within 10. min for 'difficulty speaking or understanding others, with blurred vision (in one eye), and face, arm or leg weakness or numbness (on one side of the body)'. Having a first degree relative with a history of stroke was significantly associated with greater awareness of the appropriate action to take in response to stroke symptoms. Of those reporting they had experienced 'dizziness, loss of balance or an unexplained fall' 80% did not call an ambulance at the time of experiencing this symptom. Conclusion: There appears to be high awareness of the appropriate response to take for stroke symptoms among this sample, however this does not translate into actions when individuals experience a potential stroke symptom. Practice implications: Education campaigns should be targeted towards individuals without a family history of stroke