The mystery behind the origin of the pain and the difficulty to propose methodologies for its quantitative characterization fascinated philosophers (and then scientists) from the dawn of our modern society. Nowadays, studying patterns of information flow in mesoscale activity of brain networks is a valuable strategy to offer answers in computational neuroscience. In this paper, complex network analysis was performed on the time-varying brain functional connectomes of a rat model of persistent peripheral neuropathic pain, obtained by means of local field potential and spike train analysis. A wide range of topological network measures (14 in total, the code is publicly released at: https://github.com/biomedical-cybernetics/topological_measures_wide_analysis) was employed to quantitatively investigate the rewiring mechanisms of the brain regions responsible for development and upkeep of pain along time, from three hours to 16 days after nerve injury. The time trend (across the days) of each network measure was correlated with a behavioural test for rat pain, and surprisingly we found that the rewiring mechanisms associated with two local topological measure, the local-community-paradigm and the power-lawness, showed very high statistical correlations (higher than 0.9, being the maximum value 1) with the behavioural test. We also disclosed clear functional connectivity patterns that emerged in association with chronic pain in the primary somatosensory cortex (S1) and ventral posterolateral (VPL) nuclei of thalamus. This study represents a pioneering attempt to exploit network science models in order to elucidate the mechanisms of brain region re-wiring and engram formations that are associated with chronic pain in mammalians. We conclude that the local-community-paradigm is a model of complex network organization that triggers a local learning rule, which seems associated to processing, learning and memorization of chronic pain in the brain functional connectivity. This rule is based exclusively on the network topology, hence was named epitopological learning.

Plasmacytoid dendritic cells (pDCs) regulate innate and adaptive immunity. Neurotrophins and their receptors control the function of neuronal tissue. In addition, they have been demonstrated to be part of the immune response but little is known about the effector immune cells involved. We report, for the first time, the expression and immune-regulatory function of the low affinity neurotrophin receptor p75 neurotrophin receptor (p75NTR) by the antigen-presenting pDCs, mediated by toll-like receptor (TLR) 9 activation and differential phosphorylation of interferon regulatory factor 3 and 7. The modulation of p75NTR on pDCs significantly influences disease progression of asthma in an ovalbumin-induced mouse model mediated by the TLR9 signaling pathway. p75NTR activation of pDCs from patients with asthma increased allergen-specific T cell proliferation and cytokine secretion in nerve growth factor concentration-dependent manner. Further, p75NTR activation of pDCs delayed the onset of autoimmune diabetes in RIP-CD80GP mice and aggravated graft-versus-host disease in a xenotransplantation model. Thus, p75NTR signaling on pDCs constitutes a new and critical mechanism connecting neurotrophin signaling and immune response regulation with great therapeutic potential for a variety of immune disorders.

BACKGROUND: Prolonged mechanical ventilation for acute medical conditions increases the risk of chronic critical illness (CCI). Close family members are confronted with the life-threatening condition of the CCI patients and are prone to develop posttraumatic stress disorder affecting their health-related quality of life (HRQL). Main aim of the present study was to investigate patient- and family-related risk factors for posttraumatic stress and decreased HRQL in family members of CCI patients. METHODS: In a cross-sectional design nested within a prospective longitudinal cohort study, posttraumatic stress symptoms and quality of life were assessed in family members of CCI patients (n = 83, aged between 18 and 72 years) up to 6 months after transfer from ICU at acute care hospital to post-acute rehabilitation. Patients admitted a large rehabilitation hospital for ventilator weaning. The Posttraumatic Stress Scale-10 and the Euro-Quality of life-5D-3L were applied in both patients and their family members via telephone interview. RESULTS: A significant proportion of CCI patients and their family members (14.5 and 15.7 %, respectively) showed clinically relevant scores of posttraumatic stress. Both CCI patients and family members reported poorer HRQL than a normative sample. Factors independently associated with posttraumatic stress in family members were the time following ICU discharge (β = .256, 95 % confidence interval .053-.470) and the patients\' diagnosis of PTSD (β = .264, 95 % confidence interval .045-.453). Perceived satisfaction with the relationship turned out to be a protective factor for posttraumatic stress in family members of CCI patients (β = -.231, 95 % confidence interval -.423 to -.015). Regarding HRQL in family members, patients\' acute posttraumatic stress at ICU (β = -.290, 95 % confidence interval -.360 to -.088) and their own posttraumatic stress 3 to 6 months post-transfer (β = -.622, 95 % confidence interval -.640 to -.358) turned out to be significant predictors. CONCLUSIONS: Posttraumatic stress and HRQL should be routinely assessed in family members of CCI patients at regular intervals starting early at ICU. Preventive family-centered interventions are needed to improve posttraumatic stress and HRQL in both patients and their family members.

There is no consensus about the hemodynamic significance and, therefore, the need to treat a persistent ductus arteriosus in preterm newborns. Since the diagnosis of a hemodynamically significant persistent ductus arteriosus (hsPDA) is made by a summary of non-uniform echo-criteria in combination with the clinical deterioration of the preterm neonate, standardized clinical and ultrasound scoring systems are needed. The objective of this study was the development of a clinical score for the detection and follow-up of hsPDA. In this observational cohort study of 154 preterm neonates (mean gestational age 28.1 weeks), clinical signs for the development of hsPDA were recorded in a standardized score and compared to echocardiography. Analyzing the significance of single score parameters compared to the diagnosis by echocardiography, we developed a short clinical score (calculated sensitivity 84% and specificity 80%). In conclusion, this clinical diagnostic PDA score is non-invasive and quickly to implement. The continuous assessment of defined clinical parameters allows for a more precise diagnosis of hemodynamic significance of PDA and, therefore, should help to detect preterm neonates needing PDA-treatment. The score, therefore, allows a more targeted use of echocardiography in these very fragile preterm neonates.

BACKGROUND: Prolonged mechanical ventilation for acute medical conditions increases the risk of chronic critical illness (CCI). Close family members are confronted with the life-threatening condition of the CCI patients and are prone to develop posttraumatic stress disorder affecting their health-related quality of life (HRQL). Main aim of the present study was to investigate patient- and family-related risk factors for posttraumatic stress and decreased HRQL in family members of CCI patients. METHODS: In a cross-sectional design nested within a prospective longitudinal cohort study, posttraumatic stress symptoms and quality of life were assessed in family members of CCI patients (n = 83, aged between 18 and 72 years) up to 6 months after transfer from ICU at acute care hospital to post-acute rehabilitation. Patients admitted a large rehabilitation hospital for ventilator weaning. The Posttraumatic Stress Scale-10 and the Euro-Quality of life-5D-3L were applied in both patients and their family members via telephone interview. RESULTS: A significant proportion of CCI patients and their family members (14.5 and 15.7 %, respectively) showed clinically relevant scores of posttraumatic stress. Both CCI patients and family members reported poorer HRQL than a normative sample. Factors independently associated with posttraumatic stress in family members were the time following ICU discharge (β = .256, 95 % confidence interval .053-.470) and the patients\' diagnosis of PTSD (β = .264, 95 % confidence interval .045-.453). Perceived satisfaction with the relationship turned out to be a protective factor for posttraumatic stress in family members of CCI patients (β = -.231, 95 % confidence interval -.423 to -.015). Regarding HRQL in family members, patients\' acute posttraumatic stress at ICU (β = -.290, 95 % confidence interval -.360 to -.088) and their own posttraumatic stress 3 to 6 months post-transfer (β = -.622, 95 % confidence interval -.640 to -.358) turned out to be significant predictors. CONCLUSIONS: Posttraumatic stress and HRQL should be routinely assessed in family members of CCI patients at regular intervals starting early at ICU. Preventive family-centered interventions are needed to improve posttraumatic stress and HRQL in both patients and their family members.

The mystery behind the origin of the pain and the difficulty to propose methodologies for its quantitative characterization fascinated philosophers (and then scientists) from the dawn of our modern society. Nowadays, studying patterns of information flow in mesoscale activity of brain networks is a valuable strategy to offer answers in computational neuroscience. In this paper, complex network analysis was performed on the time-varying brain functional connectomes of a rat model of persistent peripheral neuropathic pain, obtained by means of local field potential and spike train analysis. A wide range of topological network measures (14 in total, the code is publicly released at: https://github.com/biomedical-cybernetics/topological_measures_wide_analysis) was employed to quantitatively investigate the rewiring mechanisms of the brain regions responsible for development and upkeep of pain along time, from three hours to 16 days after nerve injury. The time trend (across the days) of each network measure was correlated with a behavioural test for rat pain, and surprisingly we found that the rewiring mechanisms associated with two local topological measure, the local-community-paradigm and the power-lawness, showed very high statistical correlations (higher than 0.9, being the maximum value 1) with the behavioural test. We also disclosed clear functional connectivity patterns that emerged in association with chronic pain in the primary somatosensory cortex (S1) and ventral posterolateral (VPL) nuclei of thalamus. This study represents a pioneering attempt to exploit network science models in order to elucidate the mechanisms of brain region re-wiring and engram formations that are associated with chronic pain in mammalians. We conclude that the local-community-paradigm is a model of complex network organization that triggers a local learning rule, which seems associated to processing, learning and memorization of chronic pain in the brain functional connectivity. This rule is based exclusively on the network topology, hence was named epitopological learning.

Plasmacytoid dendritic cells (pDCs) regulate innate and adaptive immunity. Neurotrophins and their receptors control the function of neuronal tissue. In addition, they have been demonstrated to be part of the immune response but little is known about the effector immune cells involved. We report, for the first time, the expression and immune-regulatory function of the low affinity neurotrophin receptor p75 neurotrophin receptor (p75NTR) by the antigen-presenting pDCs, mediated by toll-like receptor (TLR) 9 activation and differential phosphorylation of interferon regulatory factor 3 and 7. The modulation of p75NTR on pDCs significantly influences disease progression of asthma in an ovalbumin-induced mouse model mediated by the TLR9 signaling pathway. p75NTR activation of pDCs from patients with asthma increased allergen-specific T cell proliferation and cytokine secretion in nerve growth factor concentration-dependent manner. Further, p75NTR activation of pDCs delayed the onset of autoimmune diabetes in RIP-CD80GP mice and aggravated graft-versus-host disease in a xenotransplantation model. Thus, p75NTR signaling on pDCs constitutes a new and critical mechanism connecting neurotrophin signaling and immune response regulation with great therapeutic potential for a variety of immune disorders.

Background Novel theranostic options for high-risk non-muscle invasive bladder cancer are urgently needed. This requires a thorough evaluation of experimental approaches in animal models best possibly reflecting human disease before entering clinical studies. Although several bladder cancer xenograft models were used in the literature, the establishment of an orthotopic bladder cancer model in mice remains challenging. Methods Luciferase-transduced UM-UC-3LUCK1 bladder cancer cells were instilled transurethrally via 24G permanent venous catheters into athymic NMRI and BALB/c nude mice as well as into SCID-beige mice. Besides the mouse strain, the pretreatment of the bladder wall (trypsin or poly-L-lysine), tumor cell count (0.5 × 106–5.0 × 106) and tumor cell dwell time in the murine bladder (30 min – 2 h) were varied. Tumors were morphologically and functionally visualized using bioluminescence imaging (BLI), magnetic resonance imaging (MRI), and positron emission tomography (PET). Results Immunodeficiency of the mouse strains was the most important factor influencing cancer cell engraftment, whereas modifying cell count and instillation time allowed fine-tuning of the BLI signal start and duration – both representing the possible treatment period for the evaluation of new therapeutics. Best orthotopic tumor growth was achieved by transurethral instillation of 1.0 × 106 UM-UC-3LUCK1 bladder cancer cells into SCID-beige mice for 2 h after bladder pretreatment with poly-L-lysine. A pilot PET experiment using 68Ga-cetuximab as transurethrally administered radiotracer revealed functional expression of epidermal growth factor receptor as representative molecular characteristic of engrafted cancer cells in the bladder. Conclusions With the optimized protocol in SCID-beige mice an applicable and reliable model of high-risk non-muscle invasive bladder cancer for the development of novel theranostic approaches was established.

On the way towards a more biobased economy, the sustainable use of global wood resources remains a challenge as several trade-offs arise, e.g., from an increased energetic use of wood, an increased use of innovative but probably less recyclable wood composites, or from the need to conserve other forest ecosystem services. The aim of this study is to identify existing environmental indicators and methods for an evaluation of the sustainability of wood products in consideration of all life cycle stages, site-dependent aspects and later use in corporate decision-making. We chose a systematic literature review to answer the research questions explicitly and comprehensively. Qualitative content analysis was used to code indicators and scientific methods according to the Pressure-State-Response (PSR) framework. The sample (N = 118) is characterized by a high number of life cycle assessment (LCA) case studies. In 51% of all studies, the study authors use a combination of different methods. A total of 78 indicators and 20 site-dependent aspects could be identified in the sample. The study findings represent a first step towards a holistic environmental assessment of wood products.

The morbidity and societal burden of youth bipolar spectrum disorders (BSD) are high. These disorders are multisystemic in that adult populations there are clear interactions with inflammatory processes and steroidal physiological systems. There are much less data concerning these areas of study in youth populations with BSD. This is surprising given the association of youth-onset BSD with puberty and its associated physiological changes. In this mini-review, we overview the theoretical role of inflammatory processes and steroidal physiological systems in youth BSD, describe the greater literature in adult populations, detail the literature in youth populations when available, and overview current proposed molecular mechanistic pathways and interaction effects based on the available data. We also attend to the interplay of this complex system with body composition and weight gain, an especially important consideration in relation to the role of second generation antipsychotics as the first line treatment for youth with BSD in major clinical guidelines. A developmental model of early onset BSD for boys is hypothesized with pubertal hormonal changes increasing risk for first (hypo-)manic/depressive episode. The dramatic androgen rise during puberty might be relevant for first onset of BSD in boys. A shift from general hypercortisolism driven by glucocorticoid resistance to hypocortisolism with further disease progression is assumed, while increased levels of inflammation are functionally associated with endocrine dysregulation. The interacting role of overweight body habitus and obesity in youth with BSD further indicates leptin resistance to be a central moderator of the dynamic neurobiology of BSD in youth. The intent of this mini-review is to advance our knowledge of youth BSD as multisystemic disorders with important contributions from endocrinology and immunology based on a developmental perspective. This knowledge can influence current clinical care and more importantly inform future research.