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Repetitive mild traumatic brain injury (r-mTBI) has increasingly become recognised as a risk factor for the development of neurodegenerative diseases, many of which are characterised by tau pathology, metal dyshomeostasis and behavioural impairments. We aimed to characterise the status of tau and the involvement of iron dyshomeostasis in repetitive controlled cortical impact injury (5 impacts, 48 h apart) in 3-month-old C57Bl6 mice at the chronic (12-month) time point. We performed a battery of behavioural tests, characterised the status of neurodegeneration-associated proteins (tau and tau-regulatory proteins, amyloid precursor protein and iron-regulatory proteins) via western blot; and metal levels using bulk inductively coupled plasma-mass spectrometry (ICP-MS). We report significant changes in various ipsilateral iron-regulatory proteins following five but not a single injury, and significant increases in contralateral iron, zinc and copper levels following five impacts. There was no evidence of tau pathology or changes in tau-regulatory proteins following five impacts, although some changes were observed following a single injury. Five impacts resulted in significant gait deficits, mild anhedonia and mild cognitive deficits at 9–12 months post-injury, effects not seen following a single injury. To the best of our knowledge, we are the first to describe chronic changes in metals and iron-regulatory proteins in a mouse model of r-mTBI, providing a strong indication towards an overall increase in brain iron levels (and other metals) in the chronic phase following r-mTBI. These results bring to question the relevance of tau and highlight the involvement of iron dysregulation in the development and/or progression of neurodegeneration following injury, which may lead to new therapeutic approaches in the future. [ABSTRACT FROM AUTHOR]

Background and Purpose: Traumatic brain injury (TBI) remains a leading cause of mortality and morbidity in young adults. The role of iron in potentiating neurodegeneration following TBI has gained recent interest as iron deposition has been detected in the injured brain in the weeks to months post‐TBI, in both the preclinical and clinical setting. A failure in iron homeostasis can lead to oxidative stress, inflammation and excitotoxicity; and whether this is a cause or consequence of the long‐term effects of TBI remains unknown. Experimental Approach: We investigated the role of iron and the effect of therapeutic intervention using a brain‐permeable iron chelator, deferiprone, in a controlled cortical impact mouse model of TBI. An extensive assessment of cognitive, motor and anxiety/depressive outcome measures were examined, and neuropathological and biochemical changes, over a 3‐month period post‐TBI. Key Results: Lesion volume was significantly reduced at 3 months, which was preceded by a reduction in astrogliosis, microglia/macrophages and preservation of neurons in the injured brain at 2 weeks and/or 1 month post‐TBI in mice receiving oral deferiprone. Deferiprone treatment showed significant improvements in neurological severity scores, locomotor/gait performance and cognitive function, and attenuated anxiety‐like symptoms post‐TBI. Deferiprone reduced iron levels, lipid peroxidation/oxidative stress and altered expression of neurotrophins in the injured brain over this period. Conclusion and Implications: Our findings support a detrimental role of iron in the injured brain and suggest that deferiprone (or similar iron chelators) may be promising therapeutic approaches to improve survival, functional outcomes and quality of life following TBI. [ABSTRACT FROM AUTHOR]

Repetitive mild traumatic brain injury, commonly experienced following sports injuries, results in various secondary injury processes and is increasingly recognised as a risk factor for the development of neurodegenerative conditions such as chronic traumatic encephalopathy, which is characterised by tau pathology. We aimed to characterise the underlying pathological mechanisms that might contribute to the onset of neurodegeneration and behavioural changes in the less‐explored subacute (1‐month) period following single or repetitive controlled cortical impact injury (five impacts, 48 h apart) in 12‐week‐old male and female C57Bl6 mice. We conducted motor and cognitive testing, extensively characterised the status of tau and its regulatory proteins via western blot and quantified neuronal populations using stereology. We report that r‐mTBI resulted in neurobehavioural deficits, gait impairments and anxiety‐like behaviour at 1 month post‐injury, effects not seen following a single injury. R‐mTBI caused a significant increase in amyloid precursor protein, an increased trend towards tau phosphorylation and significant changes in kinase/phosphatase proteins that may promote a downstream increase in tau phosphorylation, but no changes in synaptic or neuroinflammatory markers. Lastly, we report neuronal loss in various brain regions following both single and repeat injuries. We demonstrate herein that repeated impacts are required to promote the initiation of a cascade of biochemical events that are consistent with the onset of neurodegeneration subacutely post‐injury. Identifying the timeframe in which these changes occur and the pathological mechanisms involved will be crucial for the development of future therapeutics to prevent the onset or mitigate the progression of neurodegeneration following r‐mTBI. [ABSTRACT FROM AUTHOR]

Repetitive mild traumatic brain injury (r-mTBI), commonly experienced by athletes and military personnel, causes changes in multiple intracellular pathways, one of which involves the tau protein. Tau phosphorylation plays a role in several neurodegenerative conditions including chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disorder linked to repeated head trauma. There is now mounting evidence suggesting that tau phosphorylation may be regulated by metal ions (such as iron, zinc and copper), which themselves are implicated in aging and neurodegenerative disorders such as Alzheimer's disease (AD). Recent work has also shown that a single TBI can result in age-dependent and region-specific modulation of metal ions. As such, this review explores the linkage among TBI, CTE, aging, and neurodegeneration, with a specific focus on the involvement of (and interaction between) tau pathology and metal dyshomeostasis. The authors highlight that metal dyshomeostasis has yet to be investigated in the context of repeat head trauma or CTE. Given the evidence that metal dyshomeostasis contributes to the onset and/or progression of neurodegeneration, and that CTE itself is a neurodegenerative condition, this brings to light an uncharted link that should be explored. The development of adequate models of r-mTBI and/or CTE will be crucial in deepening our understanding of the pathological mechanisms that drive the clinical manifestations in these conditions and also in the development of effective therapeutics targeted toward slowing progressive neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Objective: Breast cancer is a global public health issue. The disease can be diagnosed in both older and younger women, with the latter facing several dilemmas. Breastfeeding is of general concern to the scientific community as well as its connection with the prevention of breast cancer is being sought. The purpose of this review is to search for studies investigating the relationship between breast cancer and breastfeeding. Material and methods: The articles included in the present paper were searched in PubMed and Scopus databases according to PRISMA guidelines for systematic reviews. This systematic review sought primary studies investigating the relationship between breastfeeding and breast cancer and that were published in English between 2017-2022. Results: Seventeen articles that investigated the relationship of breast cancer with lactation duration, women's age, family history and lifestyle were included in the present review. Conclusions: It was found that, in most studies, breastfeeding could be evaluated as a protective factor of the disease. From all studied articles, the need for the design of additional studies investigating the relationship between breastfeeding and breast cancer emerges. [ABSTRACT FROM AUTHOR]

The opening of the tight junctions in the blood–brain barrier (BBB) following traumatic brain injury (TBI) is hypothesized to be sufficient to enable accumulation of large drug carriers, such as stealth liposomes, in a similar manner to the extravasation seen in tumor tissue via the enhanced permeability and retention (EPR) effect. The controlled cortical impact model of TBI was used to evaluate liposome accumulation in mice. Dual-radiolabeled PEGylated liposomes were administered either immediately after induction of TBI or at increasing times post-TBI to mimic the likely clinical scenario. The accumulation of radiolabel in the brain tissue ipsilateral and contralateral to the site of trauma, as well as in other organs, was evaluated. Selective influx of liposomes occurred at 0–8 h after injury, while the barrier closed between 8 and 24 hr after injury, consistent with reports on albumin infiltration. Significantly enhanced accumulation of liposomes occurred in mice subjected to TBI compared to anaesthetized controls, and accumulation was greater in the injured versus the contralateral side of the brain. Thus, stealth liposomes show potential to enhance drug delivery to the site of brain injury with a wide range of encapsulated therapeutic candidates. [ABSTRACT FROM AUTHOR]

Abstract: Purkinje neurons are a sensitive and specialised cell type important for fine motor movement and coordination. Purkinje cell damage manifests as motor incoordination and ataxia — a prominent feature of many human disorders including spinocerebellar ataxia and Huntington's disease. A correlation between Purkinje degeneration and excess cerebellar levels of tissue-type plasminogen activator (tPA) has been observed in multiple genetically-distinct models of ataxia. Here we show that Purkinje loss in a mouse model of Huntington's disease also correlates with a 200% increase in cerebellar tPA activity. That elevated tPA levels arise in a variety of ataxia models suggests that tPA is a common mediator of Purkinje damage. To address the specific contribution of tPA to cerebellar dysfunction we studied the T4 mice line that overexpresses murine tPA in postnatal neurons through the Thy1.2 gene promoter, which directs preferential expression to Purkinje cells within the cerebellum. Here we show that T4 mice develop signs of cerebellar damage within 10weeks of birth including atrophy of Purkinje cell soma and dendrites, astrogliosis, reduced molecular layer volume and altered gait. In contrast, T4 mice displayed no evidence of microgliosis, nor any changes in interneuron density, nor alteration in the cerebellar granular neuron layer. Thus, excess tPA levels may be sufficient to cause targeted Purkinje cell degeneration and ataxia. We propose that elevated cerebellar tPA levels exert a common pathway of Purkinje cell damage. Therapeutically lowering cerebellar tPA levels may represent a novel means of preserving Purkinje cell integrity and motor coordination across a wide range of neurodegenerative diseases. [Copyright &y& Elsevier]

The neurovascular unit provides a dynamic interface between the circulation and central nervous system. Disruption of neurovascular integrity occurs in numerous brain pathologies including neurotrauma and ischaemic stroke. Tissue plasminogen activator is a serine protease that converts plasminogen to plasmin, a protease that dissolves blood clots. Besides its role in fibrinolysis, tissue plasminogen activator is abundantly expressed in the brain where it mediates extracellular proteolysis. However, proteolytically active tissue plasminogen activator also promotes neurovascular disruption after ischaemic stroke; the molecular mechanisms of this process are still unclear. Tissue plasminogen activator is naturally inhibited by serine protease inhibitors (serpins): plasminogen activator inhibitor-1, neuroserpin or protease nexin-1 that results in the formation of serpin:protease complexes. Proteases and serpin:protease complexes are cleared through high-affinity binding to low-density lipoprotein receptors, but their binding to these receptors can also transmit extracellular signals across the plasma membrane. The matrix metalloproteinases are the second major proteolytic system in the mammalian brain, and like tissue plasminogen activators are pivotal to neurological function but can also degrade structures of the neurovascular unit after injury. Herein, we show that tissue plasminogen activator potentiates neurovascular damage in a dose-dependent manner in a mouse model of neurotrauma. Surprisingly, inhibition of activity following administration of plasminogen activator inhibitor-1 significantly increased cerebrovascular permeability. This led to our finding that formation of complexes between tissue plasminogen activator and plasminogen activator inhibitor-1 in the brain parenchyma facilitates post-traumatic cerebrovascular damage. We demonstrate that following trauma, the complex binds to low-density lipoprotein receptors, triggering the induction of matrix metalloproteinase-3. Accordingly, pharmacological inhibition of matrix metalloproteinase-3 attenuates neurovascular permeability and improves neurological function in injured mice. Our results are clinically relevant, because concentrations of tissue plasminogen activator: plasminogen activator inhibitor-1 complex and matrix metalloproteinase-3 are significantly elevated in cerebrospinal fluid of trauma patients and correlate with neurological outcome. In a separate study, we found that matrix metalloproteinase-3 and albumin, a marker of cerebrovascular damage, were significantly increased in brain tissue of patients with neurotrauma. Perturbation of neurovascular homeostasis causing oedema, inflammation and cell death is an important cause of acute and long-term neurological dysfunction after trauma. A role for the tissue plasminogen activator–matrix metalloproteinase axis in promoting neurovascular disruption after neurotrauma has not been described thus far. Targeting tissue plasminogen activator: plasminogen activator inhibitor-1 complex signalling or downstream matrix metalloproteinase-3 induction may provide viable therapeutic strategies to reduce cerebrovascular permeability after neurotrauma. [ABSTRACT FROM PUBLISHER]

Research has highlighted the wide impact of intimate partner violence (IPV) and the public health role of community health professionals in detection of victimized women. The purpose of this study was to identify postpartum emotional and physical abuse and to validate the Greek version of the Women Abuse Screening Tool (WAST) along with its sensitivity and specificity. Five hundred seventy-nine mothers within 12 weeks postpartum were recruited from the perinatal care registers of the Maternity Departments of two public hospitals in Athens, Greece. Participants were randomly selected by clinic or shift. The WAST and the Partner Violence Screen (PVS) surveys were administered in random order to the mothers from September 2007 to January 2008. The WAST was compared with the PVS as a criterion standard. Agreement between the screening instruments was examined. The psychometric measurements that were performed included: two independent sample t tests, reliability coefficients, explanatory factor analysis using a Varimax rotation, and Principal Components Method. Confirmatory analysis-also called structural equation modeling-of principal components was conducted by Linear Structural Relations. A receiver operating characteristic (ROC) analysis was carried out to evaluate the global functioning of the scale. Two hundred four (35.6%) of the mothers screened were identified as experiencing IPV. Scores on the WAST correlated well with those on the PVS; the internal consistency of the WAST Greek version-tested using Cronbach's alpha coefficient-was found to be 0.926 and that of Guttman's split-half coefficient was 0.924. Our findings confirm the multidimensionality of the WAST, demonstrating a two-factor structure. The area under ROC curve (AUC) was found to be 0.824, and the logistic estimate for the threshold score of 0/1 fitted the model sensitivity at 99.7% and model specificity at 64.4%. Our data confirm the validity of the Greek version of the WAST in identifying IPV. The validated Greek WAST scale could be used for screening purposes in both clinical practice and research. [ABSTRACT FROM AUTHOR]

The antifibrinolytic agent, tranexamic acid (TXA), an inhibitor of plasmin formation, currently is evaluated to reduce bleeding in various conditions, including traumatic brain injury (TBI). Because plasmin is implicated in inflammation and immunity, we investigated the effects of plasmin inhibition on the immune response after TBI in the presence or absence of induced pneumonia. Wild-type mice treated with vehicle or TXA or mice deficient in plasminogen (plg-/-) underwent TBI using the controlled cortical impact model. Mice were then subjected to Staphylococcus aureus induced pneumonia and the degree of immune competence determined. Significant baseline changes in the innate immune cell profile were seen in plg-/- mice with increases in spleen weight and white blood cell counts, and elevation in plasma interleukin-6 levels. The plg-/- mice subjected to TBI displayed no additional changes in these parameters at the 72 h or one week time point post-TBI. The plg-/- mice subjected to TBI did not exhibit any further increase in susceptibility to endogenous infection. Pneumonia was induced by intratracheal instillation of S. aureus. The TBI did not worsen pneumonia symptoms or delay recovery in plg-/- mice. Similarly, in wild type mice, treatment with TXA did not impact on the ability of mice to counteract pneumonia after TBI. Administration of TXA after TBI and subsequent pneumonia, however, altered the number and surface marker expression of several myeloid and lymphoid cell populations, consistent with enhanced immune activation at the 72 h time point. This investigation confirms the immune-modulatory properties of TXA, thereby highlighting its effects unrelated to inhibition of fibrinolysis. [ABSTRACT FROM AUTHOR]

Background Lysophosphatidic acid (LPA) is a bioactive phospholipid with a potentially causative role in neurotrauma. Blocking LPA signaling with the LPA-directed monoclonal antibody B3/Lpathomab is neuroprotective in the mouse spinal cord following injury. Findings Here we investigated the use of this agent in treatment of secondary brain damage consequent to traumatic brain injury (TBI). LPA was elevated in cerebrospinal fluid (CSF) of patients with TBI compared to controls. LPA levels were also elevated in a mouse controlled cortical impact (CCI) model of TBI and B3 significantly reduced lesion volume by both histological and MRI assessments. Diminished tissue damage coincided with lower brain IL-6 levels and improvement in functional outcomes. Conclusions This study presents a novel therapeutic approach for the treatment of TBI by blocking extracellular LPA signaling to minimize secondary brain damage and neurological dysfunction. [ABSTRACT FROM AUTHOR]

The neurovascular unit provides a dynamic interface between the circulation and central nervous system. Disruption of neurovascular integrity occurs in numerous brain pathologies including neurotrauma and ischaemic stroke. Tissue plasminogen activator is a serine protease that converts plasminogen to plasmin, a protease that dissolves blood clots. Besides its role in fibrinolysis, tissue plasminogen activator is abundantly expressed in the brain where it mediates extracellular proteolysis. However, proteolytically active tissue plasminogen activator also promotes neurovascular disruption after ischaemic stroke; the molecular mechanisms of this process are still unclear. Tissue plasminogen activator is naturally inhibited by serine protease inhibitors (serpins): plasminogen activator inhibitor-1, neuroserpin or protease nexin-1 that results in the formation of serpin:protease complexes. Proteases and serpin:protease complexes are cleared through high-affinity binding to low-density lipoprotein receptors, but their binding to these receptors can also transmit extracellular signals across the plasma membrane. The matrix metalloproteinases are the second major proteolytic system in the mammalian brain, and like tissue plasminogen activators are pivotal to neurological function but can also degrade structures of the neurovascular unit after injury. Herein, we show that tissue plasminogen activator potentiates neurovascular damage in a dose-dependent manner in a mouse model of neurotrauma. Surprisingly, inhibition of activity following administration of plasminogen activator inhibitor-1 significantly increased cerebrovascular permeability. This led to our finding that formation of complexes between tissue plasminogen activator and plasminogen activator inhibitor-1 in the brain parenchyma facilitates post-traumatic cerebrovascular damage. We demonstrate that following trauma, the complex binds to low-density lipoprotein receptors, triggering the induction of matrix metalloproteinase-3. Accordingly, pharmacological inhibition of matrix metalloproteinase-3 attenuates neurovascular permeability and improves neurological function in injured mice. Our results are clinically relevant, because concentrations of tissue plasminogen activator: plasminogen activator inhibitor-1 complex and matrix metalloproteinase-3 are significantly elevated in cerebrospinal fluid of trauma patients and correlate with neurological outcome. In a separate study, we found that matrix metalloproteinase-3 and albumin, a marker of cerebrovascular damage, were significantly increased in brain tissue of patients with neurotrauma. Perturbation of neurovascular homeostasis causing oedema, inflammation and cell death is an important cause of acute and long-term neurological dysfunction after trauma. A role for the tissue plasminogen activator-matrix metalloproteinase axis in promoting neurovascular disruption after neurotrauma has not been described thus far. Targeting tissue plasminogen activator: plasminogen activator inhibitor-1 complex signalling or downstream matrix metalloproteinase-3 induction may provide viable therapeutic strategies to reduce cerebrovascular permeability after neurotrauma. [ABSTRACT FROM AUTHOR]

Background: Lysophosphatidic acid (LPA) is a bioactive phospholipid with a potentially causative role in neurotrauma. Blocking LPA signaling with the LPA-directed monoclonal antibody B3/Lpathomab is neuroprotective in the mouse spinal cord following injury.Findings: Here we investigated the use of this agent in treatment of secondary brain damage consequent to traumatic brain injury (TBI). LPA was elevated in cerebrospinal fluid (CSF) of patients with TBI compared to controls. LPA levels were also elevated in a mouse controlled cortical impact (CCI) model of TBI and B3 significantly reduced lesion volume by both histological and MRI assessments. Diminished tissue damage coincided with lower brain IL-6 levels and improvement in functional outcomes.Conclusions: This study presents a novel therapeutic approach for the treatment of TBI by blocking extracellular LPA signaling to minimize secondary brain damage and neurological dysfunction. [ABSTRACT FROM AUTHOR]