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The low efficacy of antipsychotic drugs (e.g., clozapine) for negative symptoms and cognitive impairment has led to the introduction of adjuvant therapies. Because previous data suggest the procognitive potential of the antidiabetic drug metformin, this study aimed to assess the effects of chronic clozapine and metformin oral administration (alone and in combination) on locomotor and exploratory activities and cognitive function in a reward-based test in control and a schizophrenia-like animal model (Wisket rats). As impaired dopamine D1 receptor (D 1 R) function might play a role in the cognitive dysfunctions observed in patients with schizophrenia, the second goal of this study was to determine the brain-region-specific D 1 R-mediated signaling, ligand binding, and mRNA expression. None of the treatments affected the behavior of the control animals significantly; however, the combination treatment enhanced D 1 R binding and activation in the cerebral cortex. The Wisket rats exhibited impaired motivation, attention, and cognitive function, as well as a lower level of cortical D 1 R binding, signaling, and gene expression. Clozapine caused further deterioration of the behavioral parameters, without a significant effect on the D 1 R system. Metformin blunted the clozapine-induced impairments, and, similarly to that observed in the control animals, increased the functional activity of D 1 R. This study highlights the beneficial effects of metformin (at the behavioral and cellular levels) in blunting clozapine-induced adverse effects.

Traumatic brain injury (TBI) evokes widespread/diffuse axonal injury (TAI) significantly contributing to its morbidity and mortality. While classic theories suggest that traumatically injured axons are mechanically torn at the moment of injury, studies in the last two decades have not supported this premise in the majority of injured axons. Rather, current thought considers TAI a progressive process evoked by the tensile forces of injury, gradually evolving from focal axonal alteration to ultimate disconnection. Recent observations have demonstrated that traumatically induced focal axolemmal permeability leads to local influx of Ca2+ with the subsequent activation of the cysteine proteases, calpain and caspase, that then play a pivotal role in the ensuing pathogenesis of TAI via proteolytic digestion of brain spectrin, a major constituent of the subaxolemmal cytoskeletal network, the \"membrane skeleton\". In this pathological progression this local Ca2+ overloading with the activation of calpains also initiates mitochondrial injury that results in the release of cytochrome-c, with the activation of caspase. Both the activated calpain and caspases then participate in the degradation of the local axonal cytoskeleton causing local axonal failure and disconnection. In this review, we summarize contemporary thought on the pathogenesis of TAI, while discussing the potential diversity of pathological processes observed within various injured fiber types. The anterograde and retrograde consequences of TAI are also considered together with a discussion of various experimental therapeutic approaches capable of attenuating TAI.

Background Due to the lack of high-quality evidence which has hindered the development of evidence-based guidelines, there is a need to provide general guidance on cranioplasty (CP) following traumatic brain injury (TBI), as well as identify areas of ongoing uncertainty via a consensus-based approach. Methods The international consensus meeting on post-traumatic CP was held during the International Conference on Recent Advances in Neurotraumatology (ICRAN), in Naples, Italy, in June 2018. This meeting was endorsed by the Neurotrauma Committee of the World Federation of Neurosurgical Societies (WFNS), the NIHR Global Health Research Group on Neurotrauma, and several other neurotrauma organizations. Discussions and voting were organized around 5 pre-specified themes: (1) indications and technique, (2) materials, (3) timing, (4) hydrocephalus, and (5) paediatric CP. Results The participants discussed published evidence on each topic and proposed consensus statements, which were subject to ratification using anonymous real-time voting. Statements required an agreement threshold of more than 70% for inclusion in the final recommendations. Conclusions This document is the first set of practical consensus-based clinical recommendations on post-traumatic CP, focusing on timing, materials, complications, and surgical procedures. Future research directions are also presented.

The experimental values of longitudinal and transverse response functions of the 12 C nucleus have been obtained at the 3-momentum transfer q = 300  MeV/c. The data are compared with the calculations made with due regard to the dynamics of all the nucleons constituting the 12 C nucleus, and also, to the contributions of both the one-body currents only, and their combination with two-body currents.

Traumatic brain injury (TBI) evokes diffuse (traumatic) axonal injury (TAI), which contributes to morbidity and mortality. Damaged axons display progressive alterations gradually evolving to axonal disconnection. In severe TAI, the tensile forces of injury lead to a focal influx of Ca2+, initiating a series of proteolytic processes wherein the cysteine proteases, calpain and caspase modify the axonal cytoskeleton, causing irreversible damage over time postinjury. Although several studies have demonstrated that the systemic administration of calpain inhibitors reduces the extent of ischemic and traumatic contusional injury a direct beneficial effect on TAI has not been established to date. The current study was initiated to address this issue in an impact acceleration rat-TBI model in order to provide further evidence on the contribution of calpain-mediated proteolytic processes in the pathogenesis of TAI, while further supporting the utility of calpain-inhibitors. A single tail vein bolus injection of 30 mg/kg MDL-28170 was administered to Wistar rats 30 min preinjury. After injury the rats were allowed to survive 120 min when they were perfused with aldehydes. Brains were processed for immunohistochemical localization of damaged axonal profiles displaying either amyloid precursor protein (APP)- or RMO-14-immunoreactivity (IR), both considered markers of specific features of TAI. Digital data acquisition and statistical analysis demonstrated that preinjury administration of MDL-28170 significantly reduced the mean number of damaged RMO-14- as well as APP-IR axonal profiles in the brainstem fiber tracts analyzed. These results further underscore the role of calpain-mediated proteolytic processes in the pathogenesis of DAI and support the potential use of cell permeable calpain-inhibitors as a rational therapeutic approach in TBI.

Background Post-traumatic hypopituitarism is a major complication after severe head trauma. The aim of our study was to evaluate the possible role of early clinical parameters in the development of endocrine deficits. Methods Data on endocrine function, on-admission clinical-, laboratory-, and ICU-monitored parameters were available in 63 patients of the surviving 86 severe head injury patients (post-resuscitation GCS under 8) treated at one neurosurgical center during a 10-year period. Results Hypopituitarism was diagnosed in 68.3 % of the patients. The most frequently affected pituitary axis was the growth hormone (GH): GH deficiency or insufficiency was present in 50.8 %. Central hypogonadism affected 23.8 % of male patients; hypothyroidism and secondary adrenal failure were found in 22.2 and 9.5 % of the investigated population, respectively. Early onset (within 1 year of brain injury) hypopituitarism was found in 24 patients. No connection was found between the development of hypopituitarism and any of the clinical parameters assessed on-admission or at ICU. Significant correlations were found between early endocrine dysfunctions and surgical intervention (OR: 4.64) and the diagnosis of subdural hematoma (OR: 12). In our population, after road traffic accidents, the development of late-onset hypopituitarism was less prevalent (OR: 0.22). Conclusions Since our results do not indicate any reliable predictive parameter for the development of endocrine dysfunction in a cohort of patients with severe traumatic brain injury, regular endocrine screening of this specific patient population seems obligatory.

The contribution of brain edema to brain swelling in cases of traumatic brain injury (TBI) remains a critical problem. We believe that inflammatory reactions may play a fundamental role in brain swelling following a head injury. Although possible roles of microglia activation and the release of mediators have been suggested, direct evidence of cellular immune reactivity in diffuse brain injury following closed head trauma is lacking. Accordingly, the objective of this study was to assess the temporal pattern of microglia activation and lymphocyte migration in an experimental model of TBI. An impact acceleration TBI model was utilized to induce diffuse brain damage in adult Wistar rats. The animals were separated into three groups: unoperated controls, sham-operated controls and trauma group. At various times after TBI induction (5 min-24 h), rats were perfused transcardially. Sagittal brain sections were analyzed with immunohistochemical markers of CD3 to reveal the presence of T-lymphocytes, and by immunochemistry for the detection of CD11b to reveal microglia activation within the brain parenchyma. In the control groups, scattered T-cells were found in the brain parenchyma. In the trauma group, TBI induced microglia activation and a transient biphasic T-cell infiltration of the brain parenchyma in all regions was found, beginning as early as 30 min post injury and reaching its maximum values at 45 min and 3 h after trauma induction. These results lead us to suggest that the acute response to severe head trauma with early edema formation is likely to be associated with inflammatory events which might be triggered by activated microglia and infiltrating lymphocytes. It is difficult to overestimate the clinical significance of these observations, as the early and targeted treatment of patients with severe head injuries with immunosuppressive medication may result in a far more favorable outcome.

Calcium-induced proteolytic processes are considered key players in the progressive pathobiology of traumatic brain injury (TBI). Activation of calpain and caspases after TBI leads to the cleavage of cytoskeletal proteins such as non-erythroid alpha II-spectrin. Recent reports demonstrate that the levels of spectrin and spectrin breakdown products (SBDPs) are elevated in vitro after mechanical injury, in the cerebrospinal fluid (CSF) and brain tissue following experimental TBI, and in human brain tissue after TBI. This study was initiated to detect spectrin and SBDP accumulation in the ventricular CSF of 12 severe TBI-patients with raised intracranial pressure (ICP). Nine patients with non-traumatically elevated ICP and 5 undergoing diagnostic lumbar puncture (LP) served as controls. Intact spectrin and calpain and caspase specific SBDPs in CSF collected once a day over a several day period were assessed via Western blot analysis. Parameters of severity and outcome such as ICP, Glasgow Coma Scale and Glasgow Outcome Scale were also monitored in order to reveal a potential correlation between these CSF markers and clinical parameters. In control patients undergone LP no immunoreactivity was detected. Non-erythroid alpha-II-spectrin and SBDP occurred more frequently and their level was significantly higher in the CSF of TBI patients than in other pathological conditions associated with raised ICP. Those TBI patients followed for several days post-injury revealed a consistent temporal pattern for protein accumulation with the highest level achieved on the 2(nd) -3(rd) days after TBI. Elevation of calpain and caspase specific SBDPs is a significant finding in TBI patients indicating that intact brain spectrin- and SBDP-levels are closely associated with the specific neurochemical processes evoked by TBI. The results strongly support the potential utility of these surrogate markers in the clinical monitoring of patients with severe TBI and provide further evidence of the role of calcium-induced, calpain- and caspase-mediated structural proteolysis in TBI.

Background Management after severe traumatic brain injury (TBI) aims to prevent secondary injury by optimizing cerebral physiology, yet conventional metrics such as intracranial pressure (ICP) and cerebral perfusion pressure (CPP) incompletely capture the underlying pathophysiology. Impaired cerebral pressure autoregulation (CPA) is common and may exacerbate secondary injury. Proteomic blood-based biomarkers (PBBMs) of astrocytic (glial fibrillary acidic protein [GFAP], S100 calcium-binding protein B [S100B]), and neuronal/axonal injury (total tubulin associated unit [t-Tau], neurofilament light chain [NfL], ubiquitin C-terminal hydrolase-L1 [UCH-L1], neuron-specific enolase [NSE]) may provide global indicators of secondary injury. This study investigated temporal associations between PBBMs and cerebral physiological variables (ICP, CPP, pressure reactivity index [PRx], and CPP deviation from “optimal” CPP [ΔCPPopt]), and evaluated the PBBMs as surrogate short-term endpoints. Methods This retrospective, observational multi-center study, used prospective data from the CENTER-TBI cohort and included 151 patients with high-frequency cerebral physiological data and serial PBBM measurements during the first seven days post-injury. Associations were analyzed using Spearman correlations, univariate and multivariate linear mixed effects models (LMEMs), as well as cross correlation analyses adjusted for repeated measures and clinical confounders. Results Elevated PBBM levels on day 1 were associated with a greater cumulative burden of high ICP, impaired CPA (positive PRx), and negative ΔCPPopt over the subsequent seven days. Throughout the monitoring period, higher median PBBM concentrations correlated with elevated ICP and impaired CPA, with strongest associations when cerebral physiological monitoring and PBBMs were analyzed from the same day. In multivariate LMEMs, elevated ICP and most PBBMs remained significantly associated, while particularly PRx amplified this association. Conclusions Cerebral physiological disturbances during intensive care after TBI were associated with elevated PBBM levels, with ICP showing the strongest influence and impaired CPA amplifying some PBBM responses. Associations were strongest in same-day analyses and appeared bidirectional. These findings suggest that PBBM may reflect the burden of secondary cerebral insults and may serve as candidate endpoints for future trials targeting cerebral physiology, pending validation in prospective high-resolution studies. Importantly, our results highlight the potential for PBBMs to complement multimodal neuromonitoring by tracking secondary injury trajectories.