Explore the vast range of titles available.

The aim of the present study was to find out whether acute effect of different doses of selected antipsychotics including aripiprazole (ARI), amisulpride (AMI), asenapine (ASE), haloperidol (HAL), clozapine (CLO), risperidone (RIS), quetiapine (QUE), olanzapine (OLA), ziprasidone (ZIP), and paliperidone (PAL) may have a stimulatory impact on the c-Fos expression in the hypothalamic paraventricular nucleus (PVN) neurons. Adult male Wistar rats weighing 280–300 g were used. They were injected intraperitoneally with vehicle or antipsychotics in the following doses (mg/kg of b.w.): ARI (1, 10, 30), AMI (10, 30), ASE (0.3), HAL (1.0, 2.0), CLO (10, 20), RIS (0.5, 2.0), QUE (10, 20), OLA (5, 10), ZIP (10, 30), and PAL (1.0). Ninety min later, the animals were anesthetized with Zoletil and Xylariem and sacrificed by a transcardial perfusion with 60 ml of saline containing 450 μl of heparin (5000 IU/l) followed by 250 ml of fixative containing 4% paraformaldehyde in 0.1 M phosphate buffer (PB, pH 7.4). The brains were postfixed in a fresh fixative overnight, washed two times in 0.1 M PB, infiltrated with 30% sucrose for 2 days at 4 °C, frozen at −80 °C for 120 min, and cut into 30 μm thick serial coronal sections at −16 °C. c-Fos profiles were visualized by nickel intensified DAB immunohistochemistry and examined under Axio-Imager A1 (Zeiss) light microscope. From ten sorts of antipsychotics tested, only six (ARI-10, CLO-10 and CLO-20, HAL-2, AMI-30, OLA-10, RIS-2 mg/kg b.w.) induced distinct c-Fos expression in the PVN. The antipsychotics predominantly targeted the medial parvocellular subdivision of the PVN. The present pilot study revealed c-Fos expression increase predominantly in the PVN medial parvocellular subdivision neurons by action of only several sorts of antipsychotics tested indicating that this structure of the brain does not represent a common extra-striatal target area for all antipsychotics.

Although existing guidelines support the utilization of intracranial pressure (ICP) monitoring in patients with traumatic brain injury (TBI), the evidence suggesting benefit is limited. To evaluate the impact on outcome, we determined the relationship between ICP monitoring and mortality in centers participating in the American College of Surgeons Trauma Quality Improvement Program (TQIP). Data on 10,628 adults with severe TBI were derived from 155 TQIP centers over 2009–2011. Random-intercept multilevel modeling was used to evaluate the association between ICP monitoring and mortality after adjusting for important confounders. We evaluated this relationship at the patient level and at the institutional level. Overall mortality (n=3769) was 35%. Only 1874 (17.6%) patients underwent ICP monitoring, with a mortality of 32%. The adjusted odds ratio (OR) for mortality was 0.44 [95% confidence interval (CI), 0.31–0.63], when comparing patients with ICP monitoring to those without. It is plausible that patients receiving ICP monitoring were selected because of an anticipated favorable outcome. To overcome this limitation, we stratified hospitals into quartiles based on ICP monitoring utilization. Hospitals with higher rates of ICP monitoring use were associated with lower mortality: The adjusted OR of death was 0.52 (95% CI, 0.35–0.78) in the quartile of hospitals with highest use, compared to the lowest. ICP monitoring utilization rates explained only 9.9% of variation in mortality across centers. Results were comparable irrespective of the method of case-mix adjustment. In this observational study, ICP monitoring utilization was associated with lower mortality. However, variability in ICP monitoring rates contributed only modestly to variability in institutional mortality rates. Identifying other institutional practices that impact on mortality is an important area for future research.

Modified levels of pro- (caspase3, Bax) and anti-apoptotic (Bcl-2) regulatory proteins have been detected in certain brain areas of schizophrenic patients indicating a possible dysregulation of apoptosis. In the present study, effects of antipsychotics, haloperidol (HAL) and olanzapine (OLA), on the gene expression of caspase3 ( ), and were studied in mouse hippocampal mHippoE-2 cell line and in the hippocampus of MK-801 animal schizophrenia model with the aim to provide evidence that antipsychotics may affect the activity of apoptosis-related markers. mHippoE-2 cells were incubated with MK-801 (20 µM), HAL (10 µM), and OLA (10 µM) alone or combined, MK-801+HAL/OLA, for 24, 48, and 72 h. Male Sprague Dawley rats were injected with saline or MK-801 (0.5 mg/kg) for 6 days and since the 7th day, they were treated with vehicle (VEH), HAL (1 mg/kg) or OLA (2 mg/kg) for the next 7 days. The , and gene expression in mHippoE-2 cells and rat hippocampus was measured by RT-PCR. In mHippoE-2 cells, gene expression was increased by MK-801 and OLA treatments alone for 48 h, HAL treatment alone for 24 and 72 h, and co-treatment with MK-801+OLA for 24 and 72 h compared to controls. HAL and OLA suppressed the stimulatory effect of MK-801 on mRNA levels in cells after 48 h of incubation. mRNA levels in mHippoE-2 cells were decreased after HAL treatment for 24 and 48 h, and also after co-treatment with MK-801+HAL for 72 h. , MK-801 decreased mRNA levels of both pro-apoptotic markers, and , in hippocampus of VEH-treated rats and mRNA levels in hippocampus of HAL-treated animals. OLA reversed the inhibitory effect of MK-801 on expression in the VEH-treated animals. Neither MK-801 nor antipsychotics induced changes in the gene expression of anti-apoptotic marker in mHippoE-2 cells as well as hippocampus of rats. The results of the present study demonstrate that antipsychotics, HAL and OLA, may affect mRNA levels of pro-apoptotic markers in hippocampal cells , but not . The obtained data do not clearly support the assumed potentiating role of MK-801 in inducing apoptosis in specific brain areas and a possible protective role of antipsychotics against induction of apoptosis. The obtained data may contribute to a deeper insight into the neurodevelopmental changes connected with schizophrenia.

It is apparent that the c-Fos and FosB/ΔFosB immunohistochemistry has generally become a useful tool for determining the different antipsychotic (AP) drugs activities in the brain. It is also noteworthy that there are no spatial limits, while to the extent of their identification over the whole brain axis. In addition, they can be in a parallel manner utilized in the unmasking of the brain cell phenotype character activated by APs and by this way also to identify the possible brain circuits underwent to the APs action. However, up to date, the number of APs involved in the extra-striatal studies is still limited, what prevents the possibility to fully understand their extra-striatal effects as a complex as well as differentiate their extra-striatal impact in qualitative and quantitative dimensions. Actually, it is very believable that more and more anatomical/functional knowledge might bring new insights into the APs extra-striatal actions by identifying new region-specific activities of APs as well as novel cellular targets affected by APs, which might reveal more details of their possible side effects of the extra-striatal origin.

To improve clinicians' ability to predict outcome after spinal cord injury (SCI) and to help classify patients within clinical trials, we have created a novel prediction model relating acute clinical and imaging information to functional outcome at 1 year. Data were obtained from two large prospective SCI datasets. Functional independence measure (FIM) motor score at 1 year follow-up was the primary outcome, and functional independence (score ≥6 for each FIM motor item) was the secondary outcome. A linear regression model was created with the primary outcome modeled relative to clinical and imaging predictors obtained within 3 days of injury. A logistic model was then created using the dichotomized secondary outcome and the same predictor variables. Model validation was performed using a bootstrap resampling procedure. Of 729 patients, 376 met the inclusion criteria. The mean FIM motor score at 1 year was 62.9 (±28.6). Better functional status was predicted by less severe initial American Spinal Injury Association (ASIA) Impairment Scale grade, and by an ASIA motor score >50 at admission. In contrast, older age and magnetic resonance imaging (MRI) signal characteristics consistent with spinal cord edema or hemorrhage predicted worse functional outcome. The linear model predicting FIM motor score demonstrated an R-square of 0.52 in the original dataset, and 0.52 (95% CI 0.52,0.53) across the 200 bootstraps. Functional independence was achieved by 148 patients (39.4%). For the logistic model, the area under the curve was 0.93 in the original dataset, and 0.92 (95% CI 0.92,0.93) across the bootstraps, indicating excellent predictive discrimination. These models will have important clinical impact to guide decision making and to counsel patients and families.

Post-traumatic stress disorder (PTSD) is a complex psychiatric disorder that can develop after exposure to a severe traumatic event and is connected with behavioral changes and adult neurogenesis impairment. Atypical antipsychotics including aripiprazole (ARI) or enriched environment can ameliorate disturbances connected to PTSD. This study was aimed to reveal whether ARI treatment supplemented by improved living conditions, i.e. toy rotation (TR), will ameliorate behavioral outcomes and reverse assumed changes in neurogenesis more effectively than sole ARI treatment in a single prolonged stress (SPS) animal model of PTSD. Adult male Sprague-Dawley rats weighing 176–200 g were randomly assigned to 5 experimental groups: (1) VEH – control non-stressed animals injected with vehicle (VEH, 2% Tween 20 in the saline); (2) SPS – animals exposed to SPS injected with VEH; (3) SPS+ARI – SPS animals injected with ARI (5 mg/kg in VEH); (4) SPS+TR – SPS animals exposed to TR and injected with VEH; (5) SPS+ARI+TR – SPS animals exposed to TR and injected with ARI. Animals in TR groups were housed in the standard cages with two toys per cage, which were replaced every other day. Elevated plus maze (EPM), open field (OF), and novel object recognition test (NOR) were used to assess the anxiety-like behavior and learning/memory. Changes in gene and protein expression of selected neurogenic markers (BDNF, GFAP, Sox2, DCX, NeuN) and transcription factors (ΔFosB, pCREB) in the subventricular zone (SVZ) and the gyrus dentatus (GD) of the hippocampus were determined by semi-quantitative real-time PCR and immunohistochemistry, respectively. SPS animals showed increased anxiety-like behavior that was suppressed by TR and ARI+TR treatment combination. Although SPS did not affect the expression of studied neurogenic markers, ARI treatment increased the expression of doublecortin in the SVZ and TR increased expression of NeuN in the GD of PTSD-like animals. TR enhanced ARI effect on NeuN expression in the SVZ. SPS induced increase of ΔFosB positive cells, which was reduced by ARI+TR complementary treatment. Obtained results indicate that TR, in contrary to ARI, suppressed the anxiety-like behavior in PTSD-like animals. SPS does not affect the neurogenic markers expression in the SVZ or GD, but ARI and TR or their combination seems to increase the survival of the newborn cells.

Olanzapine (OLA), amisulpride (AMI), aripiprazole (ARI), and quetiapine (QUE) belong to antipsychotics, which administration represents still most reliable way for the treatment of schizophrenic and bipolar disorders. The intention of the present study was to explore whether the acute administration of a particular antipsychotic, indicated by the presence of c-Fos, will: a) stimulate neurons already activated by a long lasting homogeneous or heterogeneous stress preconditioning, indicated by the FosB/ΔFosB (ΔFosB) expression, or b) have a stimulatory effect only on a not activated, so called silent neurons. The pattern of ΔFosB and c-Fos spatial relationship was investigated in three forebrain structures, including the septal ventrolateral nucleus (seVL), the striatal dorsolateral area (stDL), and the shell of the nucleus accumbens (shell). The rats were divided into 10 groups and exposed to two types of stressors. Half of them was exposed to a sequence of homogeneous stressor – handling (HDL) and the other half to a heterogeneous stressor (CMS) daily for 20 days. CMS consisted of five types of stressors: crowding, air-puff, wet bedding, predator stress, and forced swimming applied in an unexpected order. On the 21st day of the experiment, the rats were free of the stress exposure and on the 22nd day, both groups of animals receive a single intraperitoneal injection of vehicle (4% DMSO in saline, 0.1 ml/100 g) or OLA (5 mg/kg), AMI (20 mg/kg), ARI (10 mg/kg), and QUE (15 mg/kg). 90 min after the drugs administration the animals were transcardially perfused, brains removed, cut into 30 µm thick coronal sections, and double stained: first with ΔFosB antibody linked with Alexa488 fluorescent dye and second with c-Fos antibody linked to Alexa596 one. Quantitative evaluation of ΔFosB and c-Fos colocalizations was performed on fluorescence photomicrographs transformed into a final picture containing only yellow, green, and red colored circles. The data of this investigation demonstrate that ΔFosB and c-Fos colocalizations occurred in each of the three areas investigated, i.e. seVL, stDL, and shell ones, in both HDL as well as CMS preconditioned rats. The levels of ΔFosB and c-Fos colocalizations varied in the individual forebrain areas studied. From the total 22 areas measured, level of c-Fos colocalization prevailed over ΔFosB in 18 ones. However, neither c-Fos nor ΔFosB reached 100% level of colocalization in any of the forebrain areas investigated. The present findings indicate that ΔFosB and c-Fos colocalizations occurred in each of the three areas investigated, i.e. seVL, stDL, and shell, in both HDL and CMS preconditioned rats, whereas the parallel occurrence of free c-Fos as well as c-Fos colocalized with ΔFosB might speak out for a possible involvement of the c-Fos activated by antipsychotics applied in dual, i.e. short- and long-lasting, functions.

The goal of this study was to reveal the impact of four types of atypical antipsychotics including amisulpride (AMI), olanzapine (OLA), quetiapine (QUE), and aripiprazole (ARI), with different receptor-affinity profile and dissociation constant, on the activity of hypothalamic supraoptic nucleus (SON) vasopressinergic and oxytocinergic neurons. Male Sprague Dawley rats received a single injection of vehicle (VEH) (0.1 ml/100g), AMI (20 mg/kg), OLA (5 mg/kg), QUE (15 mg/kg/) or ARI (10 mg/kg). Ninety min after treatment, the animals were fixed by transcardial perfusion, the brains removed, and cryocut into serial coronal sections of 35 µm thickness. The sections were processed for c-Fos staining using an avidin-biotin-peroxidase complex and visualized by nickel intensified diaminobenzidine to reach black end product. Afterwards, the sections were exposed to vasopressin (AVP) and oxytocin (OXY) antibodies and the reaction product visualized by biotin-labeled fluorescent Alexa Fluor 568 dye. The data were evaluated from c-Fos and AVP or OXY merged sections. The present study shows that all four antipsychotics applied induced c-Fos expression in the SON. With respect to the stimulation efficacy of the individual antipsychotics, estimated based on the quantity of c-Fos-labeled AVP and OXY neurons, could be a preferential action assigned to QUE over moderate effect of ARI and lower effect to OLA and reduced effect of AMI (VEH < AMI < OLA < ARI < QUE). The present data for the first time provide an insight into the quantitative pattern of brain activity within the clusters of SON AVP and OXY cells in response to different atypical antipsychotics single treatment.

IntroductionThe management of active patients with symptomatic knee osteoarthritis (KnOA) who are too young for total knee arthroplasty poses a specific challenge to clinicians. Research studies show that improving quadriceps muscle strength improves pain and function; however, aspects of the disease render it difficult for patients to achieve and maintain improvements. Recombinant human growth hormone (rHGH) is shown to increase the magnitude and duration of muscle growth when combined with exercise treatment in adult populations. Hence, rHGH combined with physical therapy may provide meaningful benefits in the treatment of KnOA.Methods and analysisThis is a single-centre, double-blind, randomised trial to pilot a future Phase III trial from 2025 to 2028. Participants are aged 18–60 with clinical and radiographic evidence of isolated degenerative arthritis of the knee (patellofemoral or tibiofemoral). The investigational product is rHGH (Saizen (somatropin of rDNA origin, EMD Serono)) and a saline placebo. Participants will deliver the solution via subcutaneous injection area once per day at a dose of 0.5 mg HGH per body surface area (0.5 mg/m2) for 6 weeks, alongside participation in a lower limb strengthening programme developed by rehabilitation specialists. 17 participants will be recruited into each study arm.The primary outcomes are feasibility (compliance with the study drug regimen for the 6-week administration period and enrolment rate) and safety (the proportion of minor and major adverse events between groups). The primary endpoint for these outcomes will be at 6 weeks. The secondary outcomes are knee extension strength, knee flexion strength, radiographic arthritis progression, thigh muscle circumference, MRI-measured quadriceps muscle volume and patient-reported outcome measures (Knee Osteoarthritis Outcome Score (KOOS), SF-20 and Tegner). The primary endpoint for these outcomes will be at 12 weeks, and the final endpoint will be 24 months, where final radiographic (X-ray) assessment will take place.The primary outcome of compliance will be a calculation of mean compliance between groups, which can be analysed as a t-test after the treatment period. A two-sample, two-sided t-test will compare the clinical (secondary) outcome of greatest interest: knee extension strength at baseline versus week 6 compared between treatment groups. Other secondary outcomes will be compared using a simple linear mixed-effects model. The χ2 test will be used to determine whether the number of participants who made meaningful changes was different between groups. The null hypotheses are that the rHGH and placebo groups will have no difference in compliance rates, safety events, knee extension strength at 12 weeks and arthritis grade progression at 24 months.Ethics and disseminationThis study has been approved by the Sunnybrook Research Institute Research and Ethics Board (#6427) and received a no-objection letter from Health Canada Clinical Trials. The primary sponsor is the Sunnybrook Centre for Clinical Trial Studies (CCTS). The findings of this study will be published in a peer-reviewed journal and presented at orthopaedic conferences.Trial registration numberNCT07036003.

Abstract Study Objectives: Emerging evidence suggests that periodic limb movements (PLMs) may contribute to the development of cerebrovascular disease. White matter hyperintensities (WMHs), a widely accepted biomarker for cerebral small vessel disease, are associated with incident stroke and death. We evaluated the association between increased PLM indices and WMH burden in patients presenting with stroke or transient ischemic attack (TIA), while controlling for vascular risk factors and stroke severity. Methods: Thirty patients presenting within 2 weeks of a first-ever minor stroke or high-risk TIA were prospectively recruited. PLM severity was measured with polysomnography. WMH burden was quantified using the Age Related White Matter Changes (ARWMC) scale based on neuroimaging. Partial Spearman’s rank-order correlations and multiple linear regression models tested the association between WMH burden and PLM severity. Results: Greater WMH burden was correlated with elevated PLM index and stroke volume. Partial Spearman’s rank-order correlations demonstrated that the relationship between WMH burden and PLM index persisted despite controlling for vascular risk factors. Multivariate linear regression models revealed that PLM index was a significant predictor of an elevated ARWMC score while controlling for age, stroke volume, stroke severity, hypertension, and apnea-hypopnea index. Conclusion: The quantity of PLMs was associated with WMH burden in patients with first-ever minor stroke or TIA. PLMs may be a risk factor for or marker of WMH burden, even after considering vascular risk factors and stroke severity. These results invite further investigation of PLMs as a potentially useful target to reduce WMH and stroke burden.