Alcohol is a serious public health concern that has a differential impact on individuals depending upon age and sex. Patterns of alcohol consumption have recently changed: heavy episodic ...drinking-known as binge-drinking-has become most popular among the youth. Herein, we aimed to investigate the consequences of intermittent adolescent alcohol consumption in male and female animals. Thus,
rats were given free access to ethanol (20% in drinking water) or tap water for 2-h sessions during 3 days, and for an additional 4-h session on the 4th day; every week during adolescence, from postnatal day (pnd) 28-52. During this period, animals consumed a moderate amount of alcohol despite blood ethanol concentration (BEC) did not achieve binge-drinking levels. No withdrawal signs were observed: no changes were observed regarding anxiety-like responses in the elevated plus-maze or plasma corticosterone levels (pnd 53-54). In the novel object recognition (NOR) test (pnd 63), a significant deficit in recognition memory was observed in both male and female rats. Western Blot analyses resulted in an increase in the expression of synaptophysin in the frontal cortex (FC) of male and female animals, together with a decrease in the expression of the CB2R in the same brain region. In addition, adolescent alcohol induced, exclusively among females, a decrease in several markers of dopaminergic and serotonergic neurotransmission, in which epigenetic mechanisms, i.e., histone acetylation, might be involved. Taken together, further research is still needed to specifically correlate sex-specific brain and behavioral consequences of adolescent alcohol exposure.
High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) represents a standard treatment regime for multiple myeloma (MM) patients. Common and potentially ...fatal side effects after auto-HSCT are infections due to a severely compromised immune system with hampered humoral and cellular immunity. This study delineates in depth the quantitative and functional B cell defects and investigates underlying extrinsic or intrinsic drivers.
Peripheral blood of MM patients undergoing high-dose chemotherapy and auto-HSCT (before high-dose chemotherapy and in early reconstitution after HSCT) was studied. Absolute numbers and distribution of B cell subsets were analyzed
using flow cytometry. Additionally, B cell function was assessed with T cell dependent (TD) and T cell independent (TI) stimulation assays, analyzing proliferation and differentiation of B cells by flow cytometry and numbers of immunoglobulin secreting cells in ELISpots.
Quantitative B cell defects including a shift in the B cell subset distribution occurred after auto-HSCT. Functionally, these patients showed an impaired TD as well as TI B cell immune response. Individual functional responses correlated with quantitative alterations of CD19+, CD4+, memory B cells and marginal zone-like B cells. The TD B cell function could be partially restored upon stimulation with CD40L/IL-21, successfully inducing B cell proliferation and differentiation into plasmablasts and immunoglobulin secreting cells.
Quantitative and functional B cell defects contribute to the compromised immune defense in MM patients undergoing auto-HSCT. Functional recovery upon TD stimulation and correlation with CD4+ T cell numbers, indicate these as extrinsic drivers of the functional B cell defect. Observed correlations of CD4+, CD19+, memory B and MZ-like B cell numbers with the B cell function suggest that these markers should be tested as potential biomarkers in prospective studies.
We investigated with remote sensing (APEX images) the coexistence of phytoplankton and macrophytes in three interconnected shallow and hypereutrophic fluvial lakes (Mantua Lakes, Northern Italy). ...High concentrations of chlorophyll-a, up to 60 mg m⁻³, were determined in the open water between well-developed stands of floating-leaved, submerged, and emergent macrophytes. Our data suggest a general inhibition of phytoplankton by macrophytes, evidenced by decreasing chlorophyll-a concentrations in proximity of macrophyte stands. Chlorophyll-a concentrations halved in the proximity of emergent stands (~6 mg m⁻³ within 21 m from the stand border) when compared to the outer zones (~13 mg m⁻³). Contrasting trends were observed for submerged stands, where concentrations decreased inwards from ~8 to ~3 mg m⁻³. Floating leaved stands had a neutral effect, chlorophyll-a being nearly constant in both inner and outer zones. Overall, remotely-sensed data allow evaluation of quantitative and spatially defined interactions of macrophytes and phytoplankton at the whole ecosystem scale.
Prior neuroimaging studies have reported white matter network underconnectivity as a potential mechanism for autism spectrum disorder (ASD). In this study, we examined the structural connectome of ...children with ASD using edge density imaging (EDI), and then applied machine-learning algorithms to identify children with ASD based on tract-based connectivity metrics. Boys aged 8-12 years were included: 14 with ASD and 33 typically developing children. The edge density (ED) maps were computed from probabilistic streamline tractography applied to high angular resolution diffusion imaging. Tract-based spatial statistics was used for voxel-wise comparison and coregistration of ED maps in addition to conventional diffusion tensor imaging (DTI) metrics of fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD). Tract-based average DTI/connectome metrics were calculated and used as input for different machine-learning models: naïve Bayes, random forest, support vector machines (SVMs), and neural networks. For these models, cross-validation was performed with stratified random sampling ( × 1,000 permutations). The average accuracy among validation samples was calculated. In voxel-wise analysis, the body and splenium of corpus callosum, bilateral superior and posterior corona radiata, and left superior longitudinal fasciculus showed significantly lower ED in children with ASD; whereas, we could not find significant difference in FA, MD, and RD maps between the two study groups. Overall, machine-learning models using tract-based ED metrics had better performance in identification of children with ASD compared with those using FA, MD, and RD. The EDI-based random forest models had greater average accuracy (75.3%), specificity (97.0%), and positive predictive value (81.5%), whereas EDI-based polynomial SVM had greater sensitivity (51.4%) and negative predictive values (77.7%). In conclusion, we found reduced density of connectome edges in the posterior white matter tracts of children with ASD, and demonstrated the feasibility of connectome-based machine-learning algorithms in identification of children with ASD.
This review highlights the salient findings that have furthered our understanding of how sex differences are initiated during development and maintained throughout life. First we discuss how gonadal ...steroid hormones organize the framework for sex differences within critical periods of development-namely, during those exposures which occur in utero and post-partum, as well as those which occur during puberty. Given the extensive precedence of sex differences in cannabinoid-regulated biology, we then focus on the disparities within the endogenous cannabinoid system, as well as those observed with exogenously administered cannabinoids. We start with how the expression of cannabinoid CB(1) receptors is regulated throughout development. This is followed by a discussion of differential vulnerability to the pathological sequelae stemming from cannabinoid exposure during adolescence. Next we talk about sex differences in the interactions between cannabinoids and other drugs of abuse, followed by the organizational and activational roles of gonadal steroids in establishing and maintaining the sex dependence in the biological actions of cannabinoids. Finally, we discuss ways to utilize this knowledge to strategically target critical developmental windows of vulnerability/susceptibility and thereby implement more effective therapeutic interventions for afflictions that may be more prevalent in one sex vs. the other.
The environment in which individuals develop and mature is critical for their physiological and psychological outcome; in particular, the intrauterine environment has reached far more clinical ...relevance given its potential influence on shaping brain function and thus mental health. Gestational stress and/or maternal infection during pregnancy has been related with an increased incidence of neuropsychiatric disorders, including depression and schizophrenia. In this framework, the use of animal models has allowed a formal and deep investigation of causal determinants. Despite disruption of circadian clocks often represents a hallmark of several neuropsychiatric disorders, the relationship between disruption of brain development and the circadian system has been scarcely investigated. Nowadays, there is an increasing amount of studies suggesting a link between circadian system malfunction, early-life insults and the appearance of neuropsychiatric diseases at adulthood. Here, we briefly review evidence from clinical literature and animal models suggesting that the exposure to prenatal insults, i.e. severe gestational stress or maternal immune activation, changes the foetal hormonal milieu increasing the circulating levels of both glucocorticoids and pro-inflammatory cytokines. These two biological events have been reported to affect genes expression in experimental models and critically interfere with brain development triggering and/or exacerbating behavioural anomalies in the offspring. Herein, we highlight the importance to unravel the individual components of the body circadian system that might also be altered by prenatal insults and that may be causally associated with the disruption of neural and endocrine developmental programming.
Aims
Recently, dipeptidyl peptidase 3 (DPP3) has been discovered as the peptidase responsible for cleavage of angiotensin (1–7) Ang (1–7). Ang (1–7) is part of the angiotensin‐converting enzyme–Ang ...(1–7)–Mas pathway which is considered to antagonize the renin–angiotensin–aldosterone system (RAAS). Since DPP3 inhibits the counteracting pathway of the RAAS, we hypothesize that DPP3 might be deleterious in the setting of heart failure. However, no data are available on DPP3 in chronic heart failure. We therefore investigated the clinical characteristics and outcome related to elevated DPP3 concentrations in patients with worsening heart failure.
Methods and results
Dipeptidyl peptidase 3 was measured in 2156 serum samples of patients with worsening heart failure using luminometric immunoassay (DPP3‐LIA) by 4TEEN4 Pharmaceuticals GmbH, Hennigsdorf, Germany. Predictors of DPP3 levels were selected using multiple linear regression with stepwise backward selection. Median DPP3 concentration was 11.45 ng/mL with a range from 2.8 to 84.9 ng/mL. Patients with higher DPP3 concentrations had higher renin 78.3 (interquartile range, IQR 26.3–227.7) vs. 120.7 IU/mL (IQR 34.74–338.9), P < 0.001, for Q1–3 vs. Q4 and aldosterone 88 (IQR 44–179) vs. 116 IU/mL (IQR 46–241), P < 0.001, for Q1–3 vs. Q4 concentrations. The strongest independent predictors for higher concentration of DPP3 were log‐alanine aminotransferase, log‐total bilirubin, the absence of diabetes, higher osteopontin, fibroblast growth factor‐23 and N‐terminal pro‐B‐type natriuretic peptide concentrations (all P < 0.001). In univariable survival analysis, DPP3 was associated with mortality and the combined endpoint of death or heart failure hospitalization (P < 0.001 for both). After adjustment for confounders, this association was no longer significant.
Conclusions
In patients with worsening heart failure, DPP3 is a marker of more severe disease with higher RAAS activity. It may be deleterious in heart failure by counteracting the Mas receptor pathway. Procizumab, a specific antibody against DPP3, might be a potential future treatment option for patients with heart failure.
Simplified depiction of the renin–angiotensin–aldosterone system. Angiotensin I is converted to angiotensin II by angiotensin‐converting enzyme (ACE). Angiotensin II is degraded to angiotensin III and several other angiotensins. Angiotensin II directly stimulates osteopontin (OPN) synthesis and activates the AT1 and AT2 receptors, eventually leading to increased fibroblast growth factor‐23 (FGF‐23) concentrations. FGF‐23 has a proposed direct stimulation effect on dipeptidyl peptidase 3 (DPP3), as indicated by the dotted arrow. Both OPN and FGF‐23 negatively influence ACE2 concentrations. ACE2 converts angiotensin II to angiotensin (1–7). Angiotensin (1–7) activates the Mas receptor, leading to reduction of myocardial fibrosis, increased natriuresis, vasodilatation and increased renal blood flow. DPP3 converts angiotensin (1–7) to angiotensin (3–7) and angiotensin (5–7). Diabetes has a negative effect on ACE2 concentrations. Male sex has a positive effect on ACE2 levels and a proposed direct positive effect on DPP3 levels, as indicated by the dotted arrow. Both decay of liver cells and erythrocytes will release DPP3 into the plasma, depicted by the dotted arrows.
•The relationship between surgery, neuroinflammation, and delirium remains unclear.•11CPBR28 positron emission tomography (PET) was used to image neuroinflammation.•Patients showed a global reduction ...of 11CPBR28 binding one month after surgery.•11CPBR28 binding was not related to delirium or other markers of inflammation.•Post-operative reduction in 11CPBR28 binding may reflect neuroimmune suppression.
Major surgery is associated with a systemic inflammatory cascade that is thought, in some cases, to contribute to transient and/or sustained cognitive decline, possibly through neuroinflammatory mechanisms. However, the relationship between surgery, peripheral and central nervous system inflammation, and post-operative cognitive outcomes remains unclear in humans, primarily owing to limitations of in vivo biomarkers of neuroinflammation which vary in sensitivity, specificity, validity, and reliability. In the present study, 11CPBR28 positron emission tomography, cerebrospinal fluid (CSF), and blood plasma biomarkers of inflammation were assessed pre-operatively and 1-month post-operatively in a cohort of patients (N = 36; 30 females; ≥70 years old) undergoing major orthopedic surgery under spinal anesthesia. Delirium incidence and severity were evaluated daily during hospitalization. Whole-brain voxel-wise and regions-of-interest analyses were performed to determine the magnitude and spatial extent of changes in 11CPBR28 uptake following surgery. Results demonstrated that, compared with pre-operative baseline, 11CPBR28 binding in the brain was globally downregulated at 1 month following major orthopedic surgery, possibly suggesting downregulation of the immune system of the brain. No significant relationship was identified between post-operative delirium and 11CPBR28 binding, possibly due to a small number (n = 6) of delirium cases in the sample. Additionally, no significant relationships were identified between 11CPBR28 binding and CSF/plasma biomarkers of inflammation. Collectively, these results contribute to the literature by demonstrating in a sizeable sample the effect of major surgery on neuroimmune activation and preliminary evidence identifying no apparent associations between 11CPBR28 binding and fluid inflammatory markers or post-operative delirium.
Purpose: To analyse the anti‐inflammatory effect of saffron extract, by regulating the expression of cytokines and chemokines involved in the neuroinflammatory process leading to retinal ganglion ...cell (RGC) damage, in a mouse model of unilateral laser‐induced ocular hypertension (OHT).
Methods: Three groups of Albino Swiss mice treated with saffron extract were used; saffron naïve group (SNG), saffron laser group 1 day (SLG1d) and saffron laser group 3 days (SLG3d). Both eyes with OHT (treated with laser photocoagulation) and their contralateral were analysed. Retinal samples were processed and multiarray kits (MILLIPLEX MAP Mouse Cytokine/Myokine Magnetic Bead Panel) were used to quantify the expression of: IL‐1β, IL‐4, IL‐6, IL‐10, IL‐17, IFN‐ϒ, TNF‐α, Brain‐derived Neurotrophic Factor (BDNF), Vascular Endothelial Growth Factor (VEGF) and Fractalkine. Immunohistochemical analysis was performed to locate cells expressing the factors and cytokines detected in the multiplex assay.
Results: After saffron treatment, no significant differences were found, at 1 and 3 days after laser‐induced OHT, between the concentration of proinflammatory cytokines (IL‐1β, IFN‐γ, TNF‐α and IL‐17), anti‐inflammatory cytokines (IL‐4 and IL‐10), BDNF, VEGF, and fractalkine in both the OHT eye and its contralateral eye, compared to saffron naïve. IL‐6 levels increased significantly in the OHT eye in SLG1d, reaching normal values at SLG3d compared to SNG. These results are contrary to those found in OHT eyes and their contralateral not treated with saffron, in which changes in cytokine levels were observed.
Conclusions: Saffron is effective in regulating the production of proinflammatory cytokines, VEGF, and fractalkine induced by increased IOP, thus protecting the retina from its related damage. Saffron could be beneficial as coadjutant therapies in the treatment of glaucoma, thus helping to decrease the inflammatory process that occurs in this pathology.
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