C-Reactive Protein, the Gliovascular Unit, and Alzheimer's Disease.

Alzheimer's disease (AD) pathogenesis is conditioned by the presence of amyloid beta (Aß) and neuroinflammation. The gliovascular unit (GVU) illustrates the relationship between the vascular components of the brain and glial cells, particularly astrocytes, which are seen as critical elements mainly affected in this disease. In AD patients, the impairment of the GVU is seen as blood-brain barrier breakdown, decreased clearance of Aß, and chronic inflammatory status. C-reactive protein (CRP) and its monomeric form (mCRP) are associated with endothelial dysfunction and amyloid plaque instability, contributing to neuroinflammation and neurodegeneration. The interconnections between the GVU and the dissociated form of CRP were demonstrated by mCRP implication in vascular permeability that supports inflammation and extravasation of pro-inflammatory cytokines into the brain parenchyma. Astrocytic activation and endfeet function alterations can exacerbate the progression of AD by elevating pro-inflammatory agents and vascular amyloid accumulations. This review aims to emphasize the synergistic link between the GVU and monomers of CRP in the perpetuation of the inflammatory status, exacerbating neurodegeneration and neuroinflammation. Understanding their implication in AD can bring insights into novel therapeutic strategies to reduce AD progression.

Comparative Analysis of Retinal Structural and Angiographic Parameters in Diabetic Patients, Alzheimer's Disease Patients, and Healthy Controls: An OCT-Based Study.

Objective: This study aimed to investigate the potential connections between Alzheimer's Disease (AD) and diabetes. Methods: This is a cross-sectional study in which AD and diabetes patients sent by the Psychiatry and Diabetes Departments for ophthalmological screening were observed for inclusion/exclusion criteria. Patients were divided into two comparison groups. The first group (n=3) consisted of the age-matched normal and diabetic patient of the stage 3 AD disease participant. The second group (n=3) was for the stage 5 AD patient with diabetes and normal age-matched controls. Each patient underwent a full ophthalmological examination and SS-OCT (Swept Source-Ocular Computer Tomography) for retinal evaluation. Results: A total of 6 patients (12 eyes) were obtained, three men and three women. In the early AD group, the patient with diabetes showed lower macular thickness compared to other groups. In the nasal-inferior (NI) and temporal-superior (TS) ganglion cell layer (GCL), the AD patient showed statistically significant lower values compared to the other patients. In the moderately severe AD group, we found that the AD patient had lower retinal nerve fiber layer (RNFL) thickness on the temporal side compared to the rest of the patients and both the AD patient and diabetes patient showed lower RNFL thickness in the nasal-superior (NS) quadrant. Also, the foveal avascular zone (FAZ) area was statistically significantly lower for both the diabetes and AD patients compared to the healthy control. Conclusions: In conclusion, distinct retinal findings associated with AD and diabetes in young and elderly patients were revealed in our study. The clinical implications and potential interplay between these conditions need to be elucidated by further research. Abbreviations: AD = Alzheimer's Disease, SS-OCT = Swept Source - Ocular Computer Tomography, GCL = Ganglion cell layer, RNFL = Retinal nerve fiber layer, FAZ = foveal avascular zone.

Stroke-induced excess in capillarization relative to oxidative capacity in rats is muscle specific.

Stroke is not only associated with muscle weakness, but also associated with reduced muscle fatigue resistance and reduced desaturation during exercise that may be caused by a reduced oxidative capacity and/or microvasculature. Therefore, the objective of the present study was to determine the effects of stroke on muscle mass, fiber size and shape, capillarization and oxidative capacity of the rat m. extensor carpi radialis (ECR) and m. flexor carpi ulnaris (FCU) after a photothrombotic stroke in the forelimb region of the primary sensorimotor cortex. The main observation of the present study was that 4 weeks after induction of stroke there were no significant changes in muscle fiber size and shape. Although there was no significant capillary rarefaction, there was some evidence for remodeling of the capillary bed as reflected by a reduced heterogeneity of capillary spacing (p = 0.006) that may result in improved muscle oxygenation. In the ECR, but not in the FCU, this was accompanied by reduction in muscle fiber oxidative capacity as reflected by reduced optical density of sections stained for succinate dehydrogenase (p = 0.013). The reduced oxidative capacity and absence of significant capillary rarefaction resulted in a capillary to fiber ratio per unit of oxidative capacity that was higher after stroke in the ECR (p = 0.01), but not in the FCU. This suggests that at least during the early stages, stroke is not necessarily accompanied by muscle fiber atrophy, and that stroke-induced reductions in oxidative capacity resulting in relative excess of capillarization are muscle specific.

Brain Vascular Expression of Monomeric C-Reactive Protein Is Blocked by C10M Following Intraperitoneal Injection in an ApoE-/- Murine Model of Dyslipidemia: An Immunohistochemical Analysis.

Introduction The neurovascular unit (NVU), comprising vascular and glial cells along with neurons, is vital for maintaining the blood-brain barrier (BBB) and cerebral homeostasis. Dysfunction of the NVU is implicated in key neurodegenerative disorders such as Alzheimer's disease (AD). Monomeric C-reactive protein (mCRP), the dissociated form of native, pentameric C-reactive protein (pCRP), is associated with enhanced pro-inflammatory responses in the vascular system, leading to increased permeability and potential NVU disruption. Methods This study utilized ApoE-/- mice receiving a high-fat diet which were injected intraperitoneally with either mCRP or mCRP together with a small molecule inhibitor (C10M) and investigated the deposition of mCRP and CD105 expression in the brain parenchyma and its localization within the microvasculature. Results Histological analysis revealed significant mCRP deposition in brain microvessels and neurons, indicating potential disruption of the BBB and neuronal damage. Moreover, co-administration of C10M effectively blocked mCRP accumulation in the brain parenchyma, suggesting its potential as a therapeutic agent for effectively inhibiting inflammation-associated degenerative changes. Immunohistochemical staining demonstrated co-localization of mCRP with CD105, indicating potential angiogenic activation and increased susceptibility to inflammatory insult. Discussion These findings provide evidence supporting the potential role of mCRP as a contributor to neuroinflammation in individuals with chronic systemic inflammation. Conclusion Further studies in human subjects should help validate the efficacy of C10M in preventing or halting neurodegeneration in conditions such as AD and stroke-associated dementia.

Monomeric C-Reactive Protein Potential Utilization in the Histological Assessment of Inflammatory Bowel Disease (IBD) Patients.

Introduction Inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn's disease (CD), represent chronic progressive inflammatory gastrointestinal disorders, without a single reference standard for their diagnosis. The histological assessment gained an important role in accurately measuring disease activity, and mucosal healing (MH) was recently proposed to be an ideal treatment goal for patients with IBD because of its favorable prognosis, with a lower risk of recurrence or surgical treatment. This paper aims to add to the histological classical findings for IBD patients the identification of the monomeric form of the C-reactive protein (mCRP) as a supplementary marker that could be stained at the level of tissue samples and could be correlated with the pathogenic mechanism. Methods Two groups of 10 patients were each selected for the study, for both UC and CD, together with a control group. All samples collected through digestive endoscopy were analyzed by using H&E-stained slides, followed by immunohistochemical examination with antibodies to mCRP (M8C10), and markers of inflammatory activity through CD3, CD45(leukocyte common antigen (LCA)), CD138/syndecan-1 and CD68. Results For the CD study group, all histological elements identified with H&E and afterward stained with CD138, CD68, CD3, and CD45/LCA were correlated with the standards imposed by the European Crohn's and Colitis Organization (ECCO). For the group of patients with UC, histological images obtained with H&E and IHC stainings also confirmed the recommendation of ECCO. The main cells considered in the literature as histological markers for IBD are neutrophils, lymphocytes, and plasmocytes, stained in our study with CD45/LCA, CD3, and CD138. For all 20 cases of IBD (UC and CD), the staining with anti-Ab8C10 antibodies for mCRP was positive, while negative results were noticed within the control group. An mCRP protein visualized with anti-Ab8C10 antibodies presented an intracytoplasmatic localization in the neutrophils, plasma cells, lymphocytes, and macrophages from the lamina propria and glandular epithelium, without expression in endothelial cells. Conclusions Our study represents one of the first papers that identifies the localization of mCRP molecules within the intestinal mucosa of patients with IBD (both UC and CD) by using immunohistochemistry (IHC) staining. This finding opens a new perspective for considering mCRP as a marker correlated with histological disease activity and/or definition of histological remission in IBD.

C-reactive Protein: An Inflammatory Biomarker and a Predictor of Neurodegenerative Disease in Patients With Inflammatory Bowel Disease?

Inflammatory bowel disease (IBD) refers to two chronic conditions of the digestive tract: ulcerative colitis (UC) and Crohn's disease (CD), representing a progressive inflammatory process that mainly occurs in the gut, with frequent extra-intestinal manifestations. Even if remission is periodically obtained for some patients, the histological activity and digestive symptoms may continue, maintaining a persistent systemic inflammation that could induce further extra-intestinal complications and contribute to the development of neurodegenerative disease. C-reactive protein (CRP) is an acute-phase reactant that is widely accepted as a dominant serum biomarker in IBD. CRP consequently activates the complement cascade, supports the release of pro-inflammatory cytokines, and the clearance of microbial pathogens. All these processes facilitate further processes, including atherosclerosis and hypercoagulability, alteration of the intestinal microbiota, and the increased permeability of the intestinal barrier for neurotoxic substances produced by gut microorganisms, due to the presence of a high level of lipopolysaccharides. For IBD, the connection between intestinal inflammation and central nervous system inflammation could be explained through the activity of the vagus nerve, a carrier of cytokines, CRP, and toxic materials to the brain, potentially inducing vascular lesions and damage of the glial vascular unit, with further risk for degeneration within the central nervous system. CRP is a key marker for IBD pathogenesis and is able to dissociate into its monomeric form, mCRP, on contact with activated cell and tissue components via the systemic circulation. We hypothesize that the chronic inflammatory process within IBD could initiate neuroinflammation and neurodegeneration, and therefore, further investigation of the significance of chronically raised plasma of CRP and mCRP in patients with IBD is warranted, as it may represent a critical predictive factor associated with a later neurodegenerative risk. Any future initiative aimed at pharmacologic modulation of CRP (e.g., blocking CRP-mCRP dissociation), could represent a new therapeutic approach protecting against intestinal inflammation and concomitantly reducing the risk of neuroinflammation, neurodegeneration, and cognitive decline.

A Gender-Bias-Mitigated, Data-Driven Precision Medicine System to Assist in the Selection of Biological Treatments of Grade 3 and 4 Knee Osteoarthritis: Development and Preliminary Validation of precisionKNEE.

Objective To identify key variables predictive of patient responses to microfragmented adipose tissue (MFAT) treatment in knee osteoarthritis (KOA) and evaluate its potential to delay or mitigate the need for total knee replacement (TKR). Methods We utilised a dataset comprising 329 patients treated with MFAT for KOA, incorporating variables such as gender, age, BMI, arthritic aetiology, radiological grade, and Oxford Knee Scores (OKS) pre- and post-treatment. We employed random forest regressors for model training and testing, with gender bias mitigation and outlier detection to enhance prediction accuracy. Model performance was assessed through root mean squared error (RMSE) and mean absolute error (MAE), with further validation in a TKR-suitable patient subset. Results The model achieved a test RMSE of 6.72 and an MAE of 5.38, reflecting moderate predictive accuracy across the patient cohort. Stratification by gender revealed no statistically significant differences between actual and predicted OKS improvements (p-values: males = 0.93, females = 0.92). For the subset of patients suitable for TKR, the model presented an increased RMSE of 9.77 and MAE of 7.81, indicating reduced accuracy in this group. The decision tree analysis identified pre-operative OKS, radiological grade, and gender as significant predictors of post-treatment outcomes, with pre-operative OKS being the most critical determinant. Patients with lower pre-operative OKS showed varying responses based on radiological severity and gender, suggesting a nuanced interaction between these factors in determining treatment efficacy. Conclusion This study highlights the potential of MFAT as a non-surgical alternative for KOA treatment, emphasising the importance of personalised patient assessments. While promising, the predictive model warrants further refinement and validation with a larger, more diverse dataset to improve its utility in clinical decision-making for KOA management.

mCRP-Induced Focal Adhesion Kinase-Dependent Monocyte Aggregation and M1 Polarization, Which Was Partially Blocked by the C10M Inhibitor.

Monomeric C-reactive protein (mCRP) has recently been implicated in the abnormal vascular activation associated with development of atherosclerosis, but it may act more specifically through mechanisms perpetuating damaged vessel inflammation and subsequent aggregation and internalization of resident macrophages. Whilst the direct effects of mCRP on endothelial cells have been characterized, the interaction with blood monocytes has, to our knowledge, not been fully defined. Here we showed that mCRP caused a strong aggregation of both U937 cell line and primary peripheral blood monocytes (PBMs) obtained from healthy donors. Moreover, this increase in clustering was dependent on focal adhesion kinase (FAK) activation (blocked by a specific inhibitor), as was the concomitant adhesive attachment to the plate, which was suggestive of macrophage differentiation. Confocal microscopy confirmed the increased expression and nuclear localization of p-FAK, and cell surface marker expression associated with M1 macrophage polarization (CD11b, CD14, and CD80, as well as iNOS) in the presence of mCRP. Inclusion of a specific CRP dissociation/mCRP inhibitor (C10M) effectively inhibited PBMs clustering, as well as abrogating p-FAK expression, and partially reduced the expression of markers associated with M1 macrophage differentiation. mCRP also increased the secretion of pro-inflammatory cytokines Interleukin-8 (IL-8) and Interleukin-1ß (IL-1ß), without notably affecting MAP kinase signaling pathways; inclusion of C10M did not perturb or modify these effects. In conclusion, mCRP modulates PBMs through a mechanism that involves FAK and results in cell clustering and adhesion concomitant with changes consistent with M1 phenotypical polarization. C10M has potential therapeutic utility in blocking the primary interaction of mCRP with the cells-for example, by protecting against monocyte accumulation and residence at damaged vessels that may be predisposed to plaque development and atherosclerosis.

Resveratrol Activates Antioxidant Protective Mechanisms in Cellular Models of Alzheimer's Disease Inflammation.

Resveratrol is a natural phenolic compound with known benefits against neurodegeneration. We analyzed in vitro the protective mechanisms of resveratrol against the proinflammatory monomeric C-reactive protein (mCRP). mCRP increases the risk of AD after stroke and we previously demonstrated that intracerebral mCRP induces AD-like dementia in mice. Here, we used BV2 microglia treated with mCRP for 24 h in the presence or absence of resveratrol. Cells and conditioned media were collected for analysis. Lipopolysaccharide (LPS) has also been implicated in AD progression and so LPS was used as a resveratrol-sensitive reference agent. mCRP at the concentration of 50 µg/mL activated the nitric oxide pathway and the NLRP3 inflammasome pathway. Furthermore, mCRP induced cyclooxygenase-2 and the release of proinflammatory cytokines. Resveratrol effectively inhibited these changes and increased the expression of the antioxidant enzyme genes Cat and Sod2. As central mechanisms of defense, resveratrol activated the hub genes Sirt1 and Nfe2l2 and inhibited the nuclear translocation of the signal transducer NF-ĸB. Proinflammatory changes induced by mCRP in primary mixed glial cultures were also protected by resveratrol. This work provides a mechanistic insight into the protective benefits of resveratrol in preventing the risk of AD induced by proinflammatory agents.

A Quantum-Enhanced Precision Medicine Application to Support Data-Driven Clinical Decisions for the Personalized Treatment of Advanced Knee Osteoarthritis: The Development and Preliminary Validation of precisionKNEE_QNN.

Background Quantum computing and quantum machine learning (QML) are promising experimental technologies that can improve precision medicine applications by reducing the computational complexity of algorithms driven by big, unstructured, real-world data. The clinical problem of knee osteoarthritis is that, although some novel therapies are safe and effective, the response is variable, and defining the characteristics of an individual who will respond remains a challenge. In this study, we tested a quantum neural network (QNN) application to support precision data-driven clinical decisions to select personalized treatments for advanced knee osteoarthritis. Methodology After obtaining patients' consent and Research Ethics Committee approval, we collected the clinicodemographic data before and after the treatment from 170 patients eligible for knee arthroplasty (Kellgren-Lawrence grade ≥3, Oxford Knee Score (OKS) ≤27, age ≥64 years, and idiopathic aetiology of arthritis) treated over a two-year period with a single injection of microfragmented fat. Gender classes were balanced (76 males and 94 females) to mitigate gender bias. A patient with an improvement ≥7 OKS was considered a responder. We trained our QNN classifier on a randomly selected training subset of 113 patients to classify responders from non-responders (73 responders and 40 non-responders) in pain and function at one year. Outliers were hidden from the training dataset but not from the validation set. Results We tested our QNN classifier on a randomly selected test subset of 57 patients (34 responders, 23 non-responders) including outliers. The no information rate was 0.59. Our application correctly classified 28 responders out of 34 and 6 non-responders out of 23 (sensitivity = 0.82, specificity = 0.26, F1 Statistic = 0.71). The positive and negative likelihood ratios were 1.11 and 0.68, respectively. The diagnostic odds ratio was 2. Conclusions Preliminary results on a small validation dataset showed that QML applied to data-driven clinical decisions for the personalized treatment of advanced knee osteoarthritis is a promising technology to reduce computational complexity and improve prognostic performance. Our results need further research validation with larger, real-world unstructured datasets, as well as clinical validation with an artificial intelligence clinical trial to test model efficacy, safety, clinical significance, and relevance at a public health level.

Intraplaque Neovascularization, CD68+ and iNOS2+ Macrophage Infiltrate Intensity Are Associated with Atherothrombosis and Intraplaque Hemorrhage in Severe Carotid Atherosclerosis.

BACKGROUND: Atherosclerosis is a progressive disease that results from endothelial dysfunction, inflammatory arterial wall disorder and the formation of the atheromatous plaque. This results in carotid artery stenosis and is responsible for atherothrombotic stroke and ischemic injury. Low-grade plaque inflammation determines biological stability and lesion progression. METHODS: Sixty-seven cases with active perilesional inflammatory cell infiltrate were selected from a larger cohort of patients undergoing carotid endarterectomy. CD68+, iNOS2+ and Arg1+ macrophages and CD31+ endothelial cells were quantified around the atheroma lipid core using digital morphometry, and expression levels were correlated with determinants of instability: ulceration, thrombosis, plaque hemorrhage, calcification patterns and neovessel formation. RESULTS: Patients with intraplaque hemorrhage had greater CD68+ macrophage infiltration (p = 0.003). In 12 cases where iNOS2 predominated over Arg1 positivity, the occurrence of atherothrombotic events was significantly more frequent (p = 0.046). CD31 expression, representing neovessel formation, correlated positively with atherothrombosis (p = 0.020). CONCLUSIONS: Intraplaque hemorrhage is often described against the background of an intense inflammatory cell infiltrate. Atherothrombosis is associated with the presence of neovessels and pro-inflammatory macrophages expressing iNOS2. Modulating macrophage polarization may be a successful therapeutic approach to prevent plaque destabilization.

Astrocyte Involvement in Blood-Brain Barrier Function: A Critical Update Highlighting Novel, Complex, Neurovascular Interactions.

Neurological disorders have been linked to a defective blood-brain barrier (BBB), with dysfunctions triggered by stage-specific disease mechanisms, some of these being generated through interactions in the neurovascular unit (NVU). Advanced knowledge of molecular and signaling mechanisms in the NVU and the emergence of improved experimental models allow BBB permeability prediction and the development of new brain-targeted therapies. As NVU constituents, astrocytes are the most numerous glial cells, characterized by a heterogeneity that occurs as a result of developmental and context-based gene expression profiles and the differential expression of non-coding ribonucleic acids (RNAs). Due to their heterogeneity and dynamic responses to different signals, astrocytes may have a beneficial or detrimental role in the BBB's barrier function, with deep effects on the pathophysiology of (and on the progression of) central nervous system diseases. The implication of astrocytic-derived extracellular vesicles in pathological mechanisms, due to their ability to pass the BBB, must also be considered. The molecular mechanisms of astrocytes' interaction with endothelial cells at the BBB level are considered promising therapeutic targets in different neurological conditions. Nevertheless, a personalized and well-founded approach must be addressed, due to the temporal and spatial heterogeneity of reactive astrogliosis states during disease.

Micro-Fragmented Adipose Tissue as a Natural Scaffold for Targeted Drug Delivery in Brain Cancer.

Major limitations in the effective treatment of neurological cancer include systemic cytotoxicity of chemotherapy, inaccessibility, and inoperability. The capability to successfully target a drug to the tumor site(s) without incurring serious side effects-especially in the case of aggressive tumors, such as glioblastoma and neuroblastoma-would represent a significant breakthrough in therapy. Orthotopic systems, capable of storing and releasing proteins over a prolonged period at the site of a tumor, that utilize nanoparticles, liposomes, and hydrogels have been proposed. One candidate for drug delivery is Micro-Fragmented Adipose Tissue (MFAT). Easily obtained from the patient by abdominal subcutaneous liposuction (autologous), and with a high content of Mesenchymal Stem Cells (MSCs), mechanically derived nanofat is a natural tissue graft with a structural scaffold organization. It has a well-preserved stromal vascular fraction and a prolonged capacity to secrete anti-tumorigenic concentrations of pre-absorbed chemotherapeutics within extracellular vesicles. This review discusses current evidence supporting the potential of drug-modified MFAT for the treatment of neurological cancer with respect to recent preclinical and in vitro studies. Possible limitations and future perspectives are considered.

Monomeric C-reactive protein: A novel biomarker predicting neurodegenerative disease and vascular dysfunction.

Circulating C-reactive protein (pCRP) concentrations rise dramatically during both acute (e.g., following stroke) or chronic infection and disease (e.g., autoimmune conditions such as lupus), providing complement fixation through C1q protein binding. It is now known, that on exposure to the membranes of activated immune cells (and microvesicles and platelets), or damaged/dysfunctional tissue, it undergoes lysophosphocholine (LPC)-phospholipase-C-dependent dissociation to the monomeric form (mCRP), concomitantly becoming biologically active. We review histological, immunohistochemical, and morphological/topological studies of post-mortem brain tissue from individuals with neuroinflammatory disease, showing that mCRP becomes stably distributed within the parenchyma, and resident in the arterial intima and lumen, being "released" from damaged, hemorrhagic vessels into the extracellular matrix. The possible de novo synthesis via neurons, endothelial cells, and glia is also considered. In vitro, in vivo, and human tissue co-localization analyses have linked mCRP to neurovascular dysfunction, vascular activation resulting in increased permeability, and leakage, compromise of blood brain barrier function, buildup of toxic proteins including tau and beta amyloid (Aß), association with and capacity to "manufacture" Aß-mCRP-hybrid plaques, and, greater susceptibility to neurodegeneration and dementia. Recently, several studies linked chronic CRP/mCRP systemic expression in autoimmune disease with increased risk of dementia and the mechanisms through which this occurs are investigated here. The neurovascular unit mediates correct intramural periarterial drainage, evidence is provided here that suggests a critical impact of mCRP on neurovascular elements that could suggest its participation in the earliest stages of dysfunction and conclude that further investigation is warranted. We discuss future therapeutic options aimed at inhibiting the pCRP-LPC mediated dissociation associated with brain pathology, for example, compound 1,6-bis-PC, injected intravenously, prevented mCRP deposition and associated damage, after temporary left anterior descending artery ligation and myocardial infarction in a rat model.

A meta-analysis investigating the relationship between inflammation in autoimmune disease, elevated CRP, and the risk of dementia.

Alzheimer's Disease (AD) represents the most common type of dementia and is becoming a steadily increasing challenge for health systems globally. Inflammation is developing as the main focus of research into Alzheimer's disease and has been demonstrated to be a major driver of the pathologies associated with AD. This evidence introduces an interesting research question, whether chronic inflammation due to pathologies such as inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) could lead to a higher risk of developing dementia. In both IBD and RA, increased levels of the inflammatory biomarker C-reactive protein (CRP) can be highlighted, the latter being directly implicated in neuroinflammation and AD. In this meta-analysis both the association between chronic inflammatory diseases and elevated levels of CRP during midlife were investigated to examine if they correlated with an augmented risk of dementia. Moreover, the association between increased CRP and modifications in the permeability of the Blood Brain Barrier (BBB) in the presence of CRP is explored. The results displayed that the odds ratio for IBD and dementia was 1.91 [1.15-3.15], for RA it was 1.90 [1.09-3.32] following sensitivity analysis and for CRP it was 1.62 [1.22-2.15]. These results demonstrate a higher risk of dementia in patients presenting chronic inflammation and that exists an independent association with high CRP in midlife. This paper builds on published research that suggest a critical role for CRP both in stroke and AD and provides an analysis on currently published research on multiple diseases (IBD and RA) in which CRP is raised as well as chronically elevated. CRP and the associated risk of dementia and further research indicated that the monomeric form of CRP can infiltrate the BBB/be released from damaged micro-vessels to access the brain. This meta-analysis provides first-time evidence that chronic elevation of CRP in autoimmune diseases is directly associated with an increased risk of later development of Alzheimer's disease. Therefore, greater priority should be provided to the effective control of inflammation in patients with chronic inflammatory or autoimmune conditions and further long-term assessment of circulating CRP might inform of an individual's relative risk of developing dementia.

Case Report: Coexistence of generalized arterial calcification of infancy (GACI) and maternal infections with cytomegalovirus and Toxoplasma gondii-unexpected fatal complication in a newborn.

Generalized arterial calcification of infancy (GACI) is an extremely rare autosomal recessive condition characterized by the storage of calcium at the level of internal elastic membrane of arteries. The main consequences are intimal fibrous thickening and arterial occlusion. We present the case of a preterm male infant, born from an improperly dispensed pregnancy. At birth, the newborn presented generalized edema and hypotonia, and abolished heart sounds, without response to stimulation. Despite the mechanical ventilation, the infant died 2 h after birth. The death was clinically presumed to be related to the maternal infection with cytomegalovirus (CMV) and Toxoplasma gondii. The infant's mother affirmed the history of 6 previous miscarriages and a non-consanguineous marriage. At autopsy, microscopic examination showed generalized vasculitis secondary to minimal calcification of the large and medium-sized vessels of the lungs, liver, and tongue. These findings supported the diagnosis of GACI. Hydrothorax, non-infective ascites, and necrosis of the brain parenchyma were also associated. The premature infant died due to tonsillar herniation associated with decreased vessel compliance and refractory pulmonary hypertension thus leading to congestive cardiac failure. CMV was not detected on histopathological assessment nor were signs of any other infections. To the best of our knowledge, this is the first case of GACI occurring in a baby from a mother co-infected with CMV and T. gondii.

Polydatin Prevents Neuroinflammation and Relieves Depression via Regulating Sirt1/HMGB1/NF-κB Signaling in Mice.

Depression is a prevalent psychiatric disorder with a significant health impact and economic burden worldwide. Unfortunately, the exact pathogenesis of depression is not well understood. Neuroinflammation and microglial activation play an essential role in the pathogenesis of depression. Previous studies have shown that polydatin has anti-inflammatory and antioxidant properties. However, the link between polydatin and depression remains unclear. Therefore, the objective of this study was to investigate the antidepressant effect of polydatin in lipopolysaccharide (LPS)-induced depression in mice and its possible mechanism. Adult male C57BL/6 J mice were used in this study. The polydatin and LPS were injected intraperitoneally daily for 5 days. In addition, the EX527, an inhibitor of Sirt1, was injected intraperitoneally daily and 1 h before the polydatin injection. The behavior tests were performed to elucidate the depression-like behaviors. The Sirt1/HMGB1/NF-κB pathway expression was detected by western blot, ELISA, and immunofluorescence staining. Polydatin can significantly improve LPS-induced depression-like behavior in mice. Treatment with polydatin increased the expression of the Sirt1 but decreased the expression of the HMGB1, p-NF-κB, IL-1b, and TNF-α in the LPS-induced depression mice. In addition, the EX527 abolished the anti-depressive effects of the polydatin and the levels of Sirt1 protein. These findings suggested that the polydatin reversed the depressive effects through the Sirt1/HMGB1/NF-κB signaling in the LPS-induced depression mice. Therefore, polydatin can be used in the treatment of depression.