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.

Finite Element Analysis of Various Osteotomies Used in the Treatment of Developmental Hip Dysplasia in Children.

Late-discovered developmental hip dysplasia deformities often necessitate complex surgical treatments and meticulous preoperative planning. The selection of osteotomies is contingent upon the patient's age and the specific structural deformity of the hip. In our anatomical hip model, derived from the data of a 12-year-old patient, we performed virtual osteotomies that are commonly recommended for such cases. We precisely constructed geometric models for various osteotomies, including the Dega, Pemberton, Tönnis, Ganz, Chiari pelvic, and Pauwels femoral osteotomies. We employed Autodesk Inventor for the finite element analysis of the hip joint and the corrective osteotomies. In comparing one-stage osteotomies, we noted that the Dega and Ganz pelvic osteotomies, especially when combined with the Pauwels femoral osteotomy, yielded the most favorable outcomes. These combinations led to enhanced femoral head coverage and reduced intra-articular pressure. Furthermore, we calculated the femoral head-to-acetabulum volume ratio for both the Dega and Pauwels osteotomies. The encouraging results we obtained advocate for the integration of finite element analysis in virtual osteotomies of the pelvis and femur as a preoperative tool in the management of developmental hip dysplasia.

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.

Cough-Induced Multiple, Bilateral, Asymmetrical Rib Fractures in a Scoliosis Patient: A Case Report.

Cough-induced rib fractures represent infrequent complications of strenuous and prolonged coughing, mostly provoked by respiratory tract infections, with localized chest pain being the most indicative component of the clinical picture. This paper reports a case of a 27-year-old female patient who presented with four cough-induced rib fractures following the contraction of an upper respiratory tract infection. The unique character of this case is provided by the young age of the patient, the presence of multiple and bilaterally located rib fractures, and the absence of predisposing factors related to her bone physiology. Furthermore, three of the four fractures were revealed on the left side, where a scoliotic sinistro-convex thoracic curvature is described. Following conservative treatment, the patient experienced a complete resolution of symptoms and favorable clinical outcomes. Even in the seemingly low-risk category, the diagnosis of cough-induced rib fractures should be taken into consideration, and their correlation to pre-existing rib deformities, such as the ones secondary to scoliosis, should be thoroughly investigated.

Finite Element Analysis of Normal and Dysplastic Hip Joints in Children.

From a surgical point of view, quantification cannot always be achieved in the developmental deformity in hip joints, but finite element analysis can be a helpful tool to compare normal joint architecture with a dysplastic counterpart. CT scans from the normal right hip of an 8-year-old boy and the dysplastic left hip of a 12-year-old girl were used to construct our geometric models. In a three-dimensional model construction, distinctions were made between the cortical bone, trabecular bone, cartilage, and contact nonlinearities of the hip joint. The mathematical model incorporated the consideration of the linear elastic and isotropic properties of bony tissue in children, separately for the cortical bone, trabecular bone, and articular cartilage. Hexahedral elements were used in Autodesk Inventor software version 2022 ("Ren") for finite element analysis of the two hips in the boundary conditions of the single-leg stance. In the normal hip joint on the cartilaginous surfaces of the acetabulum, we found a kidney-shaped stress distribution in a 471,672 mm2 area. The measured contact pressure values were between 3.0 and 4.3 MPa. In the dysplastic pediatric hip joint on a patch of 205,272 mm2 contact area, the contact pressure values reached 8.5 MPa. Furthermore, the acetabulum/femur head volume ratio was 20% higher in the dysplastic hip joint. We believe that the knowledge gained from the normal and dysplastic pediatric hip joints can be used to develop surgical treatment methods and quantify and compare the efficiency of different surgical treatments used in children with hip dysplasia.

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.

Blood Count-Derived Inflammatory Markers Correlate with Lengthier Hospital Stay and Are Predictors of Pneumothorax Risk in Thoracic Trauma Patients.

(1) Background: Trauma is one of the leading causes of death worldwide, with the chest being the third most frequent body part injured after abdominal and head trauma. Identifying and predicting injuries related to the trauma mechanism is the initial step in managing significant thoracic trauma. The purpose of this study is to assess the predictive capabilities of blood count-derived inflammatory markers at admission. (2) Materials and Methods: The current study was designed as an observational, analytical, retrospective cohort study. It included all patients over the age of 18 diagnosed with thoracic trauma, confirmed with a CT scan, and admitted to the Clinical Emergency Hospital of Targu Mures, Romania. (3) Results: The occurrence of posttraumatic pneumothorax is highly linked to age (p = 0.002), tobacco use (p = 0.01), and obesity (p = 0.01). Furthermore, high values of all hematological ratios, such as the NLR, MLR, PLR, SII, SIRI, and AISI, are directly associated with the occurrence of pneumothorax (p < 0.001). Furthermore, increased values of the NLR, SII, SIRI, and AISI at admission predict a lengthier hospitalization (p = 0.003). (4) Conclusions: Increased neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), systemic inflammatory index (SII), aggregate inflammatory systemic index (AISI), and systemic inflammatory response index (SIRI) levels at admission highly predict the occurrence of pneumothorax, according to our data.

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.