Lower-extremity endovascular revascularization (LER) is often required for diabetic patients with chronic limb threatening ischemia (CLTI). During the post-revascularization period patients may ...unpredictably experience major adverse cardiac events (MACE) and major adverse limb events (MALE). Several families of cytokines are involved in the inflammatory process that underlies the progression of atherosclerosis. According to current evidence, we have identified a panel of possible biomarkers related with the risk of developing MACE and MALE after LER. The aim was to study the relationship between a panel of biomarkers - Interleukin-1 (IL-1) and 6 (IL-6), C-Reactive Protein (CRP), Tumor Necrosis Factor-α (TNF-α), High-Mobility Group Box-1 (HMGB-1), Osteoprotegerin (OPG), Sortilin and Omentin-1- at baseline, with cardiovascular outcomes (MACE and MALE) after LER in diabetic patients with CLTI.
In this prospective non-randomized study, 264 diabetic patients with CLTI undergoing endovascular revascularization were enrolled. Serum levels of each biomarker were collected before revascularization and outcomes' incidence was evaluated after 1, 3, 6 and 12 months.
During the follow-up period, 42 cases of MACE and 81 cases of MALE occurred. There was a linear association for each biomarker at baseline and incident MACE and MALE, except Omentin-1 levels that were inversely related to the presence of MACE or MALE. After adjusting for traditional cardiovascular risk factors, the association between each biomarker baseline level and outcomes remained significant in multivariable analysis. Receiver operating characteristics (ROC) models were constructed using traditional clinical and laboratory risk factors and the inclusion of biomarkers significantly improved the prediction of incident events.
Elevated IL-1, IL-6, CRP, TNF-α, HMGB-1, OPG and Sortilin levels and low Omentin-1 levels at baseline correlate with worse vascular outcomes in diabetic patients with CLTI undergoing LER. Assessment of the inflammatory state with this panel of biomarkers may support physicians to identify a subset of patients more susceptible to the procedure failure and to develop cardiovascular adverse events after LER.
High-mobility group box-1 (HMGB1) protein is a nuclear DNA-binding protein released from necrotic cells, inducing inflammatory responses and promoting tissue repair and angiogenesis. Diabetic human ...and mouse tissues contain lower levels of HMGB1 than their normoglycemic counterparts. Deficient angiogenesis after ischemia contributes to worse outcomes of peripheral arterial disease in patients with diabetes. To test the hypothesis that HMGB1 enhances ischemia-induced angiogenesis in diabetes, we administered HMGB1 protein in a mouse hind limb ischemia model using diabetic mice.
After the induction of diabetes by streptozotocin, we studied ischemia-induced neovascularization in the ischemic hind limb of normoglycemic, diabetic, and HMGB1-treated diabetic mice.
We found that the perfusion recovery was significantly attenuated in diabetic mice compared with normoglycemic control mice. Interestingly, HMGB1 protein expression was lower in the ischemic tissue of diabetic mice than in normoglycemic mice. Furthermore, we observed that HMGB1 administration restored the blood flow recovery and capillary density in the ischemic muscle of diabetic mice, that this process was associated with the increased expression of vascular endothelial growth factor (VEGF), and that HMGB1-induced angiogenesis was significantly reduced by inhibiting VEGF activity.
The results of this study show that endogenous HMGB1 is crucial for ischemia-induced angiogenesis in diabetic mice and that HMGB1 protein administration enhances collateral blood flow in the ischemic hind limbs of diabetic mice through a VEGF-dependent mechanism.
Background Infective endocarditis (IE) could be suspected in any febrile patients admitted to the emergency department (ED). This study was aimed at assessing clinical criteria predictive of IE and ...identifying and prospectively validating a sensible and easy-to-use clinical prediction score for the diagnosis of IE in the ED. Methods and Results We conducted a retrospective observational study, enrolling consecutive patients with fever admitted to the ED between January 2015 and December 2019 and subsequently hospitalized. Several clinical and anamnestic standardized variables were collected and evaluated for the association with IE diagnosis. We derived a multivariate prediction model by logistic regression analysis. The identified predictors were assigned a score point value to obtain the Clinical Rule for Infective Endocarditis in the Emergency Department (CREED) score. To validate the CREED score we conducted a prospective observational study between January 2020 and December 2021, enrolling consecutive febrile patients hospitalized after the ED visit, and evaluating the association between the CREED score values and the IE diagnosis. A total of 15 689 patients (median age, 71 56-81 years; 54.1% men) were enrolled in the retrospective cohort, and IE was diagnosed in 267 (1.7%). The CREED score included 12 variables: male sex, anemia, dialysis, pacemaker, recent hospitalization, recent stroke, chest pain, specific infective diagnosis, valvular heart disease, valvular prosthesis, previous endocarditis, and clinical signs of suspect endocarditis. The CREED score identified 4 risk groups for IE diagnosis, with an area under the receiver operating characteristic curve of 0.874 (0.849-0.899). The prospective cohort included 13 163 patients, with 130 (1.0%) IE diagnoses. The CREED score had an area under the receiver operating characteristic curve of 0.881 (0.848-0.913) in the validation cohort, not significantly different from the one calculated in the retrospective cohort (
=0.578). Conclusions In this study, we propose and prospectively validate the CREED score, a clinical prediction rule for the diagnosis of IE in patients with fever admitted to the ED. Our data reflect the difficulty of creating a meaningful tool able to identify patients with IE among this general and heterogeneous population because of the complexity of the disease and its low prevalence in the ED setting.
Objective Atherosclerosis and vascular remodeling after injury are driven by inflammation and mononuclear cell infiltration. Unstable atherosclerotic plaques are characterized by a large necrotic ...core. In this study we investigated the distribution and interaction between gene polymorphisms encoding proinflammatory molecules in an Italian population with internal carotid artery stenosis (ICAS). We also evaluated whether reciprocal interaction between these gene polymorphisms increased the risk of plaque vulnerability. Methods In this genetic association study, 11 proinflammatory gene polymorphisms were analyzed in 933 individuals comprising 344 patients with ICAS who underwent carotid endarterectomy and 589 controls without ultrasound evidence of atherosclerosis or intimal thickening. Results We found that interleukin (IL) 6 ( IL-6 ), IL-1β, monocyte chemoattractant protein-1 ( CCL2 ) macrophage inflammatory protein-1α ( CCL3 ), E-selectin ( SELE ), intercellular adhesion molecule 1 ( ICAM1 ), and matrix metalloproteinase-3 ( MMP-3 ), and 9 ( MMP-9 ) gene variants were independently and significantly associated with ICAS. The association remained significant even after the Bonferroni correction. We also found a genetic profile associated with different risks for ICAS, depending on the number of high-risk genotypes simultaneously present in an individual. Furthermore, proinflammatory genetic profiles are significantly more common in individuals with unstable carotid plaque. Conclusions Our study shows, for the first time, a reciprocal interaction between proinflammatory genotypes for the development and progression of ICAS.
Rheumatoid arthritis (RA) is a chronic, definitely disabling, and potentially severe autoimmune disease. Although an increasing number of patients are affected, a key treatment for all patients has ...not been discovered. High-mobility group box-1 (HMGB1) is a nuclear protein passively and actively released by almost all cell types after several stimuli. HMGB1 is involved in RA pathogenesis, but a convincing explanation about its role and possible modulation in RA is still lacking. Microbiome and its homeostasis are altered in patients with RA, and the microbiota restoration has been proposed to patients with RA. The purpose of the present review is to analyze the available evidences regarding HMGB1 and microbiome roles in RA and the possible implications of the crosstalk between the nuclear protein and microbiome in understanding and possibly treating patients affected by this harmful condition.
Objective: Li-Fraumeni Syndrome (LFS) is a rare autosomal-dominant syndrome caused by a heterozygous germline mutation of the TP53 gene. It is characterized by early-onset malignancies and high ...penetrance. Non-bacterial thrombotic endocarditis (NBTE) is an uncommon condition for which cancer is a significant risk factor. Here we present a complex case of LFS unveiled by a NBTE-related ischemic stroke. Case presentation: A 41-year-old woman was admitted following a syncopal episode, preceded by a history of ischemic stroke. She had a notable family history of cancers. Imaging studies revealed ischemic damage and hemorrhagic infarcts, indicating a possible embolic origin or neoplastic involvement. Subsequent examinations revealed a NBTE on the aortic valve as well as multiple primary malignancies including high-grade invasive ductal carcinoma in the breast and primary lung adenocarcinoma. Genetic testing confirmed the presence of a pathogenic variant in TP53. Conclusion: This case underscores the intricate interplay between LFS, oncological manifestations, and thrombotic complications leading to ischemic stroke through NBTE embolization.
Cilostazol (CIL) is effective for the treatment of patients with peripheral arterial disease (PAD). CIL is an orally administered drug with multiple effects, including anti-platelets aggregation, ...favorable functions on plasmatic lipids and vasodilator ones, but how these effects might be related to improvement in patients walking affected by PAD is not fully understood. The latest data demonstrate that nitric oxide (NO) is induced by CIL through endothelial nitric oxide synthase (eNOS) activation via a cyclic-AMP (cAMP)/ protein kinase A (PKA)- and PI3K/Akt- dependent mechanism. This mechanism is also responsible for the vasodilatation dependent on endothelium which characterized patients receiving CIL. Other investigators have found that CIL notably reduces the exercise-induced host-inflammatory response in PAD patients, and consequently it improves lipid hydroperoxides and cell-adhesion molecule levels. We recently reported that CIL is able to cause neoangiogenesis in vivo by stimulating the production of proangiogenic proteins, such as vascular endothelial growth factor (VEGF), that increase levels of Endothelial progenitor cells (EPCs) and the formation of new blood vessels. The mechanisms of action of this drug are several and are not clear and established. The objective of the present review is to analyze the existing data about the therapeutic effects of CIL, with the purpose of providing practical indications about this topic for the management of subjects affected by ischemic disorders.
The diabetic Charcot foot syndrome is a serious and potentially limbthreatening lower-extremity complication of diabetes.
The present review provides a concise account of the advances made over the ...last twentyfive years in understanding the pathogenesis and management of Charcot neuroarthropathy (CN).
In this study, the widely known pathogenetic mechanisms underpinning CN are brought into focus, particularly the role of RANKL/RANK/OPG system and advanced glycation end production in the pathogenesis of CN. Furthermore, other potential triggering factors, namely nitric oxide, endothelial dysfunction, macro calcifications and body weight that influence CN have also been discussed.
The wide range of diagnostic tools available to clinicians for accurate staging of this pathology has been examined, particularly radiological and nuclear medicine imaging. Additionally, the difficult differential diagnosis between osteomyelitis and CN is also elucidated.
The review concludes with the comprehensive summary of the major promising therapeutic strategies, including conservative treatment involving orthopedic devices, pharmacological approach, and the most common surgical techniques currently employed in the diagnosis and treatment of this acute disease.
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