Molecular Pathogenesis of Ischemic and Hemorrhagic Strokes: Background and Therapeutic Approaches.

Stroke represents one of the neurological diseases most responsible for death and permanent disability in the world. Different factors, such as thrombus, emboli and atherosclerosis, take part in the intricate pathophysiology of stroke. Comprehending the molecular processes involved in this mechanism is crucial to developing new, specific and efficient treatments. Some common mechanisms are excitotoxicity and calcium overload, oxidative stress and neuroinflammation. Furthermore, non-coding RNAs (ncRNAs) are critical in pathophysiology and recovery after cerebral ischemia. ncRNAs, particularly microRNAs, and long non-coding RNAs (lncRNAs) are essential for angiogenesis and neuroprotection, and they have been suggested to be therapeutic, diagnostic and prognostic tools in cerebrovascular diseases, including stroke. This review summarizes the intricate molecular mechanisms underlying ischemic and hemorrhagic stroke and delves into the function of miRNAs in the development of brain damage. Furthermore, we will analyze new perspectives on treatment based on molecular mechanisms in addition to traditional stroke therapies.

Diabetes and Ischemic Stroke: An Old and New Relationship an Overview of the Close Interaction between These Diseases.

Diabetes mellitus is a comprehensive expression to identify a condition of chronic hyperglycemia whose causes derive from different metabolic disorders characterized by altered insulin secretion or faulty insulin effect on its targets or often both mechanisms. Diabetes and atherosclerosis are, from the point of view of cardio- and cerebrovascular risk, two complementary diseases. Beyond shared aspects such as inflammation and oxidative stress, there are multiple molecular mechanisms by which they feed off each other: chronic hyperglycemia and advanced glycosylation end-products (AGE) promote 'accelerated atherosclerosis' through the induction of endothelial damage and cellular dysfunction. These diseases impact the vascular system and, therefore, the risk of developing cardio- and cerebrovascular events is now evident, but the observation of this significant correlation has its roots in past decades. Cerebrovascular complications make diabetic patients 2-6 times more susceptible to a stroke event and this risk is magnified in younger individuals and in patients with hypertension and complications in other vascular beds. In addition, when patients with diabetes and hyperglycemia experience an acute ischemic stroke, they are more likely to die or be severely disabled and less likely to benefit from the one FDA-approved therapy, intravenous tissue plasminogen activator. Experimental stroke models have revealed that chronic hyperglycemia leads to deficits in cerebrovascular structure and function that may explain some of the clinical observations. Increased edema, neovascularization, and protease expression as well as altered vascular reactivity and tone may be involved and point to potential therapeutic targets. Further study is needed to fully understand this complex disease state and the breadth of its manifestation in the cerebrovasculature.

Pathogenetic Mechanisms of Hypertension-Brain-Induced Complications: Focus on Molecular Mediators.

There is growing evidence that hypertension is the most important vascular risk factor for the development and progression of cardiovascular and cerebrovascular diseases. The brain is an early target of hypertension-induced organ damage and may manifest as stroke, subclinical cerebrovascular abnormalities and cognitive decline. The pathophysiological mechanisms of these harmful effects remain to be completely clarified. Hypertension is well known to alter the structure and function of cerebral blood vessels not only through its haemodynamics effects but also for its relationships with endothelial dysfunction, oxidative stress and inflammation. In the last several years, new possible mechanisms have been suggested to recognize the molecular basis of these pathological events. Accordingly, this review summarizes the factors involved in hypertension-induced brain complications, such as haemodynamic factors, endothelial dysfunction and oxidative stress, inflammation and intervention of innate immune system, with particular regard to the role of Toll-like receptors that have to be considered dominant components of the innate immune system. The complete definition of their prognostic role in the development and progression of hypertensive brain damage will be of great help in the identification of new markers of vascular damage and the implementation of innovative targeted therapeutic strategies.

Assessment of heart rate variability (HRV) in subjects with type 2 diabetes mellitus with and without diabetic foot: correlations with endothelial dysfunction indices and markers of adipo-inflammatory dysfunction.

BACKGROUND: Some studies have suggested that patients with diabetes and foot complications have worse cardiovascular and cerebrovascular risk profiles, higher degrees of endothelial dysfunction and arterial stiffness and a higher inflammatory background than patients with diabetes without diabetic foot complications. Patients with diabetes mellitus have an alteration in the sympathovagal balance as assessed by means of heart rate variability (HRV) analysis, which is also related to the presence of endothelial dysfunction. Other studies suggest a possible role of inflammation coexisting with the alteration in the sympathovagal balance in favor of the atherosclerotic process in a mixed population of healthy subjects of middle and advanced age. AIMS: The aim of this study was to evaluate the degree of alteration of sympathovagal balance, assessed by HRV analysis, in a cohort of patients with diabetes mellitus with diabetic foot and in control subjects without diabetic foot compared with a population of healthy subjects and the possible correlation of HRV parameters with inflammatory markers and endothelial dysfunction indices. METHODS: We enrolled all patients with diabetic ulcerative lesions of the lower limb in the Internal Medicine with Stroke Care ward and of the diabetic foot outpatient clinic of P. Giaccone University Hospital of Palermo between September 2019 and July 2020. 4-h ECG Holter was performed. The following time domain HRV measures were analyzed: average heart rate, square root of the mean of successive differences of NN (RMSSD), standard deviation or square root of the variance (SD), and standard deviation of the means of the NN intervals calculated over a five-minute period (SDANN/5 min). The LF/HF ratio was calculated, reactive hyperemia was evaluated by endo-PAT, and serum levels of vaspine and omentin-1 were assessed by blood sample collection. RESULTS: 63 patients with diabetic foot, 30 patients with diabetes and without ulcerative complications and 30 patients without diabetes were enrolled. Patients with diabetic ulcers showed lower mean diastolic blood pressure values than healthy controls, lower MMSE scores corrected for age, lower serum levels of omentin-1, lower RHI values, higher body weight values and comparable body height values, HF% and LF/HF ratio values. We also reported a negative correlation between the RHI value and HRV indices and the expression of increased parasympathetic activity (RMSDD and HF%) in subjects with diabetic foot and a statistically significant positive correlation with the LF/HF ratio and the expression of the sympathovagal balance. DISCUSSION: Patients with diabetic foot show a higher degree of activation of the parasympathetic system, expressed by the increase in HF values, and a lower LF/HF ratio. Our findings may corroborate the issue that a parasympathetic dysfunction may have a possible additive role in the pathogenesis of other vascular complications in subjects with diabetic foot.

A case of infective colitis due to Yersinia enterocolitica complicated by microliver abscesses mimicking multiple liver occult metastases: a case report.

BACKGROUND: We report an unusual case of infective colitis by Yersinia enterocolitica complicated by microliver abscesses mimicking multiple liver metastases in a 79 yr old female without any risk factors for bacteriaemia by this pathogen. CASE PRESENTATION: The patient was admitted to the Internal Medicine with Stroke Care ward of University Policlinico "P. Giaccone" in Palermo because of the appearance of diarrhoea. After the antimicrobial treatment for infective colitis, the clinicians observed a persistently increased white blood cells (WBC) count and multiple hepatic lesions; after having excluded any neoplastic disease and inflammatory bowel disease (IBD), blood cultures positive for Y. enterocolitica allowed to establish the final diagnosis was infective micro liver abscesses consequent to infective colitis due to Y. enterocolitica, which were successfully treated with cefixime and doxycycline. CONCLUSIONS: This case report should make clinicians reflect on how complex the differential diagnosis between microliver abscesses and metastasis could be and the possibility of bacteriaemia by Y. enterocolitica even without iron overload conditions.

Neuroinflammatory Mechanisms in Ischemic Stroke: Focus on Cardioembolic Stroke, Background, and Therapeutic Approaches.

One of the most important causes of neurological morbidity and mortality in the world is ischemic stroke. It can be a result of multiple events such as embolism with a cardiac origin, occlusion of small vessels in the brain, and atherosclerosis affecting the cerebral circulation. Increasing evidence shows the intricate function played by the immune system in the pathophysiological variations that take place after cerebral ischemic injury. Following the ischemic cerebral harm, we can observe consequent neuroinflammation that causes additional damage provoking the death of the cells; on the other hand, it also plays a beneficial role in stimulating remedial action. Immune mediators are the origin of signals with a proinflammatory position that can boost the cells in the brain and promote the penetration of numerous inflammatory cytotypes (various subtypes of T cells, monocytes/macrophages, neutrophils, and different inflammatory cells) within the area affected by ischemia; this process is responsible for further ischemic damage of the brain. This inflammatory process seems to involve both the cerebral tissue and the whole organism in cardioembolic stroke, the stroke subtype that is associated with more severe brain damage and a consequent worse outcome (more disability, higher mortality). In this review, the authors want to present an overview of the present learning of the mechanisms of inflammation that takes place in the cerebral tissue and the role of the immune system involved in ischemic stroke, focusing on cardioembolic stroke and its potential treatment strategies.

Paraneoplastic Cerebellar Degeneration Associated with Breast Cancer: A Case Report and a Narrative Review.

Paraneoplastic neurological syndromes (PNSs) are an uncommon complication of cancer, affecting nearby 1/10,000 subjects with a tumour. PNSs can involve all the central and peripheral nervous systems, the muscular system, and the neuromuscular junction, causing extremely variable symptomatology. The diagnosis of the paraneoplastic disease usually precedes the clinical manifestations of cancer, making an immediate recognition of the pathology crucial to obtain a better prognosis. PNSs are autoimmune diseases caused by the expression of common antigens by the tumour and the nervous system. Specific antibodies can help clinicians diagnose them, but unfortunately, they are not always detectable. Immunosuppressive therapy and the treatment of cancer are the cornerstones of therapy for PNSs. This paper reports a case of PNSs associated with breast tumours and focuses on the most common paraneoplastic neurological syndromes. We report a case of a young female with a clinical syndrome of the occurrence of rigidity in the right lower limb with postural instability with walking supported and diplopia, with a final diagnosis of paraneoplastic cerebellar degeneration and seronegative rigid human syndrome associated with infiltrating ductal carcinoma of the breast.

Systematic review and meta-analysis of cardiovascular risk in rheumatological disease: Symptomatic and non-symptomatic events in rheumatoid arthritis and systemic lupus erythematosus.

Although each autoimmune disease is associated with specific tissue or organ damage, rheumatic diseases share a pro-inflammatory pattern that might increase cardiovascular risk. Retrospective and prospective studies on patients affected by systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) highlighted the concept of "accelerated atherosclerosis". Therefore, the purpose of this systematic review and meta-analysis is the assessment of symptomatic or asymptomatic cardiovascular events among patients with rheumatic diseases as RA and SLE. The literature research obtained all manuscripts published in the English language between 2015 and 2019 for a total of 2355 manuscripts. After selection through inclusion and exclusion criteria, four articles examined cardiovascular risk in RA patients, 8 in SLE patients, and 2 in RA and SLE patients. Patients with SLE had a RR of 1.98 (95% CI: 1.18-3.31) of symptomatic cardiovascular events compared to the unexposed cohort. The meta-regression analysis showed that younger patient (age per year increase ß = -0.12 95%CI: -0.20, -0.4), belonging to studies conducted in continent different from America (ß = -0.89; -95% CI: 1.67, -0.10), after 2000 (ß = 0.87; 95% CI: 0.09, 1.65) and with a higher quality score 0.80 (95% CI: 0.31, 1.29) had a higher risk of cardiovascular events. In patients with RA, the RR of cardiovascular events was 1.55 (95% CI: 1.18-2.02). These data are helpful to implement cardiovascular preventive strategies among people suffering from rheumatologic diseases to decrease the incidence of cardiovascular events. However, these implementation needs to build a higher network between rheumatologists and primary care healthcare workers to furnish the same information to patients and monitor their preventive practice compliance.

Protective and causative killer Ig-like receptor (KIR) and metalloproteinase genetic patterns associated with Herpes simplex virus 1 (HSV-1) encephalitis occurrence.

BACKGROUND: The cerebral innate immune system has a critical role in control processes of viral replication in the brain after primary infactivo and immunologic disregulation and inflammation has been reported as a primary determinant of pathogenesis and prognosis of subsequent HSV-1 related encephalitis (HSE). Interaction linking LTR3-activated DCs is also represented by the killer Ig-like receptor (KIR) + pathways on NK cells. Only a few studies analyzed the role of of MMP-9 activity regulating genetic polymorphism on clinical outcome of viral infections. Susceptibility to symptomatic encephalitis depends on SNC viral invasion and BBB disruption. We hypothesize that certain KIR genes and MMP allele may help to characterize a risk profile of developing an acute encephalitis due to HSV 1. AIM OF THE STUDY: Analyze the frequency of KIR genes and the C(-1562)T MMP-9 allels in subjects with HSV-1 encephalitis and to analyze their interaction with regard of the risk of occurrence of a symptomatic encephalitis. MATERIALS AND METHODS: Between November 2014 and January 2019, all consecutive patients with symptomatic acute encephalitis were recruited from three wards (Internal Medicine, Neurology, and Infectious Diseases) of "P. Giaccone" University Hospital, Palermo. RESULTS: Patients with acute viral encephalitis in comparison to controls showed a higher frequency AA KIR haplotype, HLA-C2 and of HLA-A-Bw4 alleles. With regard of HLA allele frequency patients with acute viral encephalitis In comparison to controls also showed a higher frequency of HLA-C2 and of HLA-A-Bw4 alleles. With regard of MMP-9 alleles, subjects with acute viral encephalitis were more likely to have the TT genotype. The multiple logistic regression analysis considering variables predictive of the occurrence of acute viral encephalitis showed the detrimental effect of AA KIR, HLAC1, HLA-A-BW4 and HLA-B-BW4T and of TT aplotype of MMP-9 genotype. CONCLUSIONS: Our study shows that in immunocompetent adult subjects there is an association between some KIR genes, MMP-9 alleles and HLA-ligand alleles and susceptibility to develop a symptomatic acute viral encephalitis. Definition of the genetic and immunological background of acute viral encephalitis can play a key role to determine personalized medicine.