Rhoa/ROCK, mTOR and Secretome-Based Treatments for Ischemic Stroke: New Perspectives.

Ischemic stroke triggers a complex cascade of cellular and molecular events leading to neuronal damage and tissue injury. This review explores the potential therapeutic avenues targeting cellular signaling pathways implicated in stroke pathophysiology. Specifically, it focuses on the articles that highlight the roles of RhoA/ROCK and mTOR signaling pathways in ischemic brain injury and their therapeutic implications. The RhoA/ROCK pathway modulates various cellular processes, including cytoskeletal dynamics and inflammation, while mTOR signaling regulates cell growth, proliferation, and autophagy. Preclinical studies have demonstrated the neuroprotective effects of targeting these pathways in stroke models, offering insights into potential treatment strategies. However, challenges such as off-target effects and the need for tissue-specific targeting remain. Furthermore, emerging evidence suggests the therapeutic potential of MSC secretome in stroke treatment, highlighting the importance of exploring alternative approaches. Future research directions include elucidating the precise mechanisms of action, optimizing treatment protocols, and translating preclinical findings into clinical practice for improved stroke outcomes.

Mass-Spectrometry-Based Research of Cosmetic Ingredients.

Cosmetic products are chemical substances or mixtures used on the skin, hair, nails, teeth, and the mucous membranes of the oral cavity, whose use is intended to clean, protect, correct body odor, perfume, keep in good condition, or change appearance. The analysis of cosmetic ingredients is often challenging because of their huge complexity and their adulteration. Among various analytical tools, mass spectrometry (MS) has been largely used for compound detection, ingredient screening, quality control, detection of product authenticity, and health risk evaluation. This work is focused on the MS applications in detecting and quantification of some common cosmetic ingredients, i.e., preservatives, dyes, heavy metals, allergens, and bioconjugates in various matrices (leave-on or rinse-off cosmetic products). As a global view, MS-based analysis of bioconjugates is a narrow field, and LC- and GC/GC×GC-MS are widely used for the investigation of preservatives, dyes, and fragrances, while inductively coupled plasma (ICP)-MS is ideal for comprehensive analysis of heavy metals. Ambient ionization approaches and advanced separation methods (i.e., convergence chromatography (UPC2)) coupled to MS have been proven to be an excellent choice for the analysis of scented allergens. At the same time, the current paper explores the challenges of MS-based analysis for cosmetic safety studies.

Oxidative Stress and Antioxidant Defense Mechanisms in Acute Ischemic Stroke Patients with Concurrent COVID-19 Infection.

Stroke remains a debilitating cerebrovascular condition associated with oxidative stress, while COVID-19 has emerged as a global health crisis with multifaceted systemic implications. This study investigates the hypothesis that patients experiencing acute ischemic stroke alongside COVID-19 exhibit elevated oxidative stress markers and altered antioxidant defense mechanisms compared to those with acute ischemic stroke. We conducted a single-center prospective cross-sectional study to investigate oxidative stress balance through oxidative damage markers: TBARS (thiobarbituric acid reactive substances level) and PCARB (protein carbonyls); antioxidant defense mechanisms: TAC (total antioxidant capacity), GPx (glutathione peroxidase), GSH (reduced glutathione), CAT (catalase), and SOD (superoxide dismutase); as well as inflammatory response markers: NLR (neutrophil-to-lymphocyte ratio), CRP (C-reactive protein), and ESR (erythrocyte sedimentation rate). Statistical analyses and correlation models were employed to elucidate potential associations and predictive factors. Our results revealed increased oxidative stress, predominantly indicated by elevated levels of TBARS in individuals experiencing ischemic stroke alongside a concurrent COVID-19 infection (p < 0.0001). The Stroke-COVID group displayed notably elevated levels of GSH (p = 0.0139 *), GPx (p < 0.0001 ****), SOD (p = 0.0363 *), and CAT (p = 0.0237 *) activities. Multivariate analysis found a significant association for TBARS (p < 0.0001 ****), PCARB (p = 0.0259 *), and GPx activity (p < 0.0001 ****), together with NLR (p = 0.0220 *) and CRP (p = 0.0008 ***). Notably, the interplay between stroke and COVID-19 infection appears to amplify oxidative damage, potentially contributing to exacerbated neurological deficits and poorer outcomes. This study highlights the intricate relationship between oxidative stress, inflammation, and concurrent health conditions. Understanding these interactions may open avenues for novel therapeutic strategies aimed at ameliorating oxidative damage in patients with acute ischemic stroke and COVID-19, ultimately improving their prognosis and quality of life.

C-Reactive Protein as a Marker of Inflammation in Children and Adolescents with Metabolic Syndrome: A Systematic Review and Meta-Analysis.

Metabolic syndrome (MetS) in the pediatric population has been reported in many studies to be associated with an inflammatory response. However, to our knowledge, there is no definitive conclusion in the form of a meta-analysis. The issue we aimed to address is whether C-reactive protein (CRP) is a trustworthy marker in detecting inflammation in children and adolescents with MetS. We systematically searched PubMed, MEDLINE, Cochrane Central Register of Controlled Trials, the ISI Web of Science, and SCOPUS until 31 June 2023 for studies involving children and adolescents with MetS where hsCRP or CRP were measured. After the screening process, we identified 24 full-text articles that compared 930 patients with MetS with either healthy (n = 3782) or obese (n = 1658) controls. The risk of bias in the included studies was assessed using the Begg's rank correlation test and Egger's regression test. Statistical analysis was carried out based on pooled mean differences (MDs) and an associated 95% CI. Data analysis showed that MetS is associated with higher levels of CRP than those in healthy controls (MD = 1.28, 95% CI: (0.49-2.08), p = 0.002) in obese patients (MD = 0.88, 95% CI: (0.38-1.39), p = 0.0006). However, conventional methods of CRP analysis were found to be more accurate in differentiating between children and adolescents with obesity and those with MetS, compared with hsCRP (MD = 0.60, 95% CI: (-0.08-1.28), p = 0.08). No risk of bias was assessed. In conclusion, CRP is a reliable inflammatory marker for differentiating pediatric patients with MetS from healthy ones. On the other hand, it did not prove to be very accurate in distinguishing between patients who had MetS and those who were obese. There should be more research performed in this field.

Vertebral Artery Dissection: A Case Report and Review of the Literature.

Arterial dissection is the result of blood entering along the intima-media plane through a breach produced either spontaneously or traumatically. Cervical arterial dissections are an important cause of acute ischemic stroke in children, young adults, and patients with cranio-cervical traumatic injuries. Arterial dissections occur either spontaneously, in genetic diseases, the most important association being with fibromuscular dysplasia. In most of the cases dissection involve the extracranial portions of the internal carotid and vertebral arteries. Magnetic resonance with T1 fat-saturation (T1 FS) sequence of the cervical region or computed tomography (CT) with computed tomography angiography (CTA) shows a very high sensitivity and specificity in the diagnosis of cervical artery dissections. Therapeutic options are still debatable in patients with acute ischemic stroke and vertebral or carotid artery dissection.

miR-499a rs3746444 A>G Polymorphism Is Correlated with Type 2 Diabetes Mellitus and Diabetic Polyneuropathy in a Romanian Cohort: A Preliminary Study.

Type 2 diabetes mellitus (T2DM) is a common metabolic disorder that results from complex interactions of both environmental and genetic factors. Many single nucleotide polymorphisms (SNPs), including noncoding RNA genes, have been investigated for their association with susceptibility to T2DM and its complications, with little evidence available regarding Caucasians. The aim of the present study was to establish whether four miRNA SNPs (miR-27a rs895819 T>C, miR-146a rs2910164 G>C, miR-196a2 rs11614913 C>T, and miR-499a rs3746444 A>G) are correlated with susceptibility to T2DM and/or diabetic polyneuropathy (DPN) in a Romanian population. A total of 167 adult T2DM patients and 324 age- and sex-matched healthy controls were included in our study. miRNA SNPs were detected by real-time PCR using a TaqMan genotyping assay. A significant association with T2DM was observed only for the miR-499a rs3746444 A>G SNP in all the tested models, and the frequencies of both the miR-499a rs3746444 AG and the GG genotypes were higher in the T2DM patients compared to the controls. No correlation was observed for the miR-27a rs895819 T>C, miR-146a rs2910164 G>C, or miR-196a2 rs11614913 C>T SNPs in any genetic model. When we assessed the association of these SNPs with DPN separately, we found a positive association for the miR-499a rs3746444 SNP in both codominant and dominant models (OR 6.47, 95% CI: 1.71-24.47; OR 2.30, 95% CI: 1.23-4.29, respectively). In conclusion, this study shows that miR-499a rs3746444 A>G may influence both T2DM and DPN susceptibility, with carriers of the GG genotype and the G allele being at an increased risk in the Romanian population.

From Molecule to Patient Rehabilitation: The Impact of Transcranial Direct Current Stimulation and Magnetic Stimulation on Stroke-A Narrative Review.

Stroke is a major health problem worldwide, with numerous health, social, and economic implications for survivors and their families. One simple answer to this problem would be to ensure the best rehabilitation with full social reintegration. As such, a plethora of rehabilitation programs was developed and used by healthcare professionals. Among them, modern techniques such as transcranial magnetic stimulation and transcranial direct current stimulation are being used and seem to bring improvements to poststroke rehabilitation. This success is attributed to their capacity to enhance cellular neuromodulation. This modulation includes the reduction of the inflammatory response, autophagy suppression, antiapoptotic effects, angiogenesis enhancement, alterations in the blood-brain barrier permeability, attenuation of oxidative stress, influence on neurotransmitter metabolism, neurogenesis, and enhanced structural neuroplasticity. The favorable effects have been demonstrated at the cellular level in animal models and are supported by clinical studies. Thus, these methods proved to reduce infarct volumes and to improve motor performance, deglutition, functional independence, and high-order cerebral functions (i.e., aphasia and heminegligence). However, as with every therapeutic method, these techniques can also have limitations. Their regimen of administration, the phase of the stroke at which they are applied, and the patients' characteristics (i.e., genotype and corticospinal integrity) seem to influence the outcome. Thus, no response or even worsening effects were obtained under certain circumstances both in animal stroke model studies and in clinical trials. Overall, weighing up risks and benefits, the new transcranial electrical and magnetic stimulation techniques can represent effective tools with which to improve the patients' recovery after stroke, with minimal to no adverse effects. Here, we discuss their effects and the molecular and cellular events underlying their effects as well as their clinical implications.

Predictive Value of Pulmonary Involvement in Stroke Patients Co-Infected with COVID-19.

In response to the intricate clinical challenges posed by the intersection of COVID-19 and acute ischemic stroke, the Neuropsychiatry Hospital of Craiova, Romania, initiated a comprehensive study. This research aims to unravel the impacts of pulmonary complications on ischemic stroke outcomes, comparing patients with concurrent SARS-CoV-2 infection to those without. The study integrates pulmonary assessments, acknowledging the significant role respiratory involvement plays in the progression and prognosis of stroke patients during the pandemic. By systematically examining individuals with both acute ischemic stroke and COVID-19, the study seeks to shed light on the complex interplay between cerebral and pulmonary health. The findings are expected to enhance patient care by informing clinical decisions and leading to more effective management approaches for stroke patients in the COVID-19 era.

Volumetric Quantitative Ablation Margins for Assessment of Ablation Completeness in Thermal Ablation of Liver Tumors.

BACKGROUND: In thermal ablation of liver tumors, complete coverage of the tumor volume by the ablation volume with a sufficient ablation margin is the most important factor for treatment success. Evaluation of ablation completeness is commonly performed by visual inspection in 2D and is prone to inter-reader variability. This work aimed to introduce a standardized approach for evaluation of ablation completeness after CT-guided thermal ablation of liver tumors, using volumetric quantitative ablation margins (QAM). METHODS: A QAM computation metric based on volumetric segmentations of tumor and ablation areas and signed Euclidean surface distance maps was developed, including a novel algorithm to address QAM computation in subcapsular tumors. The code for QAM computation was verified in artificial examples of tumor and ablation spheres simulating varying scenarios of ablation margins. The applicability of the QAM metric was investigated in representative cases extracted from a prospective database of colorectal liver metastases (CRLM) treated with stereotactic microwave ablation (SMWA). RESULTS: Applicability of the proposed QAM metric was confirmed in artificial and clinical example cases. Numerical and visual options of data presentation displaying substrata of QAM distributions were proposed. For subcapsular tumors, the underestimation of tumor coverage by the ablation volume when applying an unadjusted QAM method was confirmed, supporting the benefits of using the proposed algorithm for QAM computation in these cases. The computational code for developed QAM was made publicly available, encouraging the use of a standard and objective metric in reporting ablation completeness and margins. CONCLUSION: The proposed volumetric approach for QAM computation including a novel algorithm to address subcapsular liver tumors enables precision and reproducibility in the assessment of ablation margins. The quantitative feedback on ablation completeness opens possibilities for intra-operative decision making and for refined analyses on predictability and consistency of local tumor control after thermal ablation of liver tumors.

Accuracy of Electrode Placement in IRE Treatment with Navigated Guidance.

PURPOSE: Evaluate the accuracy of multiple electrode placements in IRE treatment of liver tumours using a stereotactic CT-based navigation system. METHOD: Analysing data from all IRE treatments of liver tumours at one institution until 31 December 2018. Comparing planned with validated electrode placement. Analysing lateral and angular errors and parallelism between electrode pairs RESULTS: Eighty-four tumours were treated in 60 patients. Forty-six per cent were hepatocellular carcinoma, and 36% were colorectal liver metastases. The tumours were located in all segments of the liver. Data were complete from 51 treatments. Two hundred and six electrodes and 336 electrode pairs were analysed. The median lateral and angular error, comparing planned and validated electrode placement, was 3.6 mm (range 0.2-13.6 mm) and 3.1° (range 0°-16.1°). All electrodes with a lateral error >10 mm were either re-positioned or excluded before treatment. The median angle between the electrode pairs was 3.8° (range 0.3°-17.2°). There were no electrode placement-related complications. CONCLUSION: The use of a stereotactic CT-based system for navigation of electrode placement in IRE treatment of liver tumours is safe, accurate and user friendly.

Staphylococcus aureus-induced septic arthritis of the ankle related to malum perforans in a diabetes patient.

Septic arthritis (SA) is a less common joint pathology with potentially fatal outcome. It is considered a medical emergency, in which prompt diagnosis and differentiation of bacterial etiology is essential for appropriate management. The knee is the most prevalent site for SA (~50% of cases), followed by hip, shoulder, and elbow. Early intervention requires an accurate diagnosis and imaging techniques enable both a positive diagnosis, as well as arthrocentesis and liquid analysis, the "gold standard" criteria. We report the case of a 70-year-old patient, with history of rheumatoid arthritis (RA), diabetes mellitus (DM) and persistent left malum perforans in the last year, with development of a severe and debilitating Staphylococcus aureus-related SA of the left ankle, which posed significant therapeutic challenges. He developed a plantar lesion at the ball of the left foot, in the past one year, which was labeled as malum perforans in the setting of DM. Musculoskeletal ultrasound was the primary imaging technique used to define the location and extent of the infectious process. Cultures drawn from the tissue were positive for S. aureus. After an antibiotic course, the apparent infectious features were remitted but the long-lasting open wound failed to improve. Antibiotic therapy was initiated in accordance with culture sensibility tests but short- and long-term outcome was unfavorable with both treatment unresponsiveness and comorbidity burden posing considerable difficulties. The association and interrelation between different comorbidities (such as hypertension, diabetes, or obesity), chronic systemic inflammation (e.g., C-reactive protein level, disease activity), and RA medication is sometimes difficult to understand and to address in daily practice, and this case report highlights multiple toils encountered in a SA patient with RA on immunosuppressive therapy and complicated DM.

Facing the Unseen - Metabolic Syndrome in Psoriatic Arthritis.

Psoriatic arthritis (PsA) is a heterogeneous multifaceted inflammatory artropathy, associated or not with psoriasis, part of the spondyloarthropaties group. Beyond articular and skin manifestations, patients with psoriatic disease are prone to associated comorbidities, including cardiovascular disease (CVD), obesity and metabolic syndrome, diabetes, or fatty liver disease; in order to improve the prognosis and the quality of life for these patients, it is mandatory to prevent, identify and properly manage any of the comorbidities. We aimed to assess the presence of traditional CV risk factors and MetS in a group of PsA patients, compared to controls and their possible inter-relation. We performed an observational study on 41 consecutive patients diagnosed with PsA based on CASPAR established criteria. Our subjects met the criteria of MetS in a percentage of 43.90% of the cases and AHT, frequently reported in higher percentages for PsA or psoriasis patients, compared to general population was also revealed in significant percentages by our data. Regarding dyslipidemia, it is confirmed and validated by several studies that patients diagnosed with PsA or psoriasis associate an altered lipid metabolism and our study noticed data accordingly. As PsA is a condition characterized by chronic inflammation, a non-traditional CV risk factor, each patient should benefit from a periodic close evaluation in order to approach a compete and early therapeutic intervention and reduce further CV morbidity and mortality rates.

New insights into IL-17/IL-23 signaling in ankylosing spondylitis (Review).

Ankylosing spondylitis (AS) is a progressive common autoimmune inflammatory disease, part of the spondylarthritis group, characterized, besides clinical spinal and peripheral joint inflammation, by enthesitis and new bone formation, that can lead to severe functional impairment. Beyond intensive and continuous research on the pathogenic process extensively performed in recent years, their impact on therapeutic management remains open to future development. Better knowledge of AS pathogenesis have shown results progressively and studies are being performed to advance our current understanding of the disease. It is well known that tumor necrosis factor (TNF) exerts a central role, along with interleukin-17 (IL-17) and interleukin-23 (IL-23), demonstrated by several clinical studies. Similar to other rheumatic inflammatory conditions, SA is associated with an early process of systemic bone loss, both trabecular and cortical, consecutive osteopenia, osteoporosis, and high fracture risk. Current personalized therapeutic options benefit from new published data, to prevent future complications and to improve quality of life.

Host immune response in chronic hepatitis C infection: involvement of cytokines and inflammasomes.

Chronic liver disease is a major health issue worldwide and chronic hepatitis C (CHC) is associated with an increased risk of cirrhosis and hepatocellular carcinoma (HCC). There is evidence that the hepatitis C virus (HCV) infection is correlated with immune senescence by way of immune activation and chronic inflammation, which lead to increased metabolic and cardiovascular risk, as well as progressive liver damage. Both the innate and adaptive immunity are firmly tied to the prognosis of an infection with HCV and its response to antiviral therapy. HCV is therefore associated with increased pro-inflammatory status, heightened production of cytokines, prolonged systemic inflammation, as well as increased morbidity and mortality, mainly due to the progression of hepatic fibrosis and HCC, but also secondary to cardiovascular diseases. Viral hepatic pathology is increasingly considered a disease that is no longer merely limited to the liver, but one with multiple metabolic consequences. Numerous in vitro studies, using experimental models of acute or chronic inflammation of the liver, has brought new information on immunopathological mechanisms resulting from viral infections and have highlighted the importance of involving complex structures, inflammasomes complex, in these mechanisms, in addition to the involvement of numerous proinflammatory cytokines. Beyond obtaining a sustained viral response and halting the aforementioned hepatic fibrosis, the current therapeutic "treat-to-target" strategies are presently focused on immune-mediated and metabolic disorders, to improve the quality of life and long-term prognosis of CHC patients.

Ultrasound Based Planning and Navigation for Non-Anatomical Liver Resections - An Ex-Vivo Study.

Goal: Non-anatomical resections of liver tumors can be very challenging as the surgeon cannot use anatomical landmarks on the liver surface or in the ultrasound image for guidance. This makes it difficult to achieve negative resection margins (R0) and still preserve as much healthy liver tissue as possible. Even though image-guided surgery systems have been introduced to overcome this challenge, they are still rarely used due to their inaccuracy, time-effort and complexity in usage and setup. Methods: We have developed a novel approach, which allows us to create an intra-operative resection plan using navigated ultrasound. First, the surface is scanned using a navigated ultrasound, followed by tumor segmentation on a midsection ultrasound image. Based on this information, the navigation system calculates an optimal resection strategy and displays it along with the tracked surgical instruments. In this study, this approach was evaluated by three experienced hepatobiliary surgeons on ex-vivo porcine models. Results: Using this technique, an R0 resection could be achieved in 22 out of 23 (95.7% R0 resection rate) cases with a median resection margin of 5.9 mm (IQR 3.5-7.7 mm). The resection margin between operators 1, 2 and 3 was 7.8 mm, 4.15 mm and 5.1 mm respectively (p = 0.054). Conclusions: This approach could represent a useful tool for intra-operative guidance in non-anatomical resection alongside conventional ultrasound guidance. However, instructions and training are essential especially if the operator has not used an image-guidance system before.

Oxidative Stress and Inflammation Interdependence in Multiple Sclerosis.

The study aims to explore the oxidative status related to inflammation in peripheral blood of stable relapsing-remitting multiple sclerosis (MS) patients with low disability. In this study, 31 people were included and divided into two groups: an MS group in which 16 relapsing-remitting MS patients with a low disability level (age 38.9 ± 7.08, EDSS median 2.5) were included and a control group that contains 15 healthy volunteers of similar age to the MS group. Thiobarbituric acid reactive substances (TBARS), protein carbonyl level (PCO), total antioxidant capacity (TAC) as oxidative stress markers, neutrophil/lymphocyte ratio (NLR), and erythrocyte sedimentation rate (ESR) were analyzed in the peripheral blood sample of the healthy and the MS patients to establish the oxidative stress/inflammatory level using conventional plasma markers. In this study, we showed that the pro-inflammatory status of the relapse-remitting stage of diseases can be easily and accurately appreciated by NLR. An increased NLR is associated with a decreased antioxidant capacity, even in the early stage of neuronal damage. Oxidative stress associated with inflammation aggravates the functional outcome, potentiates neuronal damage, and can accelerate the progression of the disease.

Neuroinflammation in systemic lupus erythematosus - a review.

Neuroinflammation is a complex process that contributes to the pathogenesis of both immune mediated and neurodegenerative pathologies. Systemic lupus erythematosus (SLE) is the prototype of connective tissue diseases that can present the complete spectrum of neurological and psychiatric dysfunctions. The precise etiological diagnosis of neuropsychiatric systemic lupus erythematosus (NPSLE) is rather difficult to be established and it is still controversial the exact timing of neuropsychiatric (NPS) events: either central nervous system (CNS) is the initial target of autoimmune abnormalities, either NPS symptoms are a part of multisystem involvement. Ischemic and inflammatory mechanisms have an important input on NPSLE pathogenesis. Neuroinflammation, consequent to blood-brain barrier (BBB) damage, local and systemic production of autoantibodies, determine neuronal injury and apoptosis, further responsible for diffuse cerebral events, mostly cognitive dysfunction and psychotic disorder. Moreover, SLE complications or therapy complications can interfere and contribute to complex clinical manifestations that can be present in SLE patients. Understanding the role of each pathogenic way can provide not only an early diagnosis, but a more accurate therapeutic approach of these patients.

Increased Degradation Rates in the Components of the Mitochondrial Oxidative Phosphorylation Chain in the Cerebellum of Old Mice.

Brain structures differ in the magnitude of age-related neuron loss with the cerebellum being more affected. An underlying cause could be an age-related decline in mitochondrial bioenergetics. Successful aging of mitochondria reflects a balanced turnover of proteins involved in mitochondrial biogenesis and mitophagy. Thus, an imbalance in mitochondrial turnover can contribute to the diminution of cellular function seen during aging. Mitochondrial biogenesis and mitophagy are mediated by a set of proteins including MFN1, MFN2, OPA1, DRP1, FIS1 as well as DMN1l and DNM1, all of which are required for mitochondrial fission. Using N15 labeling, we report that the turnover rates for DMN1l and FIS1 go in opposite directions in the cerebellum of 22-month-old C57BL6j mice as compared to 3-month-old mice. Previous studies have reported decreased turnover rates for the mitochondrial respiratory complexes of aged rodents. In contrast, we found increased turnover rates for mitochondrial proteins of the oxidative phosphorylation chain in the aged mice as compared to young mice. Furthermore, the turnover rate of the components that are most affected by aging -complex III components (ubiquinol cytochrome C oxidoreductase) and complex IV components (cytochrome C oxidase)- was significantly increased in the senescent cerebellum. However, the turnover rates of proteins involved in mitophagy (i.e., the proteasomal and lysosomal degradation of damaged mitochondria) were not significantly altered with age. Overall, our results suggest that an age-related imbalance in the turnover rates of proteins involved in mitochondrial biogenesis and mitophagy (DMN1l, FIS1) in conjunction with an age-related imbalance in the turnover rates of proteins of the complexes III and IV of the electron transfer chain, might impair cerebellar mitochondrial bioenergetics in old mice.

Present Status and Future Challenges of New Therapeutic Targets in Preclinical Models of Stroke in Aged Animals with/without Comorbidities.

The aging process, comorbidities, and age-associated diseases are closely dependent on each other. Cerebral ischemia impacts a wide range of systems in an age-dependent manner. However, the aging process has many facets which are influenced by the genetic background and epigenetic or environmental factors, which can explain why some people age differently than others. Therefore, there is an urgent need to identify age-related changes in body functions or structures that increase the risk for stroke and which are associated with a poor outcome. Multimodal imaging, electrophysiology, cell biology, proteomics, and transcriptomics, offer a useful approach to link structural and functional changes in the aging brain, with or without comorbidities, to post-stroke rehabilitation. This can help us to improve our knowledge about senescence firstly, and in this context, aids in elucidating the pathophysiology of age-related diseases that allows us to develop therapeutic strategies or prevent diseases. These processes, including potential therapeutical interventions, need to be studied first in relevant preclinical models using aged animals, with and without comorbidities. Therefore, preclinical research on ischemic stroke should consider age as the most important risk factor for cerebral ischemia. Furthermore, the identification of effective therapeutic strategies, corroborated with successful translational studies, will have a dramatic impact on the lives of millions of people with cerebrovascular diseases.

Cellular and Molecular Mechanisms Underlying Non-Pharmaceutical Ischemic Stroke Therapy in Aged Subjects.

The incidence of ischemic stroke in humans increases exponentially above 70 years both in men and women. Comorbidities like diabetes, arterial hypertension or co-morbidity factors such as hypercholesterolemia, obesity and body fat distribution as well as fat-rich diet and physical inactivity are common in elderly persons and are associated with higher risk of stroke, increased mortality and disability. Obesity could represent a state of chronic inflammation that can be prevented to some extent by non-pharmaceutical interventions such as calorie restriction and hypothermia. Indeed, recent results suggest that H2S-induced hypothermia in aged, overweight rats could have a higher probability of success in treating stroke as compared to other monotherapies, by reducing post-stroke brain inflammation. Likewise, it was recently reported that weight reduction prior to stroke, in aged, overweight rats induced by caloric restriction, led to an early re-gain of weight and a significant improvement in recovery of complex sensorimotor skills, cutaneous sensitivity, or spatial memory. CONCLUSION: animal models of stroke done in young animals ignore age-associated comorbidities and may explain, at least in part, the unsuccessful bench-to-bedside translation of neuroprotective strategies for ischemic stroke in aged subjects.