Age-related reduction of cerebral ischemic preconditioning: myth or reality?

Stroke is one of the leading causes of death in industrialized countries for people older than 65 years of age. The reasons are still unclear. A reduction of endogenous mechanisms against ischemic insults has been proposed to explain this phenomenon. The “cerebral” ischemic preconditioning mechanism is characterized by a brief episode of ischemia that renders the brain more resistant against subsequent longer ischemic events. This ischemic tolerance has been shown in numerous experimental models of cerebral ischemia. This protective mechanism seems to be reduced with aging both in experimental and clinical studies. Alterations of mediators released and/or intracellular pathways may be responsible for age-related ischemic preconditioning reduction. Agents able to mimic the “cerebral” preconditioning effect may represent a new powerful tool for the treatment of acute ischemic stroke in the elderly. In this article, animal and human cerebral ischemic preconditioning, its age-related difference, and its potential therapeutical applications are discussed

Normal and pathogenic variation of RFC1 repeat expansions: implications for clinical diagnosis

Cerebellar Ataxia, Neuropathy and Vestibular Areflexia Syndrome (CANVAS) is an autosomal recessive neurodegenerative disease, usually caused by biallelic AAGGG repeat expansions in RFC1. In this study, we leveraged whole genome sequencing (WGS) data from nearly 10,000 individuals recruited within the Genomics England sequencing project to investigate the normal and pathogenic variation of the RFC1 repeat. We identified three novel repeat motifs, AGGGC (n=6 from 5 families), AAGGC (n=2 from 1 family), AGAGG (n=1), associated with CANVAS in the homozygous or compound heterozygous state with the common pathogenic AAGGG expansion. While AAAAG, AAAGGG and AAGAG expansions appear to be benign, here we show a pathogenic role for large AAAGG repeat configuration expansions (n=5). Long read sequencing was used to fully characterise the entire repeat sequence and revealed a pure AGGGC expansion in six patients, whereas the other patients presented complex motifs with AAGGG or AAAGG interruptions. All pathogenic motifs seem to have arisen from a common haplotype and are predicted to form highly stable G quadruplexes, which have been previously demonstrated to affect gene transcription in other conditions. The assessment of these novel configurations is warranted in CANVAS patients with negative or inconclusive genetic testing. Particular attention should be paid to carriers of compound AAGGG/AAAGG expansions, since the AAAGG motif when very large (>500 repeats) or in the presence of AAGGG interruptions. Accurate sizing and full sequencing of the satellite repeat with long read is recommended in clinically selected cases, in order to achieve an accurate molecular diagnosis and counsel patients and their families

Pre-operative Renal Artery Embolization in Laparoscopic Radical and Partial Nephrectomy: A Multidisciplinary Approach to Renal Tumors

Despite being widely adopted, the laparoscopic approach to radical and partial nephrectomy is still burdened by high rates of hemorrhagic complications, which require blood transfusions and conversion to open surgery with increased morbidity. While pre-operative renal artery embolization (PRAE) can prevent intraoperative blood loss and vascular injuries, its prophylactic use is still a matter of debate. This study evaluated the safety and efficacy of PRAE in overcoming the main pitfalls of laparoscopy, which are related to the absence of tactile feedback

Long-term mortality in frail elderly subjects with osteoarthritis

Elderly subjects are characterized by a high prevalence of OA and clinical frailty. This study aimed to examine the predictive role of clinical frailty on long-term mortality in elderly subjects with and without OA. Mortality was evaluated after a 12-year follow-up in 698 subjects with and 590 subjects without OA recruited in 1992. Clinical frailty was assessed according to the Frailty Staging System and stratified in tertiles. After a 12-year follow-up, mortality was 42.2% in subjects without and 55.8% in subjects with OA (P = 0.256). With increasing frailty, mortality increased by 30.5% (P for trend < 0.001) in subjects without and by 45.6% in subjects with OA (P for trend < 0.001). Multivariate analysis showed that frailty [hazard ratio (HR) = 1.49 for each unit of increase, 95% CI 1.32, 1.94, P < 0.001) but not OA (HR = 1.28, 95% CI 0.987, 1.39, P = 0.412) was predictive of long-term mortality. Moreover, when Cox regression analysis was performed, frailty enhanced the risk of long-term mortality for each unit of increase by 32% (HR = 1.32, 95% CI 1.06, 1.65, P = 0.03) in the absence of OA and by 98% in the presence (HR = 1.98, 95% CI 1.63, 2.95, P < 0.01) of OA. Clinical frailty significantly predicts mortality in subjects without OA and even more in those with OA. Thus clinical frailty may be considered a new prognostic factor to identify subjects with OA at high risk of mortality

Age-related reduction of cerebral ischemic preconditioning: myth or reality?

Stroke is one of the leading causes of death in industrialized countries for people older than 65 years of age. The reasons are still unclear. A reduction of endogenous mechanisms against ischemic insults has been proposed to explain this phenomenon. The “cerebral” ischemic preconditioning mechanism is characterized by a brief episode of ischemia that renders the brain more resistant against subsequent longer ischemic events. This ischemic tolerance has been shown in numerous experimental models of cerebral ischemia. This protective mechanism seems to be reduced with aging both in experimental and clinical studies. Alterations of mediators released and/or intracellular pathways may be responsible for age-related ischemic preconditioning reduction. Agents able to mimic the “cerebral” preconditioning effect may represent a new powerful tool for the treatment of acute ischemic stroke in the elderly. In this article, animal and human cerebral ischemic preconditioning, its age-related difference, and its potential therapeutical applications are discussed

Cardiac Surgery in Patients with Liver Cirrhosis (CASTER) study: early and long-term outcomes

patients with liver cirrhosis (LC) undergoing cardiac surgery (CS) face perioperative high mortality and morbidity, but extensive studies on this topic are lacking

Cardiac Surgery in Patients with Liver Cirrhosis (CASTER) study: early and long-term outcomes

BACKGROUND: patients with liver cirrhosis (LC) undergoing cardiac surgery (CS) face perioperative high mortality and morbidity, but extensive studies on this topic are lacking.METHODS: All adult patients with LC undergoing a CS procedure between 2000-2017 at ten Italian Institutions were included in this retrospective cohort study. LC was classified according to preoperative Child-Turcotte-Pugh (CTP) Score and Model for End-Stage Liver Disease (MELD) score. Early and medium-term outcomes analysis was performed in the overall population and according to CTP classes.RESULTS: The study population included 144 patients (mean age:66\ub19 years; male=69%). Ninety-eight, 20 and 26 patients were in CTP class-A, in early (MELD &lt;12) or advanced (MELD &gt;12) CTP class-B respectively. The main LC etiologies were viral (43%) and alcoholic (36%). Liver-related clinical presentation (ascites, esophageal varices and encephalopathy) and laboratory values (EGFR, serum albumin and bilirubin, platelet count) significantly worsened across the CTP-classes(p=.001). CABG or valve surgery (87% bioprosthesis) were performed in 36% and 50% respectively. Postoperative complications (especially AKI, liver complication and LOS) significantly worsened in advanced CTP class-B(p=.001). Notably, observed mortality was 3 or 4-fold higher than the EuroscoreII-predicted mortality, in the overall population, and in the subgroups. At Kaplan-Meier analysis, 1- and 5-years cumulative survival in the overall population was 82\ub13% and 77\ub14% respectively. The 5-years survival in CTP class A, early- and advanced-B was 72\ub15%, 68\ub111% and 61\ub110% respectively(p=.238).CONCLUSIONS: CS outcomes in patients with LC are significantly affected in relation to the extent of preoperative liver dysfunction, but in the early CTP classes medium-term survival is acceptable. Further analysis are needed to better estimate the preoperative risk stratification of these patients