Xanthurenic acid: A role in brain intercellular signaling.

Xanthurenic acid (XA) raises a growing multidisciplinary interest based upon its oxidizing properties, its ability to complex certain metal ions, and its detoxifier capacity of 3-hydroxykynurenine (3-HK), its brain precursor. However, little is still known about the role and mechanisms of action of XA in the central nervous system (CNS). Therefore, many research groups have recently investigated XA and its central functions extensively. The present paper critically reviews and discusses all major data related to XA properties and neuronal activities to contribute to the improvement of the current knowledge on XA's central roles and mechanisms of action. In particular, our data showed the existence of a specific G-protein-coupled receptor (GPCR) for XA localized exclusively in brain neurons exhibiting Ca2+ -dependent dendritic release and specific electrophysiological responses. XA properties and central activities suggest a role for this compound in brain intercellular signaling. Indeed, XA stimulates cerebral dopamine (DA) release contrary to its structural analog, kynurenic acid (KYNA). Thus, KYNA/XA ratio could be fundamental in the regulation of brain glutamate and DA release. Cerebral XA may also represent an homeostatic signal between the periphery and several brain regions where XA accumulates easily after peripheral administration. Therefore, XA status in certain psychoses or neurodegenerative diseases seems to be reinforced by its brain-specific properties in balance with its formation and peripheral inputs.

Intracellular removal of acetyl, feruloyl and p-coumaroyl decorations on arabinoxylo-oligosaccharides imported from lignocellulosic biomass degradation by Ruminiclostridium cellulolyticum.

BACKGROUND: Xylans are polysaccharides that are naturally abundant in agricultural by-products, such as cereal brans and straws. Microbial degradation of arabinoxylan is facilitated by extracellular esterases that remove acetyl, feruloyl, and p-coumaroyl decorations. The bacterium Ruminiclostridium cellulolyticum possesses the Xua (xylan utilization associated) system, which is responsible for importing and intracellularly degrading arabinoxylodextrins. This system includes an arabinoxylodextrins importer, four intracellular glycosyl hydrolases, and two intracellular esterases, XuaH and XuaJ which are encoded at the end of the gene cluster. RESULTS: Genetic studies demonstrate that the genes xuaH and xuaJ are part of the xua operon, which covers xuaABCDD'EFGHIJ. This operon forms a functional unit regulated by the two-component system XuaSR. The esterases encoded at the end of the cluster have been further characterized: XuaJ is an acetyl esterase active on model substrates, while XuaH is a xylan feruloyl- and p-coumaryl-esterase. This latter is active on oligosaccharides derived from wheat bran and wheat straw. Modelling studies indicate that XuaH has the potential to interact with arabinoxylobiose acylated with mono- or diferulate. The intracellular esterases XuaH and XuaJ are believed to allow the cell to fully utilize the complex acylated arabinoxylo-dextrins imported into the cytoplasm during growth on wheat bran or straw. CONCLUSIONS: This study reports for the first time that a cytosolic feruloyl esterase is part of an intracellular arabinoxylo-dextrin import and degradation system, completing its cytosolic enzymatic arsenal. This system represents a new pathway for processing highly-decorated arabinoxylo-dextrins, which could provide a competitive advantage to the cell and may have interesting biotechnological applications.

Involvement of Vasopressin in Tissue Hypoperfusion during Cardiogenic Shock Complicating Acute Myocardial Infarction in Rats.

Acute heart failure (AHF) due to acute myocardial infarction (AMI) is likely to involve cardiogenic shock (CS), with neuro-hormonal activation. A relationship between AHF, CS and vasopressin response is suspected. This study aimed to investigate the implication of vasopressin on hemodynamic parameters and tissue perfusion at the early phase of CS complicating AMI. Experiments were performed on male Wistar rats submitted or not to left coronary artery ligation (AMI and Sham). Six groups were studied Sham and AMI treated or not with either a vasopressin antagonist SR-49059 (Sham-SR, AMI-SR) or agonist terlipressin (Sham-TLP, AMI-TLP). Animals were sacrificed one day after surgery (D1) and after hemodynamic parameters determination. Vascular responses to vasopressin were evaluated, ex vivo, on aorta. AHF was defined by a left ventricular ejection fraction below 40%. CS was defined by AHF plus tissue hypoperfusion evidenced by elevated serum lactate level or low mesenteric oxygen saturation (SmO2) at D1. Mortality rates were 40% in AMI, 0% in AMI-SR and 33% in AMI-TLP. Immediately after surgery, a sharp decrease in SmO2 was observed in all groups. At D1, SmO2 recovered in Sham and in SR-treated animals while it remained low in AMI and further decreased in TLP-treated groups. The incidence of CS among AHF animals was 72% in AMI or AMI-TLP while it was reduced to 25% in AMI-SR. Plasma copeptin level was increased by AMI. Maximal contractile response to vasopressin was decreased in AMI (32%) as in TLP- and SR- treated groups regardless of ligation. Increased vasopressin secretion occurring in the early phase of AMI may be responsible of mesenteric hypoperfusion resulting in tissue hypoxia. Treatment with a vasopressin antagonist enhanced mesenteric perfusion and improve survival. This could be an interesting therapeutic strategy to prevent progression to cardiogenic shock.

Effect of Moderate Hypothermia vs Normothermia on 30-Day Mortality in Patients With Cardiogenic Shock Receiving Venoarterial Extracorporeal Membrane Oxygenation: A Randomized Clinical Trial.

IMPORTANCE: The optimal approach to the use of venoarterial extracorporeal membrane oxygenation (ECMO) during cardiogenic shock is uncertain. OBJECTIVE: To determine whether early use of moderate hypothermia (33-34 °C) compared with strict normothermia (36-37 °C) improves mortality in patients with cardiogenic shock receiving venoarterial ECMO. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial of patients (who were eligible if they had been endotracheally intubated and were receiving venoarterial ECMO for cardiogenic shock for <6 hours) conducted in the intensive care units at 20 French cardiac shock care centers between October 2016 and July 2019. Of 786 eligible patients, 374 were randomized. Final follow-up occurred in November 2019. INTERVENTIONS: Early moderate hypothermia (33-34 °C; n = 168) for 24 hours or strict normothermia (36-37 °C; n = 166). MAIN OUTCOMES AND MEASURES: The primary outcome was mortality at 30 days. There were 31 secondary outcomes including mortality at days 7, 60, and 180; a composite outcome of death, heart transplant, escalation to left ventricular assist device implantation, or stroke at days 30, 60, and 180; and days without requiring a ventilator or kidney replacement therapy at days 30, 60, and 180. Adverse events included rates of severe bleeding, sepsis, and number of units of packed red blood cells transfused during venoarterial ECMO. RESULTS: Among the 374 patients who were randomized, 334 completed the trial (mean age, 58 [SD, 12] years; 24% women) and were included in the primary analysis. At 30 days, 71 patients (42%) in the moderate hypothermia group had died vs 84 patients (51%) in the normothermia group (adjusted odds ratio, 0.71 [95% CI, 0.45 to 1.13], P = .15; risk difference, -8.3% [95% CI, -16.3% to -0.3%]). For the composite outcome of death, heart transplant, escalation to left ventricular assist device implantation, or stroke at day 30, the adjusted odds ratio was 0.61 (95% CI, 0.39 to 0.96; P = .03) for the moderate hypothermia group compared with the normothermia group and the risk difference was -11.5% (95% CI, -23.2% to 0.2%). Of the 31 secondary outcomes, 30 were inconclusive. The incidence of moderate or severe bleeding was 41% in the moderate hypothermia group vs 42% in the normothermia group. The incidence of infections was 52% in both groups. The incidence of bacteremia was 20% in the moderate hypothermia group vs 30% in the normothermia group. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial involving patients with refractory cardiogenic shock treated with venoarterial ECMO, early application of moderate hypothermia for 24 hours did not significantly increase survival compared with normothermia. However, because the 95% CI was wide and included a potentially important effect size, these findings should be considered inconclusive. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02754193.

Restrictive Transfusion Strategy after Cardiac Surgery.

BACKGROUND: Recent guidelines on transfusion in cardiac surgery suggest that hemoglobin might not be the only criterion to trigger transfusion. Central venous oxygen saturation (Svo2), which is related to the balance between tissue oxygen delivery and consumption, may help the decision process of transfusion. We designed a randomized study to test whether central Svo2-guided transfusion could reduce transfusion incidence after cardiac surgery. METHODS: This single center, single-blinded, randomized controlled trial was conducted on adult patients after cardiac surgery in the intensive care unit (ICU) of a tertiary university hospital. Patients were screened preoperatively and were assigned randomly to two study groups (control or Svo2) if they developed anemia (hemoglobin less than 9 g/dl), without active bleeding, during their ICU stay. Patients were transfused at each anemia episode during their ICU stay except the Svo2 patients who were transfused only if the pretransfusion central Svo2 was less than or equal to 65%. The primary outcome was the proportion of patients transfused in the ICU. The main secondary endpoints were (1) number of erythrocyte units transfused in the ICU and at study discharge, and (2) the proportion of patients transfused at study discharge. RESULTS: Among 484 screened patients, 100 were randomized, with 50 in each group. All control patients were transfused in the ICU with a total of 94 transfused erythrocyte units. In the Svo2 group, 34 (68%) patients were transfused (odds ratio, 0.031 [95% CI, 0 to 0.153]; P < 0.001 vs. controls), with a total of 65 erythrocyte units. At study discharge, eight patients of the Svo2 group remained nontransfused and the cumulative count of erythrocyte units was 96 in the Svo2 group and 126 in the control group. CONCLUSIONS: A restrictive transfusion strategy adjusted with central Svo2 may allow a significant reduction in the incidence of transfusion.

Right coronary artery ligation in mice: a novel method to investigate right ventricular dysfunction and biventricular interaction.

Right ventricular (RV) dysfunction can lead to complications after acute inferior myocardial infarction (MI). However, it is unclear how RV failure after MI contributes to left-sided dysfunction. The aim of the present study was to investigate the consequences of right coronary artery (RCA) ligation in mice. RCA ligation was performed in C57BL/6JRj mice ( n = 38). The cardiac phenotypes were characterized using high-resolution echocardiography performed up to 4 wk post-RCA ligation. Infarct size was measured using 2,3,5-triphenyltetrazolium chloride staining 24 h post-RCA ligation, and the extent of the fibrotic area was determined 4 wk after MI. RV dysfunction was confirmed 24 h post-RCA ligation by a decrease in the tricuspid annular plane systolic excursion ( P < 0.001) and RV longitudinal strain analysis ( P < 0.001). Infarct size measured ex vivo represented 45.1 ± 9.1% of the RV free wall. RCA permanent ligation increased the RV-to-left ventricular (LV) area ratio ( P < 0.01). Septum hypertrophy ( P < 0.01) was associated with diastolic septal flattening. During the 4-wk post-RCA ligation, LV ejection fraction was preserved, yet it was associated with impaired LV diastolic parameters ( E/ E', global strain rate during early diastole). Histological staining after 4 wk confirmed the remodeling process with a thin and fibrotic RV. This study validates that RCA ligation in mice is feasible and induces RV heart failure associated with the development of LV diastolic dysfunction. Our model offers a new opportunity to study mechanisms and treatments of RV/LV dysfunction after MI. NEW & NOTEWORTHY Right ventricular (RV) dysfunction frequently causes complications after acute inferior myocardial infarction. How RV failure contributes to left-sided dysfunction is elusive because of the lack of models to study molecular mechanisms. Here, we created a new model of myocardial infarction by permanently tying the right coronary artery in mice. This model offers a new opportunity to unravel mechanisms underlying RV/left ventricular dysfunction and evaluate drug therapy.

Acute kidney injury during daptomycin versus vancomycin treatment in cardiovascular critically ill patients: a propensity score matched analysis.

BACKGROUND: Gram-positive organisms are a leading cause of infection in cardiovascular surgery. Furthermore, these patients have a high risk of developing postoperative renal failure in intensive care unit (ICU). Some antibiotic drugs are known to impair renal function. The aim of the study was to evaluate whether patients treated for Gram-positive cardiovascular infection with daptomycin (DAP) experienced a lower incidence of acute kidney injury (AKI) when compared to patients treated with vancomycin (VAN), with comparable efficacy. METHODS: ICU patients who received either DAP or VAN, prior to or after cardiovascular surgery or mechanical circulatory support, from January 2010 to December 2012, were included in this observational retrospective cohort study. We excluded patients with end stage renal disease and antibiotic prophylaxis. The primary endpoint was the incidence of AKI within the first week of treatment. Secondary endpoints were the incidence of AKI within the first 14 days of treatment, the severity of AKI including renal replacement therapy (RRT), the rates of clinical failure (unsuccessful infection treatment) and of premature discontinuation and mortality. To minimize selection bias, we used a propensity score to compare the 2 groups. Univariate and multivariate analysis were performed to determine factors associated with AKI. RESULTS: Seventy two patients, treated for infective endocarditis, cardiovascular foreign body infection, or surgical site infection were included (DAP, n = 28 and VAN, n = 44). AKI at day 7 was observed in 28 (64%) versus 6 (21%) of the VAN and DAP patients, respectively (p = 0.001). In the multivariate analysis adjusted to the propensity score, vancomycin treatment was the only factor associated with AKI (Odds Ratio 4.42; 95% CI: 1.39-15.34; p = 0.014). RRT was required for 2 (7%) DAP patients and 13 (30%) VAN patients, p = 0.035. Premature discontinuation and clinical failure occurred more frequently in VAN group than in DAP group (25% versus 4%, p = 0.022 and 42% versus 12%, respectively, p = 0.027). CONCLUSIONS: Daptomycin appears to be safer than vancomycin in terms of AKI risk in ICU patients treated for cardiovascular procedure-related infection. Daptomycin could be considered as a first line treatment to prevent AKI in high-risk patients.

From Systemic Inflammation to Neuroinflammation: The Case of Neurolupus.

It took decades to arrive at the general consensus dismissing the notion that the immune system is independent of the central nervous system. In the case of uncontrolled systemic inflammation, the relationship between the two systems is thrown off balance and results in cognitive and emotional impairment. It is specifically true for autoimmune pathologies where the central nervous system is affected as a result of systemic inflammation. Along with boosting circulating cytokine levels, systemic inflammation can lead to aberrant brain-resident immune cell activation, leakage of the blood⁻brain barrier, and the production of circulating antibodies that cross-react with brain antigens. One of the most disabling autoimmune pathologies known to have an effect on the central nervous system secondary to the systemic disease is systemic lupus erythematosus. Its neuropsychiatric expression has been extensively studied in lupus-like disease murine models that develop an autoimmunity-associated behavioral syndrome. These models are very useful for studying how the peripheral immune system and systemic inflammation can influence brain functions. In this review, we summarize the experimental data reported on murine models developing autoimmune diseases and systemic inflammation, and we explore the underlying mechanisms explaining how systemic inflammation can result in behavioral deficits, with a special focus on in vivo neuroimaging techniques.

Modulation by the Noble Gas Helium of Tissue Plasminogen Activator: Effects in a Rat Model of Thromboembolic Stroke.

INTERVENTIONS: Helium has been shown to provide neuroprotection in mechanical model of acute ischemic stroke by inducing hypothermia, a condition shown by itself to reduce the thrombolytic and proteolytic properties of tissue plasminogen activator. However, whether or not helium interacts with the thrombolytic drug tissue plasminogen activator, the only approved therapy of acute ischemic stroke still remains unknown. This point is not trivial since previous data have shown the critical importance of the time at which the neuroprotective noble gases xenon and argon should be administered, during or after ischemia, in order not to block tissue plasminogen activator-induced thrombolysis and to obtain neuroprotection and inhibition of tissue plasminogen activator-induced brain hemorrhages. MEASUREMENTS AND MAIN RESULTS: We show that helium of 25-75 vol% inhibits in a concentration-dependent fashion the catalytic and thrombolytic activity of tissue plasminogen activator in vitro and ex vivo. In vivo, in rats subjected to thromboembolic brain ischemia, we found that intraischemic helium at 75 vol% inhibits tissue plasminogen activator-induced thrombolysis and subsequent reduction of ischemic brain damage and that postischemic helium at 75 vol% reduces ischemic brain damage and brain hemorrhages. CONCLUSIONS: In a clinical perspective for the treatment of acute ischemic stroke, these data suggest that helium 1) should not be administered before or together with tissue plasminogen activator therapy due to the risk of inhibiting the benefit of tissue plasminogen activator-induced thrombolysis; and 2) could be an efficient neuroprotective agent if given after tissue plasminogen activator-induced reperfusion.

Autoimmunity, neuroinflammation, pathogen load: A decisive crosstalk in neuropsychiatric SLE.

Depicting the cellular and molecular bases of the continuous dialogue existing between the peripheral immune and the central nervous systems, as in neurolupus, is fundamental to improve, and better apprehend the role played by immune cells and mediators in the initiation and progression of neurological and psychiatric diseases, which nowadays remain a major public health issue. The relative frequency of neurological symptoms occurring in systemic autoimmunity is particularly worrying as, for example, two-thirds of patients with lupus will eventually experience the disabling effects of neuropsychiatric lupus. Neurolupus is a particularly severe form of lupus with wide-ranging symptoms, which contribute to increased mortality and morbidity in patients. In this context, infections, which suddenly trigger exacerbations of the otherwise mild lupus disease, may drive the progression of neuroinflammation and neurodegeneration via different mechanisms involving a network of effector molecules and cells. The complex interaction of neuroimmunology and neuroinfectiology represents a genuine challenge for basic scientists and clinicians to understand the mechanisms that are implicated, and identify possible biomarkers of severity that might predict the development of this devastating form of lupus. The ultimate goal is to design appropriate, personalised therapeutic strategies to improve the outcome of the disease.

Crystallographic studies with xenon and nitrous oxide provide evidence for protein-dependent processes in the mechanisms of general anesthesia.

BACKGROUND: The mechanisms by which general anesthetics, including xenon and nitrous oxide, act are only beginning to be discovered. However, structural approaches revealed weak but specific protein-gas interactions. METHODS: To improve knowledge, we performed x-ray crystallography studies under xenon and nitrous oxide pressure in a series of 10 binding sites within four proteins. RESULTS: Whatever the pressure, we show (1) hydrophobicity of the gas binding sites has a screening effect on xenon and nitrous oxide binding, with a threshold value of 83% beyond which and below which xenon and nitrous oxide, respectively, binds to their sites preferentially compared to each other; (2) xenon and nitrous oxide occupancies are significantly correlated respectively to the product and the ratio of hydrophobicity by volume, indicating that hydrophobicity and volume are binding parameters that complement and oppose each other's effects; and (3) the ratio of occupancy of xenon to nitrous oxide is significantly correlated to hydrophobicity of their binding sites. CONCLUSIONS: These data demonstrate that xenon and nitrous oxide obey different binding mechanisms, a finding that argues against all unitary hypotheses of narcosis and anesthesia, and indicate that the Meyer-Overton rule of a high correlation between anesthetic potency and solubility in lipids of general anesthetics is often overinterpreted. This study provides evidence that the mechanisms of gas binding to proteins and therefore of general anesthesia should be considered as the result of a fully reversible interaction between a drug ligand and a receptor as this occurs in classical pharmacology.

Early temporary mechanical circulatory support for cardiogenic shock: Real-life data from a regional cardiac assistance network.

BACKGROUND: Temporary mechanical circulatory support as well as multidisciplinary team approach in a regional care organization might improve survival of cardiogenic shock. No study has evaluated the relative effect of each temporary mechanical circulatory support on mortality in the context of a regional network. METHODS: Prospective observational data were retrieved from patients consecutively admitted with cardiogenic shock to the intensive care units in 3 centers organized into a regional cardiac assistance network. Temporary mechanical circulatory support indication was decided by a heart team, based on the initial shock severity or if shock was refractory to medical treatment within 24 hours of admission. A propensity score for circulatory support use was used as an adjustment co-variable to emulate a target trial. The primary endpoint was in-hospital mortality. RESULTS: Two hundred and forty-six patients were included in the study (median age: 59.5 years, 71.9% male): 121 received early mechanical assistance. The main etiologies were acute myocardial infraction (46.8%) and decompensated heart failure (27.2%). Patients who received early mechanical assistance had more severe conditions than other patients. Their crude in-hospital mortality was 38% and 22.4% in other patients but adjusted in-hospital mortality was not different (hazard ratio 0.91, 95% CI:0.65-1.26). Patients with mechanical assistance had a higher rate of complications than others with longer Intensive Care Unit and hospital stays. CONCLUSIONS: In the conditions of a cardiac assistance regional network, in-hospital mortality was not improved by early mechanical assistance implantation. A high incidence of complications of temporary mechanical circulatory support may have jeopardized its potential benefit.

Short-term development of behavioral sensitization to amphetamine requires N-methyl-D-aspartate- and nicotinic-dependent mechanisms in the nucleus accumbens.

Repeated administration of psychostimulant drugs, such as amphetamine, induces an enhanced behavioral response to subsequent drug challenge. This behavioral sensitization is proposed to model the increased drug craving observed in human psychostimulant abusers. Current thinking is that the ventral tegmental area, but not the nucleus accumbens, plays a critical role in the development of behavioral sensitization. Here, we report that the concomitant blockade of glutamatergic and nicotinic ionotropic receptors in the core of the nucleus accumbens blocks the development of behavioral sensitization to amphetamine and further abolishes the increase in extracellular dopamine release induced by amphetamine in the nucleus accumbens. These findings demonstrate that the development of behavioral sensitization to amphetamine depends, in addition to the well-known role of the ventral tegmental area, on glutamatergic and nicotinic-dependent mechanisms in the core of the nucleus accumbens and further indicate that the dopaminergic mesolimbic pathway must be viewed as a single coordinated system of critical importance in the development of behavioral sensitization to psychostimulant drugs.

Myelin in Alzheimer's disease: culprit or bystander?

Alzheimer's disease (AD) is a neurodegenerative disorder with neuronal and synaptic losses due to the accumulation of toxic amyloid ß (Αß) peptide oligomers, plaques, and tangles containing tau (tubulin-associated unit) protein. While familial AD is caused by specific mutations, the sporadic disease is more common and appears to result from a complex chronic brain neuroinflammation with mitochondriopathies, inducing free radicals' accumulation. In aged brain, mutations in DNA and several unfolded proteins participate in a chronic amyloidosis response with a toxic effect on myelin sheath and axons, leading to cognitive deficits and dementia. Αß peptides are the most frequent form of toxic amyloid oligomers. Accumulations of misfolded proteins during several years alters different metabolic mechanisms, induce chronic inflammatory and immune responses with toxic consequences on neuronal cells. Myelin composition and architecture may appear to be an early target for the toxic activity of Aß peptides and others hydrophobic misfolded proteins. In this work, we describe the possible role of early myelin alterations in the genesis of neuronal alterations and the onset of symptomatology. We propose that some pathophysiological and clinical forms of the disease may arise from structural and metabolic disorders in the processes of myelination/demyelination of brain regions where the accumulation of non-functional toxic proteins is important. In these forms, the primacy of the deleterious role of amyloid peptides would be a matter of questioning and the initiating role of neuropathology would be primarily the fact of dysmyelination.

Pressure-response analysis of anesthetic gases xenon and nitrous oxide on urate oxidase: a crystallographic study.

The remarkably safe anesthetics xenon (Xe) and, to lesser extent, nitrous oxide (N(2)O) possess neuroprotective properties in preclinical studies. To investigate the mechanisms of pharmacological action of these gases, which are still poorly known, we performed both crystallography under a large range of gas pressure and biochemical studies on urate oxidase, a prototype of globular gas-binding proteins whose activity is modulated by inert gases. We show that Xe and N(2)O bind to, compete for, and expand the volume of a hydrophobic cavity located just behind the active site of urate oxidase and further inhibit urate oxidase enzymatic activity. By demonstrating a significant relationship between the binding and biochemical effects of Xe and N(2)O, given alone or in combination, these data from structure to function highlight the mechanisms by which chemically and metabolically inert gases can alter protein function and produce their pharmacological effects. Interestingly, the effects of a Xe:N(2)O equimolar mixture were found to be equivalent to those of Xe alone, thereby suggesting that gas mixtures containing Xe and N(2)O could be an alternative and efficient neuroprotective strategy to Xe alone, whose widespread clinical use is limited due to the cost of production and availability of this gas.

Interactions between nitrous oxide and tissue plasminogen activator in a rat model of thromboembolic stroke.

BACKGROUND: Preclinical evidence in rodents has suggested that inert gases, such as xenon or nitrous oxide, may be promising neuroprotective agents for treating acute ischemic stroke. This has led to many thinking that clinical trials could be initiated in the near future. However, a recent study has shown that xenon interacts with tissue-type plasminogen activator (tPA), a well-recognized approved therapy of acute ischemic stroke. Although intraischemic xenon inhibits tPA-induced thrombolysis and subsequent reduction of brain damage, postischemic xenon virtually suppresses both ischemic brain damage and tPA-induced brain hemorrhages and disruption of the blood-brain barrier. The authors investigated whether nitrous oxide could also interact with tPA. METHODS: The authors performed molecular modeling of nitrous oxide binding on tPA, characterized the concentration-dependent effects of nitrous oxide on tPA enzymatic and thrombolytic activity in vitro, and investigated the effects of intraischemic and postischemic nitrous oxide in a rat model of thromboembolic acute ischemic stroke. RESULTS: The authors demonstrate nitrous oxide is a tPA inhibitor, intraischemic nitrous oxide dose-dependently inhibits tPA-induced thrombolysis and subsequent reduction of ischemic brain damage, and postischemic nitrous oxide reduces ischemic brain damage, but in contrast with xenon, it increases brain hemorrhages and disruption of the blood-brain barrier. CONCLUSIONS: In contrast with previous studies using mechanical acute stroke models, these data obtained in a clinically relevant rat model of thromboembolic stroke indicate that nitrous oxide should not be considered a good candidate agent for treating acute ischemic stroke compared with xenon.

Development and validation of a novel prognostic score for elderly head-and-neck cancer patients undergoing radiotherapy or chemoradiation.

BACKGROUND AND PURPOSE: To establish a clinically feasible prognostic score and nomogram based on easily accessible clinical data that will aid decision-making in elderly head-and-neck squamous cell carcinoma (HNSCC) patients undergoing (chemo)radiotherapy. MATERIAL AND METHODS: 284 elderly HNSCC patients (≥65 years) undergoing curative (chemo)radiotherapy were included for the development of a score predicting overall survival (OS) based on the beta regression coefficients from significant parameters in a multivariate Cox regression analysis with p < 0.1 as inclusion criterion. A second, external cohort of 217 elderly HNSCC patients receiving (chemo)radiotherapy was used for validation. Using the aggregated data (n = 501), a nomogram was developed to predict 2- and 4-year OS. RESULTS: Karnofsky Performance Status (HR = 2.654; p < 0.001), Charlson Comorbidity Index (HR = 2.598; p < 0.001) and baseline C-reactive protein (CRP) level (HR = 1.634; p = 0.068) were prognostic for OS in the multivariate analysis. An OS score based on beta regression coefficients was created, in which reduced performance status, increased comorbidity burden and increased CRP levels were included, leading to 3 distinct survival groups. The median OS for the 3 groups amounted to 107, 28 and 6 months, respectively (p < 0.001). The developed score was able to significantly differentiate between a favorable (median OS = 130 months), intermediate (29 months) and unfavorable prognosis (9 months) also in the external validation cohort (p = 0.005). CONCLUSION: We propose a novel, validated prognostic score based on easily accessible clinical data allowing stratification between prognostic groups of elderly HNSCC patients receiving (chemo)radiotherapy. The derived nomogram for the prediction of 2-year and 4-year OS may aid decision-making for this vulnerable population.

Experimental Myocardial Infarction Elicits Time-Dependent Patterns of Vascular Hypoxia in Peripheral Organs and in the Brain.

Aims: Microvascular alterations occurring after myocardial infarction (MI) may represent a risk factor for multi-organ failure. Here we used in vivo photoacoustic (PA) imaging to track and define the changes in vascular oxygen saturation (sO2) occurring over time after experimental MI in multiple peripheral organs and in the brain. Methods and Results: Experimental MI was obtained in BALB/c mice by permanent ligation of the left anterior descending artery. PA imaging (Vevo LAZR-X) allowed tracking mouse-specific sO2 kinetics in the cardiac left ventricular (LV) anterior wall, brain, kidney, and liver at 4 h, 1 day, and 7 days post-MI. Here we reported a correlation between LV sO2 and longitudinal anterior myocardial strain after MI (r = -0.44, p < 0.0001, n = 96). Acute LV dysfunction was associated with global hypoxia, specifically a decrease in sO2 level in the brain (-5.9%), kidney (-6.4%), and liver (-7.3%) at 4 and 24 h post-MI. Concomitantly, a preliminary examination of capillary NG2DsRed pericytes indicated cell rarefication in the heart and kidney. While the cardiac tissue was persistently impacted, sO2 levels returned to pre-MI levels in the brain and in peripheral organs 7 days after MI. Conclusions: Collectively, our data indicate that experimental MI elicits precise trajectories of vascular hypoxia in peripheral organs and in the brain. PA imaging enabled the synchronous tracking of oxygenation in multiple organs and occurring post-MI, potentially enabling a translational diagnostic modality for the identification of vascular modifications in this disease setting.

The Value of Laboratory Parameters for Anemia, Renal Function, Systemic Inflammation and Nutritional Status as Predictors for Outcome in Elderly Patients with Head-and-Neck Cancers.

The purpose of this study was to evaluate the value of routine blood markers regarding their predictive potential for treatment outcomes of elderly head-and-neck squamous cell carcinoma (HNSCC) patients. In total, 246 elderly HNSCC patients (≥65 years) undergoing (chemo)radiotherapy from 2010 to 2018 were analyzed for treatment outcomes, depending on their hemoglobin, glomerular filtration rate (GFR), C-reactive protein (CRP) and albumin values, representing anemia, kidney function, inflammation and nutrition status, respectively. Local/locoregional control, progression-free and overall survival (OS) were calculated using the Kaplan-Meier method. Cox analyses were performed to examine the influence of blood parameters on oncological outcomes. In the univariate Cox regression analysis, hemoglobin ≤ 12 g/dL (HR = 1.536, p < 0.05), a GFR ≤ 60 mL/min/1.73 m2 (HR = 1.537, p < 0.05), a CRP concentration > 5 mg/L (HR = 1.991, p < 0.001) and albumin levels ≤ 4.2 g/dL (HR = 2.916, p < 0.001) were significant risk factors for OS. In the multivariate analysis including clinical risk factors, only performance status (HR = 2.460, p < 0.05) and baseline albumin (HR = 2.305, p < 0.05) remained significant prognosticators. Additionally, baseline anemia correlated with the prevalence of higher-grade chronic toxicities. We could show for the first time that laboratory parameters for anemia (and at least partly, tumor oxygenation), decreased renal function, inflammation and reduced nutrition status are associated with impaired survival in elderly HNSCC patients undergoing (chemo)radiotherapy.