Targeting ferroptosis with the lipoxygenase inhibitor PTC-041 as a therapeutic strategy for the treatment of Parkinson's disease.

Parkinson's disease is the second most common neurodegenerative disorder, affecting nearly 10 million people worldwide. Ferroptosis, a recently identified form of regulated cell death characterized by 15-lipoxygenase-mediated hydroperoxidation of membrane lipids, has been implicated in neurodegenerative disorders including amyotrophic lateral sclerosis and Parkinson's disease. Pharmacological inhibition of 15 -lipoxygenase to prevent iron- and lipid peroxidation-associated ferroptotic cell death is a rational strategy for the treatment of Parkinson's disease.

Endovascular removal of a large free-floating thrombus of the descending thoracic aorta using the AngioVac system.

Free-floating aortic mural thrombus in the minimally diseased or nonaneurysmal aorta is a rare, clinically significant source of peripheral embolism. We describe a 41-year-old woman with a history of left brachial thromboembolectomy who presented atypical chest pain. Computed tomography angiography and transesophageal echocardiography revealed a 14.

Redosing of long acting cardioplegic solutions in adult cardiac surgery: A comparative study.

Introduction: Despite promising results regarding using long-acting cardioplegia in the adult population, little data exists specifically for operations requiring prolonged aortic cross-clamp needing additional doses. In this pilot study, we evaluated the outcomes of patients undergoing surgery with prolonged cross-clamp time based on four different redosing compositions.

Methods: During the period from January 2019 until June 2022, 288 patients undergoing cardiac surgery with an expected cross-clamp time over 60 min were prospectively randomized regarding the type of the cardioplegia used: Group 1 ( = 150)- single-dose del Nido antegrade cardioplegia and Group 2 ( = 138)- single-dose Histidine-Tryptophane-Ketoglutarate (HTK) antegrade cardioplegia.

Clinical outcomes of single-dose cardioplegia in high-risk coronary bypass.

Background: Despite the increasing popularity of single-dose cardioplegia techniques in coronary artery bypass grafting, the time window for successful reperfusion remains unclear. This study aimed to compare different cardioplegic techniques based on early and 30-day clinical outcomes via thorough monitoring.

Methods: This prospective cohort study included high-risk patients undergoing coronary artery bypass grafting and receiving 3 different types of cardioplegia between January 2017 and June 2019.

Long-Term Protective Effects of Single-Dose Cardioplegic Solutions in Cell Culture Models.

Despite the popularity of single-dose cardioplegic techniques, the time window and targeted population for successful reperfusion remain unclear. We tested currently available techniques based on cell viability and integrity to demonstrate long-term cardioprotection and clarify whether these solutions were performed on neonatal/adult endothelium and myocardium by examining different cell lines. Cell viability with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test proliferation assay and membrane integrity with the lactic dehydrogenase (LDH) cytotoxicity test were documented in a cell culture/microscopy setting on adult (human umbilical vein endothelium [HUVEC]), neonatal (H9C2-cardiomyocytes), and myofibroblast (L929) cell lines.

Comparative Effects of Single-Dose Cardioplegic Solutions Especially in Repeated Doses During Minimally Invasive Aortic Valve Surgery.

Objective: This study aims to compare del Nido cardioplegia (DNC) and histidine-tryptophan-ketoglutarate (HTK) cardioplegic solutions in minimally invasive aortic valve replacement (mini-AVR) surgery to discuss the safety level of myocardial protection and rationale for redosing intervals.

Methods: During the period from January 2017 to June 2019, 200 patients undergoing mini-AVR (solely or with concomitant procedures) were prospectively randomized to DNC ( = 100) andHTK ( = 100), both up to 90 minutes ischemic time. Patients with ischemic time over 90 minutes, needing a redosing, were further analyzed in 2 subgroups with DNC-R ( = 30) and HTK-R ( = 36).

Minimally Invasive Aortic Valve Replacement on Minimally Invasive Extracorporeal Circulation: Going beyond Aesthetics.

We present our multidisciplinary and multistep strategy in patients undergoing minimally invasive aortic valve replacement (mAVR) on minimally invasive extracorporeal circulation (MiECC) compared with control groups of a single strategy and conventional techniques. This cohort study included high-risk patients (Society of Thoracic Surgeons [STS] risk score >8%) undergoing aortic valve surgery under different strategies during the period from January 2017 until March 2019. Patients were matched for age, gender, body mass index, and STS score: group 1 (MiAVR) based on a minimally invasive technique with J-mini-sternotomy, rapid deployment valve (RDV), and type IV customized MiECC; group 2 (control-mAVR) consisted of minimally invasive technique with only J mini-sternotomy and RDV on a conventional extracorporeal system; group 3 (control-MiECC): full sternotomy and type IV customized MiECC; and group 4 (control): full sternotomy on a conventional extracorporeal system.

Vitamin E hydroquinone is an endogenous regulator of ferroptosis via redox control of 15-lipoxygenase.

Ferroptosis is a form of programmed cell death associated with inflammation, neurodegeneration, and ischemia. Vitamin E (alpha-tocopherol) has been reported to prevent ferroptosis, but the mechanism by which this occurs is controversial. To elucidate the biochemical mechanism of vitamin E activity, we systematically investigated the effects of its major vitamers and metabolites on lipid oxidation and ferroptosis in a striatal cell model.

A Cardiopulmonary Bypass Based Blood Management Strategy in Adult Cardiac Surgery.

Background: Despite the recent introduction of a number of technical and pharmacologic blood conservation measures, bleeding and allogeneic transfusion remain persistent problems in open-heart surgical procedures. Efforts should be made to decrease or completely avoid transfusions to avoid these negative reactions.

Methods: Our coronary artery bypass grafting database was reviewed retrospectively and a total of 243 patients who underwent cardiac surgery with cardiopulmonary bypass (CPB) were studied in a 12-month period (January-December 2016) after the implementation of the new program, and compared with 275 patients of the previous 12-month period.

Experimental demonstration of interaction-free all-optical switching via the quantum Zeno effect.

We experimentally demonstrate all-optical interaction-free switching using the quantum Zeno effect, achieving a high contrast of 35:1. The experimental data match a zero-parameter theoretical model for several different regimes of operation, indicating a good understanding of the switch's characteristics. We also discuss extensions of this work that will allow for significantly improved performance, and the integration of this technology onto chip-scale devices, which can lead to ultra-low-power all-optical switching, a long-standing goal with applications to both classical and quantum information processing.

Covalent intermediate in the catalytic mechanism of the radical S-adenosyl-L-methionine methyl synthase RlmN trapped by mutagenesis.

The posttranscriptional modification of ribosomal RNA (rRNA) modulates ribosomal function and confers resistance to antibiotics targeted to the ribosome. The radical S-adenosyl-L-methionine (SAM) methyl synthases, RlmN and Cfr, both methylate A2503 within the peptidyl transferase center of prokaryotic ribosomes, yielding 2-methyl- and 8-methyl-adenosine, respectively. The C2 and C8 positions of adenosine are unusual methylation substrates due to their electrophilicity.

The chemistry of peptidyltransferase center-targeted antibiotics: enzymatic resistance and approaches to countering resistance.

The continued ability to treat bacterial infections requires effective antibiotics. The development of new therapeutics is guided by knowledge of the mechanisms of action of and resistance to these antibiotics. Continued efforts to understand and counteract antibiotic resistance mechanisms at a molecular level have the potential to direct development of new therapeutic strategies in addition to providing insight into the underlying biochemical functions impacted by antibiotics.

Effects of maternal supplementary oxygen on the newborn for elective cesarean deliveries under spinal anesthesia.

Purpose: The aim of this investigation was to determine whether supplementary oxygen provided by either nasal cannula or face mask versus room air might affect fetal oxygenation during elective cesarean section under spinal anesthesia by assessing maternal and neonatal regional cerebral oxygenation (rSO(2)) with a cerebral oximeter.

Methods: Ninety parturients were randomly allocated into three groups: two groups received 5 L/min oxygen by either nasal cannula (Group NC, n = 30) or face mask (Group FM, n = 30), respectively, and the third group was allowed to breathe room air (Group RA, n = 30). After maternal mean arterial pressure, heart rate and peripheral oxygen saturation had been monitored, rSO(2) was determined by cerebral oximeter.

Perioperative blood conservation strategies in pediatric patients undergoing open-heart surgery: impact of non-autologous blood transfusion and surface-coated extracorporeal circuits.

Background: The aim of this study was to explore the relative clinical and biomaterial effects of blood transfusions (Tx) and novel low-prime, surface-coated circuitry on perioperative outcome in a pediatric population undergoing cardiac surgery with cardiopulmonary bypass (CPB).

Methods: Over a 12-month period, 80 patients weighing >10 kg undergoing ventricular septal defect (VSD) repair with CPB were prospectively randomized into two groups according to the type of CBP circuit used, then each randomized group was enrolled into two groups again, according to the need for transfusion (N=20): Group 1- Tx-free procedures on low-prime, surface-coated extracorporeal circuitry (FX05, Terumo); Group 2- procedures requiring Tx on coated circuitry; Group 3- Tx-free procedures with standard uncoated circuitry (D902, Sorin); Group 4 (Control)- procedures requiring Tx on uncoated circuitry. Blood samples were collected at baseline (T1), at the end of the CPB (T2) and 24 h (T3) postoperatively.

Hyaluronan based heparin free coated open and closed extracorporeal circuits for high risk coronary revascularization.

This prospective randomized study compares the inflammatory response and fibrinolytic activation of fully coated/uncoated and open/closed extracorporeal circuits (ECC) in high risk patients. Over a 2-month period, 48 patients with EuroSCOREs 6 or greater undergoing coronary revascularization were prospectively randomized to one of the four perfusion protocols: Group 1: Closed and totally hyaluronan based heparin free coated (Vision HFO-GBS-HF, Gish Biomedical, Rancho Santa Margarita, CA) ECC with a soft-shell coated venous reservoir (SVR11S2-HFC, Gish Biomedical) and a hard-shell cardiotomy (CAPVRF44, Gish Biomedical) (n = 12); Group 2: Closed and totally uncoated identical ECC with soft-shell uncoated venous reservoir and a hard-shell cardiotomy (n = 12); Group 3: Open, totally hyaluronan based heparin free coated ECC (n = 12); and Group 4: Control-open, uncoated ECC (n = 12). Blood samples were collected at T1: Baseline; T2: 15 minutes after cardiopulmonary bypass (CPB) initiation; T3: before cessation of CPB; T4: 15 minutes after protamine reversal, and T5: in the intensive care unit.

An active-site phenylalanine directs substrate binding and C-H cleavage in the alpha-ketoglutarate-dependent dioxygenase TauD.

Enzymes that cleave C-H bonds are often found to depend on well-packed hydrophobic cores that influence the distance between the hydrogen donor and acceptor. Residue F159 in taurine alpha-ketoglutarate dioxygenase (TauD) is demonstrated to play an important role in the binding and orientation of its substrate, which undergoes a hydrogen atom transfer to the active site Fe(IV)=O. Mutation of F159 to smaller hydrophobic side chains (L, V, A) leads to substantially reduced rates for substrate binding and for C-H bond cleavage, as well as increased contribution of the chemical step to k(cat) under steady-state turnover conditions.

Clinical performance and biocompatibility of hyaluronan-based heparin-bonded extracorporeal circuits in different risk cohorts.

This prospective randomized study compares novel hyaluronan-based heparin-bonded circuits vs. uncoated controls across EuroSCORE patient risk strata including biomaterial evaluation. Over a two-year period, 90 patients undergoing coronary artery bypass grafting were prospectively randomized to one of the two perfusion protocols: Group 1 was treated with hyaluronan-based heparin-bonded preconnected circuits (Vision HFO-GBS, Gish, CA, USA) and Group 2 with identical uncoated controls.

Clinical and biomaterial evaluation of a new condensed dual-function extracorporeal circuit in reoperation for coronary artery bypass surgery.

Purpose: This prospective, randomized study compared the clinical performance of three types of circuits: a newly introduced, fully-coated, interchangeable open-closed circuit with a dual configuration (hard shell with a bypass shunt), reduced length, and reduced prime of less than 800 cc (CondECC); a completely coated circuit (ECC); and a similar uncoated, open circuit with standard length and prime (CONT).

Methods: 75 patients undergoing reoperation for coronary revascularization were randomly allocated into three groups (N=25): Group 1: CondECC with shortened tubing, components and an open-closed configuration of low priming volume with a centrifugal pump and a shunt which bypassed the reservoir for closed configuration; Group 2: ECC with a roller pump and hard-shell reservoir; Group 3: CONT. Blood samples for CBC, inflammatory mediators [Interleukin-2 (IL-2), Complement-3a (C3a)] and flow cytometry (CD11b/CD18) were collected after induction (T1) and heparin administration (T2), 15 min after cardiopulmonary bypass (CPB) (T3), before cessation of CPB (T4), 15 min after reversal (T5), and the first postoperative day (T6).

Efficient optical quantum state engineering.

We discuss a novel method of efficiently producing multiphoton states using repeated spontaneous parametric down-conversion. Specifically, by attempting down-conversion several times, we can pseudodeterministically add photons to a mode, producing various several-photon states, e.g.

Modular behavior of tauD provides insight into the origin of specificity in alpha-ketoglutarate-dependent nonheme iron oxygenases.

Taurine alpha-ketoglutarate dioxygenase (tauD) is one of the best-studied alpha-ketoglutarate (alphaKG)-dependent nonheme iron oxygenases. As with all oxygenases, a fine balance must be struck between generating a species sufficiently reactive for the required chemistry and controlling that species to prevent undesirable side reactions [Klinman JP (2007) Accts Chem Res 40:325-333]. In the case of tauD, the substrate oxidizing species has been shown to be a ferryl-oxo, and the introduction of deuterium at the reactive position of substrate results in an enormous kinetic isotope effect together with a partial uncoupling of oxygen activation from substrate oxidation [Price JC, Barr EW, Glass TE, Krebs C, Bollinger JM (2003) J Am Chem Soc 125:13008-13009].

Clinical evaluation of minimized extracorporeal circulation in high-risk coronary revascularization: impact on air handling, inflammation, hemodilution and myocardial function.

Objective: We examined intraoperative microembolic signals (GME), inflammatory response, hemolysis, perioperative regional cerebral oxygen saturation (rSO(2)), myocardial protection and desorbed protein amount on oxygenator fibers in high-risk patients undergoing coronary revascularization (CABG) with minimized and conventional cardiopulmonary bypass (CPB).

Methods: Over a ten-month period, 40 Euroscore 6+ patients undergoing CABG were prospectively randomized to one of the two perfusion protocols (N=20): Group 1: minimized extracorporeal circuits (Mini-CPB) (ROCsafe MPC, Terumo, Ann Arbor, MI, USA) and Group 2: conventional extracorporeal circuits (CECC) (Capiox SX18, Terumo, USA). Serum creatinine kinase-MB (CKMB), free hemoglobin, interleukin-6 (IL-6) and C3a levels were measured.

Clinical and biomaterial evaluation of hyaluronan-based heparin-bonded extracorporeal circuits with reduced versus full systemic anticoagulation in reoperation for coronary revascularization.

Objective: This prospective randomized study compares full and reduced heparinization on novel hyaluronan-based heparin-bonded circuits vs. uncoated controls under challenging clinical setting including biomaterial evaluation.

Methods: 100 patients undergoing reoperation for coronary artery bypass grafting were allocated into two equal groups (n = 50): Group one was treated with hyaluronan-based heparin bonded preconnected circuits (Vision HFOGBS, Gish, California, USA) and Group two with identical uncoated controls (Vision HFO, Gish, USA).

18O kinetic isotope effects in non-heme iron enzymes: probing the nature of Fe/O2 intermediates.

Contrasted here are the competitive 18O/16O kinetic isotope effects (18O KIEs) on kcat/Km(O2) for three non-heme iron enzymes that activate O2 at an iron center coordinated by a 2-His-1-carboxylate facial triad: taurine dioxygenase (TauD), (S)-(2)-hydroxypropylphosphonic acid epoxidase (HppE), and 1-aminocyclopropyl-1-carboxylic acid oxidase (ACCO). Measured 18O KIEs of 1.0102 +/- 0.

Cardiopulmonary bypass recommendations in adults: the northern New England experience.

Using a regional cardiopulmonary bypass (CPB) registry, we compared the practice of CPB at eight northern New England institutions to recently published recommendations. We examined CPB practice among 3597 adult patients undergoing isolated coronary artery bypass grafting surgery from January 2004 to June 2005. Registry variables were used to compare regional CPB practice to recommendations on topics of neurologic protection (pH management, avoidance of hyperthermia, minimizing return of pericardial suction blood, aortic assessment, arterial line filtration), maintenance of euglycemia, reduction of hemodilution, and attenuation of the inflammatory response.

Clinical effects of leukofiltration and surface modification on post-cardiopulmonary bypass atrial fibrillation in different risk cohorts.

Objective: A manifestation of inflammatory injury to the heart, atrial fibrillation (AF), ranks among the most frequent and potentially life-threatening post-operative complications.

Methods: In a prospective randomized study, 120 patients undergoing CABG were allocated into two groups (N = 60): Group 1: Polymethoxyethylacry late-coated circuits + Leukocyte filters (Terumo,USA); Group 2:

Control: Uncoated circuits (Terumo,USA). Each group was further divided into three subgroups (N = 20) with respect to low (Euroscore 0-2), medium (3-5) and high (6+) risk patients.