Low Levels of IgM Recognizing 4-Hydroxy-2-Nonenal-Modified Apolipoprotein A-I Peptide and Its Association with the Severity of Coronary Artery Disease in Taiwanese Patients.

Autoantibodies against apolipoprotein A-I (ApoA-I) are associated with cardiovascular disease risks. We aimed to examine the 4-hydroxy-2-nonenal (HNE) modification of ApoA-I in coronary artery disease (CAD) and evaluate the potential risk of autoantibodies against their unmodified and HNE-modified peptides. We assessed plasma levels of ApoA-I, HNE-protein adducts, and autoantibodies against unmodified and HNE-peptide adducts, and significant correlations and odds ratios (ORs) were examined. Two novel CAD-specific HNE-peptide adducts, ApoA-I251-262 and ApoA-I70-83, were identified. Notably, immunoglobulin G (IgG) anti-ApoA-I251-262 HNE, IgM anti-ApoA-I70-83 HNE, IgG anti-ApoA-I251-262, IgG anti-ApoA-I70-83, and HNE-protein adducts were significantly correlated with triglycerides, creatinine, or high-density lipoprotein in CAD with various degrees of stenosis (<30% or >70%). The HNE-protein adduct (OR = 2.208-fold, p = 0.020) and IgM anti-ApoA-I251-262 HNE (2.046-fold, p = 0.035) showed an increased risk of progression from >30% stenosis in CAD. HNE-protein adducts and IgM anti-ApoA-I251-262 HNE may increase the severity of CAD at high and low levels, respectively.

Therapeutic potential of mitochondrial transplantation in modulating immune responses post-cardiac arrest: a narrative review.

BACKGROUND: Mitochondrial transplantation (MTx) has emerged as a novel therapeutic strategy, particularly effective in diseases characterized by mitochondrial dysfunction. This review synthesizes current knowledge on MTx, focusing on its role in modulating immune responses and explores its potential in treating post-cardiac arrest syndrome (PCAS). METHODS: We conducted a comprehensive narrative review of animal and human studies that have investigated the effects of MTx in the context of immunomodulation. This included a review of the immune responses following critical condition such as ischemia reperfusion injury, the impact of MTx on these responses, and the therapeutic potential of MTx in various conditions. RESULTS: Recent studies indicate that MTx can modulate complex immune responses and reduce ischemia-reperfusion injury post-CA, suggesting MTx as a novel, potentially more effective approach. The review highlights the role of MTx in immune modulation, its potential synergistic effects with existing treatments such as therapeutic hypothermia, and the need for further research to optimize its application in PCAS. The safety and efficacy of autologous versus allogeneic MTx, particularly in the context of immune reactions, are critical areas for future investigation. CONCLUSION: MTx represents a promising frontier in the treatment of PCAS, offering a novel approach to modulate immune responses and restore cellular energetics. Future research should focus on long-term effects, combination therapies, and personalized medicine approaches to fully harness the potential of MTx in improving patient outcomes in PCAS.

Insufficient oxygen inhalation during cardiopulmonary resuscitation induces early changes in hemodynamics followed by late and unfavorable systemic responses in post-cardiac arrest rats.

Cardiac arrest (CA) and concomitant post-CA syndrome lead to a lethal condition characterized by systemic ischemia-reperfusion injury. Oxygen (O2 ) supply during cardiopulmonary resuscitation (CPR) is the key to success in resuscitation, but sustained hyperoxia can produce toxic effects post CA. However, only few studies have investigated the optimal duration and dosage of O2 administration. Herein, we aimed to determine whether high concentrations of O2 at resuscitation are beneficial or harmful. After rats were resuscitated from the 10-min asphyxia, mechanical ventilation was restarted at an FIO2 of 1.0 or 0.3. From 10 min after initiating CPR, FIO2 of both groups were maintained at 0.3. Bio-physiological parameters including O2 consumption (VO2 ) and mRNA gene expression in multiple organs were evaluated. The FIO2 0.3 group decreased VO2 , delayed the time required to achieve peak MAP, lowered ejection fraction (75.1 ± 3.3% and 59.0 ± 5.7% with FIO2 1.0 and 0.3, respectively; p < .05), and increased blood lactate levels (4.9 ± 0.2 mmol/L and 5.6 ± 0.2 mmol/L, respectively; p < .05) at 10 min after CPR. FIO2 0.3 group had significant increases in hypoxia-inducible factor, inflammatory, and apoptosis-related mRNA gene expression in the brain. Likewise, significant upregulations of hypoxia-inducible factor and apoptosis-related gene expression were observed in the FIO2 0.3 group in the heart and lungs. Insufficient O2 supplementation in the first 10 min of resuscitation could prolong ischemia, and may result in unfavorable biological responses 2 h after CA. Faster recovery from the impairment of O2 metabolism might contribute to the improvement of hemodynamics during the early post-resuscitation phase; therefore, it may be reasonable to provide the maximum feasible O2 concentrations during CPR.

Exogenous mitochondrial transplantation improves survival and neurological outcomes after resuscitation from cardiac arrest.

BACKGROUND: Mitochondrial transplantation (MTx) is an emerging but poorly understood technology with the potential to mitigate severe ischemia-reperfusion injuries after cardiac arrest (CA). To address critical gaps in the current knowledge, we test the hypothesis that MTx can improve outcomes after CA resuscitation. METHODS: This study consists of both in vitro and in vivo studies. We initially examined the migration of exogenous mitochondria into primary neural cell culture in vitro. Exogenous mitochondria extracted from the brain and muscle tissues of donor rats and endogenous mitochondria in the neural cells were separately labeled before co-culture. After a period of 24 h following co-culture, mitochondrial transfer was observed using microscopy. In vitro adenosine triphosphate (ATP) contents were assessed between freshly isolated and frozen-thawed mitochondria to compare their effects on survival. Our main study was an in vivo rat model of CA in which rats were subjected to 10 min of asphyxial CA followed by resuscitation. At the time of achieving successful resuscitation, rats were randomly assigned into one of three groups of intravenous injections: vehicle, frozen-thawed, or fresh viable mitochondria. During 72 h post-CA, the therapeutic efficacy of MTx was assessed by comparison of survival rates. The persistence of labeled donor mitochondria within critical organs of recipient animals 24 h post-CA was visualized via microscopy. RESULTS: The donated mitochondria were successfully taken up into cultured neural cells. Transferred exogenous mitochondria co-localized with endogenous mitochondria inside neural cells. ATP content in fresh mitochondria was approximately four times higher than in frozen-thawed mitochondria. In the in vivo survival study, freshly isolated functional mitochondria, but not frozen-thawed mitochondria, significantly increased 72-h survival from 55 to 91% (P = 0.048 vs. vehicle). The beneficial effects on survival were associated with improvements in rapid recovery of arterial lactate and glucose levels, cerebral microcirculation, lung edema, and neurological function. Labeled mitochondria were observed inside the vital organs of the surviving rats 24 h post-CA. CONCLUSIONS: MTx performed immediately after resuscitation improved survival and neurological recovery in post-CA rats. These results provide a foundation for future studies to promote the development of MTx as a novel therapeutic strategy to save lives currently lost after CA.

CRISPR/Cas9 technology: applications in oocytes and early embryos.

CRISPR/Cas9, a highly versatile genome-editing tool, has garnered significant attention in recent years. Despite the unique characteristics of oocytes and early embryos compared to other cell types, this technology has been increasing used in mammalian reproduction. In this comprehensive review, we elucidate the fundamental principles of CRISPR/Cas9-related methodologies and explore their wide-ranging applications in deciphering molecular intricacies during oocyte and early embryo development as well as in addressing associated diseases. However, it is imperative to acknowledge the limitations inherent to these technologies, including the potential for off-target effects, as well as the ethical concerns surrounding the manipulation of human embryos. Thus, a judicious and thoughtful approach is warranted. Regardless of these challenges, CRISPR/Cas9 technology undeniably represents a formidable tool for genome and epigenome manipulation within oocytes and early embryos. Continuous refinements in this field are poised to fortify its future prospects and applications.

Preserving Brain LPC-DHA by Plasma Supplementation Attenuates Brain Injury after Cardiac Arrest.

OBJECTIVE: Cardiac arrest (CA) is a major health burden with brain damage being a significant contributor to mortality. We found lysophosphatidylcholine (LPC), including a species containing docosahexaenoic acid (LPC-DHA), was significantly decreased in plasma post-CA, supplementation of which significantly improved neurological outcomes. The aim of this study is to understand the protective role of LPC-DHA supplementation on the brain post-CA. METHODS: We first evaluated associations between the plasma level of LPC-DHA and neurological injury and outcomes of human patients with CA. We then utilized a rat CA model and cell cultures to investigate therapeutic and mechanistic aspects of plasma LPC-DHA supplementation. RESULTS: We found that decreased plasma LPC-DHA was strongly associated with neurological outcomes and disappearance of the difference between gray and white matter in the brain after CA in human patients. In rats, the decreased plasma LPC-DHA was associated with decreased levels of brain LPC-DHA after CA, and supplementing plasma LPC-DHA normalized brain levels of LPC-DHA and alleviated neuronal cell death, activation of astrocytes, and expression of various inflammatory and mitochondrial dynamics genes. We also observed deceased severity of metabolic alterations with LPC-DHA supplementation using untargeted metabolomics analysis. Furthermore, LPC treatment showed a similar protective effect for neurons and astrocytes in mixed primary brain cell cultures. INTERPRETATION: The observed neuroprotection accompanied with normalized brain LPC-DHA level by plasma supplementation implicate the importance of preventing the decrease of brain LPC-DHA post-CA for attenuating brain injury. Furthermore, the data supports the causative role of decreased plasma LPC-DHA for brain damage after CA. ANN NEUROL 2022;91:389-403.

Metformin-mediated mitochondrial protection post-cardiac arrest improves EEG activity and confers neuroprotection and survival benefit.

Cardiac arrest (CA) produces global ischemia/reperfusion injury resulting in substantial multiorgan damage. There are limited efficacious therapies to save lives despite CA being such a lethal disease process. The small population of surviving patients suffer extensive brain damage that results in substantial morbidity. Mitochondrial dysfunction in most organs after CA has been implicated as a major source of injury. Metformin, a first-line treatment for diabetes, has shown promising results in the treatment for other diseases and is known to interact with the mitochondria. For the treatment of CA, prior studies have utilized metformin in a preconditioning manner such that animals are given metformin well before undergoing CA. As the timing of CA is quite difficult to predict, the present study, in a clinically relevant manner, sought to evaluate the therapeutic benefits of metformin administration immediately after resuscitation using a 10 min asphxyial-CA rat model. This is the first study to show that metformin treatment post-CA (a) improves 72 h survival and neurologic function, (b) protects mitochondrial function with a reduction in apoptotic brain injury without activating AMPK, and (c) potentiates earlier normalization of brain electrophysiologic activity. Overall, as an effective and safe drug, metformin has the potential to be an easily translatable intervention for improving survival and preventing brain damage after CA.

Phospholipid Screening Postcardiac Arrest Detects Decreased Plasma Lysophosphatidylcholine: Supplementation as a New Therapeutic Approach.

OBJECTIVES: Cardiac arrest and subsequent resuscitation have been shown to deplete plasma phospholipids. This depletion of phospholipids in circulating plasma may contribute to organ damage postresuscitation. Our aim was to identify the diminishment of essential phospholipids in postresuscitation plasma and develop a novel therapeutic approach of supplementing these depleted phospholipids that are required to prevent organ dysfunction postcardiac arrest, which may lead to improved survival. DESIGN: Clinical case control study followed by translational laboratory study. SETTING: Research institution. PATIENTS/SUBJECTS: Adult cardiac arrest patients and male Sprague-Dawley rats. INTERVENTIONS: Resuscitated rats after 10-minute asphyxial cardiac arrest were randomized to be treated with lysophosphatidylcholine specie or vehicle. MEASUREMENTS AND MAIN RESULTS: We first performed a phospholipid survey on human cardiac arrest and control plasma. Using mass spectrometry analysis followed by multivariable regression analyses, we found that plasma lysophosphatidylcholine levels were an independent discriminator of cardiac arrest. We also found that decreased plasma lysophosphatidylcholine was associated with poor patient outcomes. A similar association was observed in our rat model, with significantly greater depletion of plasma lysophosphatidylcholine with increased cardiac arrest time, suggesting an association of lysophosphatidylcholine levels with injury severity. Using a 10-minute cardiac arrest rat model, we tested supplementation of depleted lysophosphatidylcholine species, lysophosphatidylcholine(18:1), and lysophosphatidylcholine(22:6), which resulted in significantly increased survival compared with control. Furthermore, the survived rats treated with these lysophosphatidylcholine species exhibited significantly improved brain function. However, supplementing lysophosphatidylcholine(18:0), which did not decrease in the plasma after 10-minute cardiac arrest, had no beneficial effect. CONCLUSIONS: Our data suggest that decreased plasma lysophosphatidylcholine is a major contributor to mortality and brain damage postcardiac arrest, and its supplementation may be a novel therapeutic approach.

Unconventional phonon blockade via atom-photon-phonon interaction in hybrid optomechanical systems.

Phonon nonlinearities play an important role in hybrid quantum networks and on-chip quantum devices. We investigate the phonon statistics of a mechanical oscillator in hybrid systems composed of an atom and one or two standard optomechanical cavities. An efficiently enhanced atom-phonon interaction can be derived via a tripartite atom-photon-phonon interaction, where the atom-photon coupling depends on the mechanical displacement without practically changing a cavity frequency. This novel mechanism of optomechanical interactions, as predicted recently by Cotrufo et al. [Phys. Rev. Lett.118, 133603 (2017)10.1103/PhysRevLett.118.133603], is fundamentally different from standard ones. In the enhanced atom-phonon coupling, the strong phonon nonlinearity at a single-excitation level is obtained in the originally weak-coupling regime, which leads to the appearance of phonon blockade. Moreover, the optimal parameter regimes are presented both for the cases of one and two cavities. We compared phonon-number correlation functions of different orders for mechanical steady states generated in the one-cavity hybrid system, revealing the occurrence of phonon-induced tunneling and different types of phonon blockade. Our approach offers an alternative method to generate and control a single phonon in the quantum regime and could have potential applications in single-phonon quantum technologies.

Oxyhaemoglobin Level Measured Using Near-Infrared Spectrometer Is Associated with Brain Mitochondrial Dysfunction After Cardiac Arrest in Rats.

Cerebral blood oxygenation (CBO), measured using near-infrared spectroscopy (NIRS), can play an important role in post-cardiac arrest (CA) care as this emerging technology allows for noninvasive real-time monitoring of the dynamic changes of tissue oxygenation. We recently reported that oxyhaemoglobin (oxy-Hb), measured using NIRS, may be used to evaluate the quality of chest compressions by monitoring the brain tissue oxygenation, which is a critical component for successful resuscitation. Mitochondria are the key to understanding the pathophysiology of post-CA oxygen metabolism. In this study, we focused on mitochondrial dysfunction, aiming to explore its association with CBO parameters such as oxy-Hb and deoxyhaemoglobin (deoxy-Hb) or tissue oxygenation index (TOI). Male Sprague-Dawley rats were used in the study. We applied NIRS between the nasion and the upper cervical spine. Following 10 min of CA, the rats underwent cardiopulmonary resuscitation (CPR) with a bolus injection of 20 µg/kg epinephrine. At 10 and 20 min after CPR, brain, and kidney tissues were collected. We isolated mitochondria from these tissues and evaluated the association between CBO and mitochondrial oxygen consumption ratios. There were no significant differences in the mitochondrial yields (10 vs. 20 min after resuscitation: brain, 1.33 ± 0.68 vs. 1.30 ± 0.75 mg/g; kidney, 19.5 ± 3.2 vs. 16.9 ± 5.3 mg/g, respectively). State 3 mitochondrial oxygen consumption rates, known as ADP-stimulated respiration, demonstrated a significant difference at 10 vs. 20 min after CPR (brain, 170 ± 26 vs. 115 ± 17 nmol/min/mg protein; kidney, 170 ± 20 vs. 130 ± 16 nmol/min/mg protein, respectively), whereas there was no significant difference in ADP non-dependent state 4 oxygen consumption rates (brain, 34.0 ± 6.7 vs. 31.8 ± 10 nmol/min/mg protein; kidney, 29.8 ± 4.8 vs. 21.0 ± 2.6 nmol/min/mg protein, respectively). Consequently, the respiratory control ratio (RCR = state 3/state 4) showed a significant difference over time, but this was only noted in the brain (brain, 5.0 ± 0.29 vs. 3.8 ± 0.64; kidney, 5.8 ± 0.53 vs. 6.2 ± 0.25 nmol/min/mg protein, respectively). The oxy-Hb levels had a dynamic change after resuscitation, and they had a significant association with the RCR of the brain mitochondria (r = 0.8311, p = 0.0102), whereas deoxy-Hb and TOI did not (r = -0.1252, p = 0.7677; r = 0.4186, p = 0.302, respectively). The RCRs of the kidney mitochondria did not have a significant association with CBO (oxy-Hb, r = -0.1087, p = 0.7977; deoxy-Hb, r = 0.1565, p = 0.7113; TOI, r = -0.1687, p = 0.6896, respectively). The brain mitochondrial respiratory dysfunction occurred over time, and it was seen at the time points between 10 and 20 min after CPR. The oxy-Hb level was associated with brain mitochondrial dysfunction during the early post-resuscitation period.

Increased plasma disequilibrium between pro- and anti-oxidants during the early phase resuscitation after cardiac arrest is associated with increased levels of oxidative stress end-products.

BACKGROUND: Cardiac arrest (CA) results in loss of blood circulation to all tissues leading to oxygen and metabolite dysfunction. Return of blood flow and oxygen during resuscitative efforts is the beginning of reperfusion injury and is marked by the generation of reactive oxygen species (ROS) that can directly damage tissues. The plasma serves as a reservoir and transportation medium for oxygen and metabolites critical for survival as well as ROS that are generated. However, the complicated interplay among various ROS species and antioxidant counterparts, particularly after CA, in the plasma have not been evaluated. In this study, we assessed the equilibrium between pro- and anti-oxidants within the plasma to assess the oxidative status of plasma post-CA. METHODS: In male Sprague-Dawley rats, 10 min asphyxial-CA was induced followed by cardiopulmonary resuscitation (CPR). Plasma was drawn immediately after achieving return of spontaneous circulation (ROSC) and after 2 h post-ROSC. Plasma was isolated and analyzed for prooxidant capacity (Amplex Red and dihydroethidium oxidation, total nitrate and nitrite concentration, xanthine oxidase activity, and iron concentration) and antioxidant capacity (catalase and superoxide dismutase activities, Total Antioxidant Capacity, and Iron Reducing Antioxidant Power Assay). The consequent oxidative products, such as 4-Hydroxyl-2-noneal, malondialdehyde, protein carbonyl, and nitrotyrosine were evaluated to determine the degree of oxidative damage. RESULTS: After CA and resuscitation, two trends were observed: (1) plasma prooxidant capacity was lower during ischemia, but rapidly increased post-ROSC as compared to control, and (2) plasma antioxidant capacity was increased during ischemia, but either decreased or did not increase substantially post-ROSC as compared to control. Consequently, oxidation products were increased post-ROSC. CONCLUSION: Our study evaluated the disbalance of pro- and anti-oxidants after CA in the plasma during the early phase after resuscitation. This disequilibrium favors the prooxidants and is associated with increased levels of downstream oxidative stress-induced end-products, which the body's antioxidant capacity is unable to directly mitigate. Here, we suggest that circulating plasma is a major contributor to oxidative stress post-CA and its management requires substantial early intervention for favorable outcomes.

Hydrogen gas with extracorporeal cardiopulmonary resuscitation improves survival after prolonged cardiac arrest in rats.

BACKGROUND: Despite the benefits of extracorporeal cardiopulmonary resuscitation (ECPR) in cohorts of selected patients with cardiac arrest (CA), extracorporeal membrane oxygenation (ECMO) includes an artificial oxygenation membrane and circuits that contact the circulating blood and induce excessive oxidative stress and inflammatory responses, resulting in coagulopathy and endothelial cell damage. There is currently no pharmacological treatment that has been proven to improve outcomes after CA/ECPR. We aimed to test the hypothesis that administration of hydrogen gas (H2) combined with ECPR could improve outcomes after CA/ECPR in rats. METHODS: Rats were subjected to 20 min of asphyxial CA and were resuscitated by ECPR. Mechanical ventilation (MV) was initiated at the beginning of ECPR. Animals were randomly assigned to the placebo or H2 gas treatment groups. The supplement gas was administered with O2 through the ECMO membrane and MV. Survival time, electroencephalography (EEG), brain functional status, and brain tissue oxygenation were measured. Changes in the plasma levels of syndecan-1 (a marker of endothelial damage), multiple cytokines, chemokines, and metabolites were also evaluated. RESULTS: The survival rate at 4 h was 77.8% (7 out of 9) in the H2 group and 22.2% (2 out of 9) in the placebo group. The Kaplan-Meier analysis showed that H2 significantly improved the 4 h-survival endpoint (log-rank P = 0.025 vs. placebo). All animals treated with H2 regained EEG activity, whereas no recovery was observed in animals treated with placebo. H2 therapy markedly improved intra-resuscitation brain tissue oxygenation and prevented an increase in central venous pressure after ECPR. H2 attenuated an increase in syndecan-1 levels and enhanced an increase in interleukin-10, vascular endothelial growth factor, and leptin levels after ECPR. Metabolomics analysis identified significant changes at 2 h after CA/ECPR between the two groups, particularly in D-glutamine and D-glutamate metabolism. CONCLUSIONS: H2 therapy improved mortality in highly lethal CA rats rescued by ECPR and helped recover brain electrical activity. The underlying mechanism might be linked to protective effects against endothelial damage. Further studies are warranted to elucidate the mechanisms responsible for the beneficial effects of H2 on ischemia-reperfusion injury in critically ill patients who require ECMO support.

Biological roles of l-carnitine in oocyte and early embryo development.

Poor oocyte quality is responsible for female infertility. Multiple studies have been carried out to find supplements to enhance oocyte quality and mitigate infertility problems. l-carnitine and its derivatives have diverse roles in developing oocytes and early embryos. This review focuses on the in vitro and in vivo studies that using l-carnitine alone or in combination with other supplements for oocyte quality enhancement. The key roles of l-carnitine in oocyte quality and embryo growth were summarized, and the underlying mechanism was also elucidated. l-carnitine helps in the lipid metabolism process by controlling the transfer of fatty acids to mitochondria for ß-oxidation. l-carnitine modulates glucose metabolism and enhances respiratory chain enzyme activity. Furthermore, it acts as an antioxidant to prevent oxidative damage and inhibit apoptosis, a signal in response to oxidative stress. Results show the potential of l-carnitine as a potential agent in assisted reproductive technology to improve oocyte quality and the subsequent embryonic development.

Effect of Adrenaline on Cerebral Blood Oxygenation Measured by NIRS in a Rat Asphyxia Cardiac Arrest Model.

Adrenaline is an important pharmacologic treatment during cardiac arrest (CA) for resuscitation. Recent studies suggest that adrenaline increases the likelihood of return of spontaneous circulation (ROSC) but does not contribute to improving neurological outcomes of CA. The mechanisms have not been elucidated yet. A bimodal increase in mean arterial pressure (MAP) is observed after adrenaline injection in rodent CA models [17]. In this study, we focused on alteration of systemic arterial pressure in conjunction with the measurement of cerebral blood oxygenation (CBO) such as oxyhemoglobin (Oxy-Hb), deoxyhemoglobin (Deoxy-Hb), and tissue oxygenation index (TOI) by near-infrared spectroscopy (NIRS). Male Sprague-Dawley rats were used. We attached NIRS between the nasion and the upper cervical spine. Rats underwent 10-minute asphyxia to induce CA. Then, cardiopulmonary resuscitation (CPR) was started, followed by a 20 µg/kg of bolus adrenaline injection at 30 seconds of CPR. This injection accelerated the first increase in MAP, and ROSC was observed with an abrupt increase in CBO. Interestingly, the second increase in MAP, once it exceeded a certain value, was accompanied by paradoxical decreases of Oxy-Hb and TOI, while Deoxy-Hb increased. Based on this finding, we compared Oxy-Hb, Deoxy-Hb, and TOI at the first MAP ≈ 100 mmHg and the second MAP ≈ 100 mmHg. The average of Oxy-Hb and TOI from the 13 animals significantly decreased at the second increase in MAP over 100 mmHg, while Deoxy-Hb significantly increased. NIRS identified a decrease in Oxy-Hb after ROSC. These findings may be a clue to understanding the mechanism of how and why adrenaline alters the neurological outcomes of CA post-resuscitation.

Evaluation of the Quality of Chest Compression with Oxyhemoglobin Level by Near-Infrared Spectroscopy in a Rat Asphyxia Cardiac Arrest Model.

The real-time evaluation of chest compression during cardiopulmonary resuscitation is important to increase the chances of survival from a cardiac arrest (CA). In addition, cerebral oxygen level measured by near-infrared spectroscopy (NIRS) plays an important role as an indicator of return of spontaneous circulation. Recently, we developed a new method to improve the quality of chest compression using a thoracic pump in conjunction with the classic cardiac pump in a rat asphyxia CA model. This study evaluated the quality of chest compression using NIRS in male Sprague-Dawley rats. NIRS was attached between the nasion and the upper cervical spine, and rats underwent 10 minute asphyxia CA. After CA, we alternately performed three different types of chest compression (cardiac, thoracic, and cardiac plus thoracic pumps) every 30 seconds for up to 4 and a half minutes. We measured the oxyhemoglobin (Oxy-Hb), deoxyhemoglobin (Deoxy-Hb), and tissue oxygenation index (TOI) and compared these values between the groups. Oxy-Hb was significantly different among the groups (cardiac, thoracic, and cardiac plus thoracic, 1.5 ± 0.9, 4.4 ± 0.7, and 5.9 ± 2.1 µmol/L, p < 0.01, respectively), while Deoxy-Hb and TOI were not (Deoxy-HB -2.7 ± 1.2, -1.1 ± 3.2, and -1.6 ± 10.1 µmol/L; TOI, 1.8 ± 1.8, 5.5 ± 1.3, and 9.5 ± 8.0%, respectively). Oxy-Hb showed potential to evaluate the quality of chest compression in a rat asphyxia CA model.

Effect of Adrenaline on Cerebral Blood Oxygenation Measured by NIRS in a Rat Asphyxia Cardiac Arrest Model.

Adrenaline is an important pharmacologic treatment during cardiac arrest (CA) for resuscitation. Recent studies suggest that adrenaline increases the likelihood of return of spontaneous circulation (ROSC) but does not contribute to improving neurological outcomes of CA. The mechanisms have not been elucidated yet. A bimodal increase in mean arterial pressure (MAP) is observed after adrenaline injection in rodent CA models (Okuma et al. Intensive Care Med Exp 7(1), 2019). In this study, we focused on alteration of systemic arterial pressure in conjunction with the measurement of cerebral blood oxygenation (CBO) such as oxyhemoglobin (Oxy-Hb), deoxyhemoglobin (Deoxy-Hb), and tissue oxygenation index (TOI) by near-infrared spectroscopy (NIRS). Male Sprague-Dawley rats were used. We attached NIRS between the nasion and the upper cervical spine. Rats underwent 10 minute asphyxia to induce CA. Then, cardiopulmonary resuscitation (CPR) was started, followed by a 20 µg/kg of bolus adrenaline injection at 30 seconds of CPR. This injection accelerated the first increase in MAP, and ROSC was observed with an abrupt increase in CBO. Interestingly, the second increase in MAP, once it exceeded a certain value, was accompanied by paradoxical decreases of Oxy-Hb and TOI while Deoxy-Hb increased. Based on this finding, we compared Oxy-Hb, Deoxy-Hb, and TOI at the first MAP ≈ 100 mmHg and the second MAP ≈ 100 mmHg. The average of Oxy-Hb and TOI from the 13 animals significantly decreased at the second increase in MAP over 100 mmHg while Deoxy-Hb significantly increased. NIRS identified a decrease in Oxy-Hb after ROSC. These findings may be a clue in understanding the mechanism of how and why adrenaline alters the neurological outcomes of CA post resuscitation.

Assessment of Cerebral Blood Oxygenation by Near-Infrared Spectroscopy before and after Resuscitation in a Rat Asphyxia Cardiac Arrest Model.

Clinical investigators have focused on the real-time evaluation of cerebral blood oxygenation (CBO) by near-infrared spectroscopy (NIRS) during cardiopulmonary resuscitation (CPR). A previous study showed that an abrupt increase of oxy-hemoglobin (Hb) level and tissue oxygenation index (TOI) was associated with the timing of return of spontaneous circulation (ROSC). However, it is not clear how TOI alters before and after CPR including a period of cardiac arrest (CA). Therefore, this study aimed to assess CBO with asphyxia CA and its association with CPR to ROSC in rats. Male Sprague-Dawley rats were used. We attached NIRS (NIRO-200NX, Hamamatsu Photonics, Japan) from the nasion to the upper cervical spine in rats. A ten-minute asphyxia was given to induce CA. After CA, mechanical ventilation was restarted, and manual CPR was performed. We examined the mean arterial pressure (MAP), end-tidal carbon dioxide (ETCO2), and Oxy/Deoxy-Hb and TOI. Out of 14 rats, 11 obtained sustained ROSC. After the induction of asphyxia, a rapid drop of TOI was observed, followed by a subsequent increase of Oxy-Hb, Deoxy-Hb, and TOI with CPR. Recent CPR guidelines suggest the use of ETCO2 during CPR since its abrupt increase is a reasonable indicator of ROSC. In this study, abrupt increases in MAP, ETCO2, and TOI were observed at the time of ROSC. TOI can be an alternative to ETCO2 for identifying ROSC after CA, and it also has the capability of monitoring CBO during and after CPR.

Gut microbiome and cancer immunotherapy.

Gut microbiome has received significant attention for its influences on a variety of host functions, especially immune modulation. With the next-generation sequencing methodologies, more knowledge is gathered about gut microbiome and its irreplaceable role in keeping the balance between human health and diseases is figured out. Immune checkpoint inhibitors (ICIs) are one of the most innovational cancer immunotherapies across cancer types and significantly expand the therapeutic options of cancer patients. However, a proportion of patients show no effective responses or develop immune-related adverse events when responses do occur. More important, it is demonstrated that the therapeutic response or treatment-limiting toxicity of cancer immunotherapy can be ameliorated or diminished by gut microbiome modulation. In this review, we first introduce the relationship between gut microbiome and cancer immunotherapy. And then, we expound the impact of gut microbiome on efficacy and toxicity of cancer immunotherapy. Further, we review approaches to manipulating gut microbiome to regulate response to ICIs. Finally, we discuss the current challenges and propose future directions to improve cancer immunotherapy via gut microbiome manipulation.

Chromosomal polymorphisms associated with reproductive outcomes after IVF-ET.

PURPOSE: This study aimed to investigate the effect of the detail type of chromosomal polymorphisms (1/9/16qh+/-, D/G group polymorphisms, and inv(9)) on the IVF-ET outcomes. METHODS: A total of 1335 infertile couples undergoing IVF/ICSI were enrolled and comprehensively analyzed the correlation between three detail types of chromosomal polymorphisms (1/9/16qh+/-, D/G group polymorphisms, and inv(9)) and the outcome of IVF/ICSI embryo transfer. The fertilized rate, cleaved embryo rate, good-quality embryo rate, clinical pregnancy rate, implantation rate, and early stage miscarriage rate were compared between the chromosomal polymorphisms groups and the control group. RESULTS: Both the inv(9) and D/G group chromosomal polymorphisms related to female infertility significantly lead to a lower 2PN cleavage rate (86.44% vs. 97.58% and 90.67% vs. 97.58%, respectively, P < 0.05) undergoing IVF insemination, the inv(9) adversely increasing the early miscarriage rate, either undergoing IVF (21.4% vs. 3.0%, P < 0.05) or ICSI (50.0% vs. 2.0%, P < 0.05) insemination, female carriers (23.08% vs. 2.87%, P < 0.05) or male carriers (44.44% vs. 2.87%, P < 0.05). For D/G groups, ICSI insemination may increase the implantation rate (44.8% vs. 23.69%, P < 0.05) and clinical pregnancy rate (78.6% vs. 40.65%, P < 0.05). 1/9/16qh+/- had no apparent adverse effect on the patient's clinical outcomes. CONCLUSIONS: Our study suggests that chromosome karyotype analysis is necessary for IVF patients in clinical practice; we should afford individual genetic counseling suggestion according to the polymorphism types.

Sulforaphane ameliorates high-fat diet-induced spermatogenic deficiency in mice†.

Sulforaphane (SFN), a dietary isothiocyanate that is mainly found in cruciferous vegetables, possesses anti-oxidative and anticancer activity and modulates inflammation. However, little is known about the role of SFN in obesity-related male reproductive defects. The present study aimed to investigate the effects of SFN on high-fat diet (HFD)-induced male spermatogenic impairment and further clarify the possible underlying mechanisms. In this study, 8-week-old mice were randomly divided into four groups. Mice were fed a normal diet or an HFD with or without SFN supplementation. Sulforaphane was subcutaneously injected at a dose of 0.5 mg/kg 5 days/week for 4 weeks beginning 8 weeks after initiation of the HFD. The results demonstrated that SFN could protect against HFD-induced reproductive dysfunction in male mice. Moreover, SFN also improved reproductive ability, as demonstrated by an increased pregnancy rate and decreased embryo resorption rate in comparison to the corresponding HFD group. We also observed a decrease in apoptosis and an attenuation of endoplasmic reticulum (ER) stress after SFN treatment. In vitro studies of mouse and human sperm samples also revealed that SFN protects against the palmitic acid-induced reduction in sperm viability and motility by inhibiting ER stress in an AMP-activated protein kinase (AMPK)-dependent manner. AMPK-dependent ER stress attenuation by SFN was further confirmed using AMPK knockout mice. Taken together, these data show that SFN protects against HFD-induced male reproductive dysfunction by inhibiting ER stress and apoptosis. These findings may be helpful for identifying new therapeutic methods to treat male infertility.