Impact of Antithrombin Activity Levels Following Recombinant Antithrombin Gamma Therapy in Patients with Sepsis-Induced Disseminated Intravascular Coagulation.

Recombinant antithrombin gamma (rAT) is reported as an effective drug for patients with disseminated intravascular coagulation (DIC) in Japan. As the appropriate dose and targeted AT activity remain unknown, this study aimed to determine these aspects for sepsis-induced DIC. Thirty-one patients with septic shock and DIC with AT levels <70% were treated with rAT between May 2018 and December 2020. The recovery rates from DIC were 32.2% and 63.3% on day 3 and 5 post administration, respectively. Recovery and survival rates were significantly higher in patients who achieved AT activity ≥70% or 80% on day 3 post administration. Receiver operating characteristic curve analysis revealed that the cutoff values of post-treatment AT activity on day 3 for 28-day survival and 5-day recovery from DIC were 79.5% and 81.5%, respectively. Patients who did not achieve AT activity ≥80% on day 3 presented a lower base level of AT activity and lower dose supplementation. Our results suggest that targeted AT activity should be at least 70%, and ideally 80%, and sufficient doses to maintain this activity are required to achieve better outcomes.

Prevalence and Risk Factor Analysis of Post-Intensive Care Syndrome in Patients with COVID-19 Requiring Mechanical Ventilation: A Multicenter Prospective Observational Study.

INTRODUCTION: Post-intensive care syndrome (PICS) is an emerging problem in critically ill patients and the prevalence and risk factors are unclear in patients with severe coronavirus disease 2019 (COVID-19). This multicenter prospective observational study aimed to investigate the prevalence and risk factors of PICS in ventilated patients with COVID-19 after ICU discharge. METHODS: Questionnaires were administered twice in surviving patients with COVID-19 who had required mechanical ventilation, concerning Barthel Index, Short-Memory Questionnaire, and Hospital Anxiety and Depression Scale scores. The risk factors for PICS were examined using a multivariate logistic regression analysis. RESULTS: The first and second PICS surveys were obtained at 5.5 and 13.5 months (mean) after ICU discharge, with 251 and 209 patients completing the questionnaires and with a prevalence of PICS of 58.6% and 60.8%, respectively, along with the highest percentages of cognitive impairment. Delirium (with an odds ratio of (OR) 2.34, 95% CI 1.1-4.9, and p = 0.03) and the duration of mechanical ventilation (with an OR of 1.29, 95% CI 1.05-1.58, and p = 0.02) were independently identified as the risk factors for PICS in the first PICS survey. CONCLUSION: Approximately 60% of the ventilated patients with COVID-19 experienced persistent PICS, especially delirium, and required longer mechanical ventilation.

Prediction of intracranial lesions in patients with consciousness disturbance by ultrasonography in the intensive care unit.

OBJECTIVE: This study was performed to evaluate the correlation between parameters measured by bedside ultrasonography and detection of intracranial organic lesions in patients with impaired consciousness in an intensive care unit (ICU) setting. METHODS: We retrospectively reviewed the medical records of patients who were admitted to our ICU from April 2017 to July 2019. Patients who underwent computed tomography or magnetic resonance imaging examination and measurement of the flow velocity of the carotid and intracranial arteries and the optic nerve sheath diameter by ultrasonography were selected for analysis. RESULTS: In total, 64 patients were analyzed in this study. Of these, intracranial lesions were detected by computed tomography or magnetic resonance imaging in 17 (27%) patients. The left:right ratio of the end-diastolic velocity of the bilateral common carotid artery (CCA-ED ratio) and the pulsatility index of the middle cerebral artery (MCA-PI) were significantly higher in patients with than in those without intracranial lesions. The cut-off value of the CCA-ED ratio was 1.55 (sensitivity, 66.7%; specificity, 81.6%), and that of the MCA-PI was 1.21 (sensitivity, 57.1%; specificity, 76.7%). CONCLUSION: Bedside ultrasonography is useful for predicting intracranial lesions requiring therapeutic intervention in ICU patients with impaired consciousness.

Noninvasive Diagnosis of the Mitochondrial Function of Doxorubicin-Induced Cardiomyopathy Using In Vivo Dynamic Nuclear Polarization-Magnetic Resonance Imaging.

Doxorubicin (DOX) induces dose-dependent cardiotoxicity via oxidative stress and abnormal mitochondrial function in the myocardium. Therefore, a noninvasive in vivo imaging procedure for monitoring the redox status of the heart may aid in monitoring diseases and developing treatments. However, an appropriate technique has yet to be developed. In this study, we demonstrate a technique for detecting and visualizing the redox status of the heart using in vivo dynamic nuclear polarization-magnetic resonance imaging (DNP-MRI) with 3-carbamoyl-PROXYL (CmP) as a molecular imaging probe. Male C57BL/6N mice were administered DOX (20 mg/kg) or saline. DNP-MRI clearly showed a slower DNP signal reduction in the DOX group than in the control group. Importantly, the difference in the DNP signal reduction rate between the two groups occurred earlier than that detected by physiological examination or clinical symptoms. In an in vitro experiment, KCN (an inhibitor of complex IV in the mitochondrial electron transport chain) and DOX inhibited the electron paramagnetic resonance change in H9c2 cardiomyocytes, suggesting that the redox metabolism of CmP in the myocardium is mitochondrion-dependent. Therefore, this molecular imaging technique has the potential to monitor the dynamics of redox metabolic changes in DOX-induced cardiomyopathy and facilitate an early diagnosis of this condition.

A new combination technique of the modified Robicsek wire fixation and plate fixation achieves effective repair of transverse sternal fracture: a report of two cases.

BACKGROUND: To maximize the therapeutic effect for complicated sternal fracture, we should know advantages and disadvantages of each surgical repositioning technique, and the choice of an appropriate procedure is essential. We report two successful cases for which a combination of two existing techniques, modified Robicsek wire fixation and locked titanium plate fixation, was applied to transverse sternal fracture with flail chest. CASE PRESENTATION: One patient experienced a transverse sternal and rib fracture due to a traffic injury. Flail chest due to a highly displaced transverse sternal fracture made withdrawal of the ventilator impossible. Another patient, who developed fulminant myocarditis, experienced a transverse sternal fracture resulting from chest compression during cardiopulmonary resuscitation. Severe paradoxical respiratory movement was a limiting factor for cardiac and respiratory rehabilitation. In both cases, a transverse sternal fracture was difficult to correct non-invasively and indicated surgical repair. The surgical repositioning and fixation greatly contributed to the improvement of the respiratory movement, and the patients were successfully withdrawn ventilator support. CONCLUSION: The combination of modified Robicsek wire fixation and locked titanium plate fixation for a complicated sternal fracture employs the complementary and comparative advantages of each procedure and effective fixation may be achieved.

Efficacy of thromboelastography in the management of anticoagulation for veno-venous extracorporeal membrane oxygenation in a coronavirus disease 2019 patient: A case report.

RATIONALE: In coronavirus disease 2019 (COVID-19) patients with acute respiratory distress syndrome refractory to optimal conventional management, we should consider the indication for veno-venous extracorporeal membrane oxygenation (V-V ECMO). Growing evidence indicates that COVID-19 frequently causes coagulopathy, presenting as hypercoagulation and incidental thrombosis. For these reasons, a multifactorial approach with several anticoagulant markers should be considered in the management of anticoagulation using heparin in COVID-19 patients on V-V ECMO. PATIENT CONCERNS: A 48-year-old man was infected with COVID-19 with a worsening condition manifesting as acute respiratory distress syndrome. DIAGNOSES: He was refractory to conventional therapy, thus we decided to introduce V-V ECMO. We used heparin as an anticoagulant therapy for V-V ECMO and adjusted the doses of heparin by careful monitoring of the activated clotting time (ACT) and activated partial thromboplastin time (APTT) to avoid both hemorrhagic and thrombotic complications. We controlled the doses of heparin in the therapeutic ranges of ACT and APTT, but clinical hemorrhaging and profound elevation of coagulant marker became apparent. INTERVENTIONS: Using thromboelastography (TEG; Haemonetics) in addition to ACT and APTT, we were able to clearly detect not only sufficient coagulability of COVID19 on V-V ECMO (citrated rapid thromboelastography-R 0.5 min, angle 75.5°, MA 64.0 mm, citrated functional fibrinogen-MA 20.7 mm) but also an excessive effect of heparin (citrated kaolin -R 42.7 min, citrated kaolin with heparinase 11.7 min). OUTCOMES: Given the TEG findings indicating an excessive heparin effect, the early withdrawal of ECMO was considered. After an evaluation of the patient's respiratory capacity, withdrawal from V-V ECMO was achieved and then anticoagulation was stopped. The hemorrhagic complications and elevated thrombotic marker levels dramatically decreased. LESSONS: TEG monitoring might be a useful option for managing anticoagulation in COVID-19 patients on V-V ECMO frequently showing a hypercoagulative state and requiring massive doses of heparin, to reduce both hemorrhagic and thrombotic complications.

Surgical treatment for breast cancer in a patient with erythropoietic protoporphyria and photosensitivity: a case report.

BACKGROUND: Erythropoietic protoporphyria (EPP) is a rare disorder of heme synthesis. Patients with EPP mainly show symptoms of photosensitivity, but approximately 20% of EPPs are associated with the liver-related complications. We report a case of breast cancer in a 48-year-old female patient with EPP in whom meticulous perioperative management was required in order to avoid complications resulting from this disease. CASE PRESENTATION: The patient was diagnosed with EPP at the age of 33 and had a rich family history of the disease. For right breast cancer initially considered as TisN0M0 (Stage 0), the right mastectomy and sentinel lymph node biopsy were performed, while the final stage was pT1bN0M0, pStage I. In the perioperative period, we limited the drug use and monitored light wavelength measurements. Besides, we covered surgical lights, headlights, and laryngoscope's light with a special polyimide film that filtered the wavelength of light causing dermal photosensitivity. After the surgery, any emerging complications were closely monitored. CONCLUSIONS: The surgery, internal medicine, anesthesiology, and operation departments undertook all possible measures through close cooperation to ensure a safe surgery for the patient with a rare condition.

Prognostic factors for the short-term mortality of patients with rheumatoid arthritis admitted to intensive care units.

BACKGROUND: Patients with rheumatoid arthritis (RA) have high mortality risk and are frequently treated in intensive care units (ICUs). METHODS: This was a retrospective observational study. This study included 67 patients (20 males, 47 females) with RA who were admitted at the ICU of our institution for ≥48 h between January 2008 and December 2017. We analyzed the 30-day mortality of these patients and the investigated prognostic factors in RA patients admitted to our ICU. RESULTS: Upon admission, the median age was 70 (range, 33-96) years, and RA duration was 10 (range, 0-61) years. The 5-year survival after ICU admission was 47%, and 30-day, 90-day, and 1-year mortality rates were 22, 27, and 37%, respectively. The major reasons for ICU admission were cardiovascular complications (24%) and infection (40%) and the most common ICU treatments were mechanical ventilation (69%), renal replacement (25%), and vasopressor (78%). In the 30-day mortality group, infection led to a fatal outcome in most cases (67%), and nonsurvival was associated with a significantly higher glucocorticoid dose, updated Charlson's comorbidity index (CCI), and acute physiology and chronic health evaluation (APACHE) II score. Laboratory data obtained at ICU admission showed that lower platelet number and total protein and higher creatinine and prothrombin time international normalized ratio (PT-INR) indicated significantly poorer prognosis. The multivariate Cox proportional hazard model revealed that nonuse of csDMARDs, high updated CCI, increased APACHE II score, and prolonged PT-INR were associated with a higher risk of mortality after ICU admission. CONCLUSION: Our study demonstrated that the nonuse of csDMARDs, high updated CCI, elevated APACHE II score, and coagulation abnormalities predicted poorer prognosis in RA patients admitted to the ICU.

Exosomes from adipose tissue-derived mesenchymal stem cells ameliorate histone-induced acute lung injury by activating the PI3K/Akt pathway in endothelial cells.

BACKGROUND: Mesenchymal stem cells (MSCs), including adipose-derived mesenchymal stem cells (ADSCs), have been shown to attenuate organ damage in acute respiratory distress syndrome (ARDS) and sepsis; however, the underlying mechanisms are not fully understood. In this study, we aimed to explore the potential roles and molecular mechanisms of action of ADSCs in histone-induced endothelial damage. METHODS: Male C57BL/6 N mice were intravenously injected with ADSCs, followed by histones or a vehicle. The mice in each group were assessed for survival, pulmonary vascular permeability, and histological changes. A co-culture model with primary human umbilical vein endothelial cells (HUVECs) exposed to histones was used to clarify the paracrine effect of ADSCs. Overexpression and inhibition of miR-126 ADSCs were also examined as causative factors for endothelial protection. RESULTS: The administration of ADSCs markedly improved survival, inhibited histone-mediated lung hemorrhage and edema, and attenuated vascular hyper-permeability in mice. ADSCs were engrafted in the injured lung and attenuated histone-induced endothelial cell apoptosis. ADSCs showed endothelial protection (via a paracrine effect) and Akt phosphorylation in the histone-exposed HUVECs. Notably, increased Akt phosphorylation by ADSCs was mostly mediated by exosomes in histone-induced cytotoxicity and lung damage. Moreover, the expression of miR-126 was increased in exosomes from histone-exposed ADSCs. Remarkably, the inhibition of miR-126 in ADSCs failed to increase Akt phosphorylation in histone-exposed HUVECs. CONCLUSION: ADSC-derived exosomes may exert protective effects on endothelial cells via activation of the PI3K/Akt pathway.

Clinical improvement in a patient with severe coronavirus disease 2019 after administration of hydroxychloroquine and continuous hemodiafiltlation with nafamostat mesylate.

The number of people infected with severe acute respiratory syndrome coronavirus 2 is increasing globally, and some patients have a fatal clinical course. In light of this situation, the World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19) a pandemic on March 11, 2020. While clinical studies and basic research on a treatment for COVID-19 are ongoing around the world, no treatment has yet been proven to be effective. Several clinical studies have demonstrated the efficacy of chloroquine phosphate and nafamostat mesylate with COVID-19. Here, we report the case of a Japanese patient with COVID-19 with severe respiratory failure who improved following the administration of hydroxychloroquine and continuous hemodiafiltlation with nafamostat mesylate. Hence, hydroxychloroquine with nafamostat mesylate might be a treatment option for severe COVID-19.

Sodium thiosulfate prevents doxorubicin-induced DNA damage and apoptosis in cardiomyocytes in mice.

AIM: Doxorubicin (DOX) induces dose-dependent cardiotoxicity due to reactive oxygen species (ROS)-mediated oxidative stress and subsequent apoptosis of cardiomyocytes. We aimed to assess whether sodium thiosulfate (STS), which has antioxidant and antiapoptotic properties, exerts cardioprotective effects on DOX-induced cardiomyopathy. MAIN METHODS: Male C57BL/6N mice were divided into four groups, control, DOX, STS, and DOX + STS, and administered DOX (20 or 30 mg/kg) or normal saline intraperitoneally, followed by an injection of STS (2 g/kg) or normal saline 4 h later. KEY FINDINGS: The DOX group showed a poorer 6-day survival and decreased cardiac function than the DOX + STS group. The DOX group showed a marked increase in the plasma creatine kinase isoenzyme myocardial band (CK-MB) and lactate dehydrogenase (LDH) levels 10 h after DOX injection, while the DOX + STS group showed suppression of DOX-induced elevation of CK-MB and LDH levels. The DOX group showed increased 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in the heart, whereas the DOX + STS group showed increased catalase and superoxide dismutase (SOD) activities and decreased 8-OHdG levels in the heart compared with DOX group, suggesting that STS reduces DOX-induced DNA damage by improving antioxidant enzymes activities in cardiomyocytes. Additionally, the DOX + STS group showed attenuation of cleaved caspase-3 and DNA fragmentation in cardiomyocytes compared with the DOX group, suggesting that STS suppresses DOX-induced apoptosis in cardiomyocytes. SIGNIFICANCE: STS exerts cardioprotective effects against DOX-induced cardiac dysfunction partly by improving antioxidant defense and suppressing apoptosis, indicating the therapeutic potential of STS against DOX-induced cardiomyopathy.

Tracheal Size and Morphology on the Reconstructed CT Imaging.

OBJECTIVES: To characterize the real size and morphology of tracheas in childhood for the optimal selection of endotracheal tube. DESIGN: A retrospective cohort study of pediatric patients who received CT scan of the cervical spine from July 2011 to March 2018. Cross-sectional CT images vertical to trachea were reconstructed and the accurate tracheal diameters were measured. The validity of the traditional age-based formula for predicting the endotracheal tube size was assessed for the best fit to trachea. SETTING: Tertiary Emergency and Critical Care Center of Kyushu University Hospital. PATIENTS: Children, who are 1 month to 15 years old, received CT scan of the cervical spine. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We enrolled 86 children with median age of 53 months. The cross-sectional shape of pediatric trachea was circular at the cricoid level and elliptical at the infraglottic level. The narrowest part of pediatric trachea was the transverse diameter at the infraglottic level at any age. Significant positive correlation between age and the narrowest diameter was observed. When compared the transverse diameter at the infraglottic level with the outer diameter of endotracheal tubes, uncuffed endotracheal tubes selection based on the traditional age-based formula ran a significant risk of oversized endotracheal intubation until 10 years old compared with cuffed endotracheal tubes selection (60.0% vs 23.8%; p < 0.05). CONCLUSIONS: These findings indicate the safety and efficacy of cuffed endotracheal tubes in infants and children and the reconsideration for the airway management in pediatric anesthesia and intensive care.

Breathing hydrogen sulfide prevents delayed paraplegia in mice.

Delayed paraplegia complicates the recovery from spinal cord ischemia or traumatic spinal cord injury. While delayed motor neuron apoptosis is implicated in the pathogenesis, no effective treatment or preventive measures is available for delayed paraplegia. Hydrogen sulfide exerts anti-apoptotic effects. Here, we examined effects of hydrogen sulfide breathing on the recovery from transient spinal cord ischemia. Breathing hydrogen sulfide starting 23 h after reperfusion for 5 h prevented delayed paraplegia after 5 min of spinal cord ischemia. Beneficial effects of hydrogen sulfide were mediated by upregulation of anti-apoptotic Bcl-XL and abolished by nitric oxide synthase 2 deficiency. S-nitrosylation of NFkB p65 subunit, which is induced by nitric oxide derived from nitric oxide synthase 2, facilitated subsequent sulfide-induced persulfidation of p65 and transcription of anti-apoptotic genes. These results uncover the molecular mechanism of the anti-apoptotic effects of sulfide based on the interaction between nitric oxide and sulfide. Exploitation of the anti-apoptotic effects of delayed hydrogen sulfide breathing may provide a new therapeutic approach for delayed paraplegia.

Esophageal perforation due to blunt chest trauma: Difficult diagnosis because of coexisting severe disturbance of consciousness.

Esophageal perforation due to blunt trauma is a rare clinical condition, and the diagnosis is often difficult because patients have few specific symptoms. Delayed diagnosis may result in a fatal clinical course due to mediastinitis and subsequent sepsis. In this article, we describe a 26-year-old man with esophageal perforation due to blunt chest trauma resulting from a motor vehicle accident. Because a severe disturbance of consciousness masked the patient's trauma-induced thoracic symptoms, we required 11h to diagnose the esophageal perforation. Therefore, the patient developed septic shock due to mediastinitis. However, his subsequent clinical course was good because of prompt combined therapy involving surgical repair and medical treatment after the diagnosis.

Clinical characteristics of type A acute aortic dissection with CNS symptom.

BACKGROUND AND PURPOSE: Accurate diagnosis of acute aortic dissection (AAD) is sometimes difficult because of accompanying central nervous system (CNS) symptoms. The purpose of this study was to investigate the clinical characteristics of Type A AAD (TAAAD) with CNS symptoms. METHODS: We retrospectively reviewed the medical records of 8403 patients ambulanced to our emergency and critical care center between April 2009 and May 2014. RESULTS: We identified 59 TAAAD patients for the analysis (mean age, 67.3±10.5years; 37 (62.0%) male). Eleven patients (18.6%) presented CNS symptoms at the onset of TAAAD, and these patients complained less frequently of typical chest and back pain than those without CNS symptoms (p<0.0001). Initial systolic and diastolic blood pressure were lower (p=0.003, and p=0.049, respectively) and involvement of the supra-aortic artery was more frequent in patients with CNS symptoms (p<0.0001). CONCLUSION: Because CNS symptom can mask chest and back pain caused by TAAAD, physicians should always consider the possibility of TAAAD in patients with CNS symptoms in emergency medicine settings.

The effects of anesthetic agents on pupillary function during general anesthesia using the automated infrared quantitative pupillometer.

Pupil reactivity can be used to evaluate central nervous system function and can be measured using a quantitative pupillometer. However, whether anesthetic agents affect the accuracy of the technique remains unclear. We examined the effects of anesthetic agents on pupillary reactivity. Thirty-five patients scheduled for breast or thyroid surgery were enrolled in the study. Patients were divided into four groups based on the technique used to maintain anesthesia: a sevoflurane-remifentanil (SEV/REM) group, a sevoflurane (SEV) group, a desflurane-remifentanil (DES/REM) group, and a propofol-remifentanil (PRO/REM) group. We measured maximum resting pupil size (MAX), reduction pupil size ratio (%CH), latency duration (LAT) and neurological pupil index (NPi). A marked reduction in MAX and %CH compared with baseline was observed in all groups, but LAT was unchanged during surgery. NPi reduced within the first hour of surgery in the SEV/REM, SEV, and DES/REM groups, but was not significantly different in the PRO/REM group. Compared with the PRO/REM group, mean %CH and NPi in patients anesthetized with SEV/REM, SEV or DES/REM were markedly lower at 1 h after surgery had commenced. There was no correlation between NPi and bispectral index. Fentanyl given alone decreased pupil size and %CH in light reflex, but did not change the NPi. NPi was decreased by inhalational anesthesia not but intravenous anesthesia. The difference in pupil reactivity between inhalational anesthetic and propofol may indicate differences in the alteration of midbrain reflexs in patients under inhalational or intravenous anesthesia.

Sarcopenia is a predictive factor for prolonged intensive care unit stays in high-energy blunt trauma patients.

Aim: Sarcopenia has been increasingly reported as a prognostic factor for outcome in settings such as cirrhosis, liver transplantation, and emergent surgery. We aimed to elucidate the significance of sarcopenia in severe blunt trauma patients. Methods: We retrospectively analyzed 84 patients emergently admitted to the intensive care unit at Kyushu University Hospital (Fukuoka, Japan) from May 2012 to April 2015. We assessed the amount of skeletal muscle present according to computed tomography and its relevance to ventilation-free days, patients' length of stay in the intensive care unit, and 28-day mortality. Results: Twenty-five (29.7%) patients were defined as sarcopenic. Sixteen (19.7%) patients required 15 days or more in the intensive care unit. The major reason was a prolonged ventilation requirement due to flail chest (n = 7) or pneumonia (n = 3). Sarcopenic patients' stays in intensive care were significantly longer than those of non-sarcopenic patients (18.7 versus 6.4 days, respectively; P < 0.001). Univariate and multivariate analyses showed sarcopenia to be a significant risk factor for prolonged intensive care unit stay. Conclusion: Sarcopenia is a risk factor that predicts prolonged intensive care unit stay in high-energy blunt trauma patients.

Case of a Cardiopulmonary Arrest Due to Postoperative Subglottic Stenosis Developed on the Second Day after Lung Surgery.

We experienced a case of the cardiopulmonary arrest due to subglottic stenosis developed on the second day after lung cancer surgery. Case : A 73-year-old female who was diagnosed with primary lung cancer was referred to our department for surgery. The second day after left lung segmentectomy, she showed respiratory discomfort symptoms and exhibited hoarseness and stridor, which were revealed as the subglottic stenosis by bronchoscopy. During the emergency airway management, she went into cardiopulmonary arrest. We performed cardiopulmonary resuscitation and simultaneous urgent tracheotomy.

Thiosulfate Mediates Cytoprotective Effects of Hydrogen Sulfide Against Neuronal Ischemia.

BACKGROUND: Hydrogen sulfide (H2S) exhibits protective effects in various disease models including cerebral ischemia-reperfusion (I/R) injury. Nonetheless, mechanisms and identity of molecules responsible for neuroprotective effects of H2S remain incompletely defined. In the current study, we observed that thiosulfate, an oxidation product of H2S, mediates protective effects of an H2S donor compound sodium sulfide (Na2S) against neuronal I/R injury. METHODS AND RESULTS: We observed that thiosulfate in cell culture medium is not only required but also sufficient to mediate cytoprotective effects of Na2S against oxygen glucose deprivation and reoxygenation of human neuroblastoma cell line (SH-SY5Y) and murine primary cortical neurons. Systemic administration of sodium thiosulfate (STS) improved survival and neurological function of mice subjected to global cerebral I/R injury. Beneficial effects of STS, as well as Na2S, were associated with marked increase of thiosulfate, but not H2S, in plasma and brain tissues. These results suggest that thiosulfate is a circulating "carrier" molecule of beneficial effects of H2S. Protective effects of thiosulfate were associated with inhibition of caspase-3 activity by persulfidation at Cys163 in caspase-3. We discovered that an SLC13 family protein, sodium sulfate cotransporter 2 (SLC13A4, NaS-2), facilitates transport of thiosulfate, but not sulfide, across the cell membrane, regulating intracellular concentrations and thus mediating cytoprotective effects of Na2S and STS. CONCLUSIONS: The protective effects of H2S are mediated by thiosulfate that is transported across cell membrane by NaS-2 and exerts antiapoptotic effects via persulfidation of caspase-3. Given the established safety track record, thiosulfate may be therapeutic against ischemic brain injury.

Cystathionine γ-lyase deficiency protects mice from galactosamine/lipopolysaccharide-induced acute liver failure.

AIMS: Acute liver failure (ALF) is a fatal syndrome attributed to massive hepatocyte death. Hydrogen sulfide (H2S) has been reported to exert cytoprotective or cytotoxic effects. Here, we examined the role of cystathionine γ-lyase (CSE, an enzyme produces H2S) in ALF induced by D-Galactosamine (GalN) and lipopolysaccharide (LPS). RESULTS: Wild-type (WT) mice exhibited high mortality rate, prominent liver injury, and increased plasma alanine aminotransferase levels after GalN/LPS challenge. Congenital deficiency or chemical inhibition of CSE by DL-propargylglycine attenuated GalN/LPS-induced liver injury. CSE deficiency markedly improved survival rate and attenuated GalN/LPS-induced upregulation of inflammatory cytokines and activation of caspase 3 and poly (ADP-ribose) polymerase (PARP) in the liver. CSE deficiency protected primary hepatocytes from GalN/tumor necrosis factor-α (TNF-α)-induced cell death without affecting LPS-induced TNF-α production from primary peritoneal macrophages. Beneficial effects of CSE deficiency were associated with markedly elevated homocysteine and thiosulfate levels, upregulation of NF-E2 p45-related factor 2 (Nrf2) and antioxidant proteins, activation of Akt-dependent anti-apoptotic signaling, and inhibition of GalN/LPS-induced JNK phosphorylation in the liver. Finally, administration of sodium thiosulfate (STS) attenuated GalN/LPS-induced liver injury via activation of Akt- and Nrf2-dependent signaling and inhibition of GalN/LPS-induced JNK phosphorylation in WT mice. INNOVATION: These results suggest that inhibition of CSE or administration of STS prevents acute inflammatory liver failure by augmenting thiosulfate levels and upregulating antioxidant and anti-apoptotic defense in the liver. CONCLUSION: Congenital deficiency or chemical inhibition of CSE increases thiosulfate levels in the liver and prevents ALF at least in part by augmentation of antioxidant and anti-apoptotic mechanisms.