Albuminuria, Cerebrovascular Disease and Cortical Atrophy: among Cognitively Normal Elderly Individuals

We tested the hypothesis that decreased glomerular filtration rate and albuminuria have different roles in brain structure alterations. We enrolled 1,215 cognitively normal individuals, all of whom underwent high-resolution T1-weighted volumetric magnetic resonance imaging scans. The cerebral small vessel disease burdens were assessed with white matter hyperintensities (WMH), lacunes, and microbleeds. Subjects were considered to have an abnormally elevated urine albumin creatinine ratio if the value was ≥17 mg/g for men and ≥25 mg/g for women. Albuminuria, but not estimated glomerular filtration rate (eGFR), was associated with increased WMH burdens (p = 0.002). The data was analyzed after adjusting for age, sex, education, history of hypertension, diabetes mellitus, hyperlipidemia, ischemic heart disease, stroke, total cholesterol level, body mass index, status of smoking and alcohol drinking, and intracranial volume. Albuminuria was also associated with cortical thinning, predominantly in the frontal and occipital regions (both p < 0.01) in multiple linear regression analysis. However, eGFR was not associated with cortical thickness. Furthermore, path analysis for cortical thickness showed that albuminuria was associated with frontal thinning partially mediated by WMH burdens. The assessment of albuminuria is needed to improve our ability to identify individuals with high risk for cognitive impairments, and further institute appropriate preventive measures

Peroxiredoxin 3 deficiency induces cardiac hypertrophy and dysfunction by impaired mitochondrial quality control

Mitochondrial quality control (MQC) consists of multiple processes: the prevention of mitochondrial oxidative damage, the elimination of damaged mitochondria via mitophagy and mitochondrial fusion and fission. Several studies proved that MQC impairment causes a plethora of pathological conditions including cardiovascular diseases. However, the precise molecular mechanism by which MQC reverses mitochondrial dysfunction, especially in the heart, is unclear. The mitochondria-specific peroxidase Peroxiredoxin 3 (Prdx3) plays a protective role against mitochondrial dysfunction by removing mitochondrial reactive oxygen species. Therefore, we investigated whether Prdx3-deficiency directly leads to heart failure via mitochondrial dysfunction. Fifty-two-week-old Prdx3-deficient mice exhibited cardiac hypertrophy and dysfunction with giant and damaged mitochondria. Mitophagy was markedly suppressed in the hearts of Prdx3-deficient mice compared to the findings in wild-type and Pink1-deficient mice despite the increased mitochondrial damage induced by Prdx3 deficiency. Under conditions inducing mitophagy, we identified that the damaged mitochondrial accumulation of PINK1 was completely inhibited by the ablation of Prdx3. We propose that Prdx3 interacts with the N-terminus of PINK1, thereby protecting PINK1 from proteolytic cleavage in damaged mitochondria undergoing mitophagy. Our results provide evidence of a direct association between MQC dysfunction and cardiac function. The dual function of Prdx3 in mitophagy regulation and mitochondrial oxidative stress elimination further clarifies the mechanism of MQC in vivo and thereby provides new insights into developing a therapeutic strategy for mitochondria-related cardiovascular diseases such as heart failure. © 20221

Inhibition of gap junctional intercellular communication by an anti-migraine agent, flunarizine.

Gap junctions (GJs), which consist of proteins called connexins, are intercellular channels that allow the passage of ions, second messengers, and small molecules. GJs and connexins are considered as emerging therapeutic targets for various diseases. Previously, we screened numerous compounds using our recently developed iodide yellow fluorescent protein gap junctional intercellular communication (I-YFP GJIC) assay and found that flunarizine (FNZ), used for migraine prophylaxis and as an add-on therapy for epilepsy, inhibits GJIC in LN215 human glioma cells. In this study, we confirmed that FNZ inhibits GJIC using the I-YFP GJIC assay. We demonstrated that FNZ inhibits GJ activities via a mechanism that is independent of calcium channels and dopaminergic D2, histaminergic H1, or 5-HT receptors. In addition, we showed that FNZ significantly increases connexin 43 (Cx43) phosphorylation on the cell surface, but does not alter the total amount of Cx43. The beneficial effects of FNZ on migraines and epilepsy might be related to GJ inhibition

Interhospital Transport System for Critically Ill Patients: Mobile Extracorporeal Membrane Oxygenation without a Ventilator

Background: Extracorporeal membrane oxygenation (ECMO) has been successfully used as a method for the interhospital transportation of critically ill patients. In South Korea, a well-established ECMO interhospital transport system is lacking due to limited resources. We developed a simplified ECMO transport system without mechanical ventilation for use by public emergency medical services. Methods: Eighteen patients utilized our ECMO transport system from December 2011 to September 2015. We retrospectively analyzed the indications for ECMO, the patient status during transport, and the patient outcomes. Results: All transport was conducted on the ground by ambulance. The distances covered ranged from 26 to 408 km (mean, 65.9±88.1 km) and the average transport time was 56.1±57.3 minutes (range, 30 to 280 minutes). All patients were transported without adverse events. After transport, 4 patients (22.2%) underwent lung transplantation because of interstitial lung disease. Eight patients who had severe acute respiratory distress syndrome showed recovery of heart and lung function after ECMO therapy. A total of 13 patients (70.6%) were successfully taken off ECMO, and 11 patients (61.1%) survived. Conclusion: Our ECMO transport system without mechanical ventilation can be considered a safe and useful method for interhospital transport and could be a good alternative option for ECMO transport in Korean hospitals with limited resources

Successful combined second redo lungkidney transplantation in a patient who developed end-stage renal disease after a previous lung transplantation

Several lung transplantation (LTx) patients develop end-stage renal disease (ESRD) and often need a kidney transplant. Recently, the number of multiorgan transplantation cases has increased; however, no successfully combined redo lung-kidney transplantation has been reported in Korea. We present the first case of combined second redo lung-kidney transplantation in a patient with ESRD after LTx. In November 2018, a 40-year-old man with dyspnea was admitted to our hospital. Seventeen years ago, he underwent right pneumonectomy owing to refractory extensive drug-resistant tuberculosis. Four years ago, he underwent left single-LTx due to chronic respiratory failure. He was diagnosed with chronic lung allograft dysfunction and ESRD (glomerular filtration rate, <15). He underwent a second LTx that resulted in acute graft failure. Despite the empirical management, he was not responsive to treatment. He was required to use a home ventilator, but was able to maintain good muscle strength and to walk. However, regular dialysis was required. In January 2019, he underwent combined second redo lung-kidney transplantation and was discharged. At 1-year follow-up, his pulmonary and renal functions were stable without rejection. Combined lung-kidney transplantation could be an effective treatment for selective young patients with respiratory and renal failure who have undergone LTx

Effect of Rhus verniciflua

Rhus verniciflua is widely known for its antioxidant, antibacterial, anticancer, and antiaging efficacy and α-lucosidase inhibition. This study was designed whether Rhus verniciflua extracts inhibit the IgE-antigen-mediated allergic reaction in RBL-2H3 mast cells, and it further investigated the FcϵRI- and arachidonate-signaling by which Rhus verniciflua extracts exert its antiallergic effects. IgE-antigen-sensitized RBL-2H3 mast cells were investigated for the cytotoxicity of Rhus verniciflua extracts and β-hexosaminidase release, and inflammatory mediators(e.g., TNF-α, IL-4, IL-6, histamine, and PGD2)were then assessed. Additionally, we examined expressions of genes involved in arachidonate- and FcϵRI-signaling pathway in RBL-2H3. Rhus verniciflua extracts inhibited β-hexosaminidase release and production of the inflammatory mediators in RBL-2H3. Rhus verniciflua extracts reduced amounts of histamine and expressions of FcϵRI signaling-related genes such as Lyn and Syk and phosphorylation of extracellular signal-regulated kinase in mast cells. Finally, in late allergic responses, Rhus verniciflua extracts reduced PGD2 release and COX-2 and cPLA2 phosphorylation expressions from IgE-antigen-mediated mast cells. Lastly, 250-500 mg/kg RVE significantly attenuated the Ag/IgE-induced passive cutaneous anaphylaxis (PCA) reaction in mice. These findings provide novel information on the molecular mechanisms underlying the antiallergy properties of Rhus verniciflua extracts in FcϵRI-mediated allergic reaction. © 2019 Hyun Ju Do et al.1

Extracorporeal membrane oxygenation for life-threatening asthma refractory to mechanical ventilation: analysis of the Extracorporeal Life Support Organization registry

Abstract Background The use of extracorporeal membrane oxygenation (ECMO) in cases of near-fatal asthma (NFA) has increased, but the benefits and potential complications of this therapy have yet to be fully investigated. Methods Cases were extracted from the Extracorporeal Life Support Organization Registry between March 1992 and March 2016. All patients with a diagnosis of asthma (according to the International Classification of Diseases 9th edition), who also received ECMO, were extracted. Exclusion criteria included patients who underwent multiple courses of ECMO; those who received ECMO for cardiopulmonary resuscitation or cardiac dysfunction; and those with another primary diagnosis, such as sepsis. We analyzed survival to hospital discharge, complications, and clinical factors associated with in-hospital mortality, in patients with severe life-threatening NFA requiring ECMO support. Results In total 272 patients were included. The mean time spent on ECMO was 176.4 hours. Ventilator settings, including rate, fraction of inspired oxygen (FiO2), peak inspiratory pressure (PIP), and mean airway pressure, significantly improved after ECMO initiation (rate (breaths/min), 19.0 vs. 11.3, p < 0.001; FiO2 (%), 81.2 vs. 48.8, p < 0.001; PIP (cmH2O), 38.2 vs. 25.0, p < 0.001; mean airway pressure (cmH2O): 21.4 vs. 14.2, p < 0.001). In particular, driving pressure was significantly decreased after ECMO support (29.5 vs. 16.8 cmH2O, p < 0.001). The weaning success rate was 86.7%, and the rate of survival to hospital discharge was 83.5%. The total complication rate was 65.1%, with hemorrhagic complications being the most common (28.3%). Other complications included renal (26.8%), cardiovascular (26.1%), mechanical (24.6%), metabolic (22.4%), infection (16.5%), neurologic (4.8%), and limb ischemia (2.6%). Of the hemorrhagic complications, cannulation site hemorrhage was the most common (13.6%). Using multivariate logistic regression analysis, it was found that hemorrhage was associated with increased in-hospital mortality (odds ratio, 2.97; 95% confidence interval, 1.07–8.24; p = 0.036). Hemorrhage-induced death occurred in four patients (1.5%). The most common reason for death was organ failure (37.8%). Conclusions ECMO can provide adequate gas exchange and prevent lung injury induced by mechanical ventilation, and may be an effective bridging strategy to avoid aggressive ventilation in refractory NFA. However, careful management is required to avoid complications

BCI-215, a Dual-Specificity Phosphatase Inhibitor, Reduces UVB-Induced Pigmentation in Human Skin by Activating Mitogen-Activated Protein Kinase Pathways

Background: The dysregulation of melanin production causes skin-disfiguring ultraviolet (UV)-associated hyperpigmented spots. Previously, we found that the activation of c-Jun N-terminal kinase (JNK), a mitogen-activated protein kinase (MAPK), inhibited melanogenesis. Methods: We selected BCI-215 as it may modify MAPK expression via a known function of a dual-specificity phosphatase (DUSP) 1/6 inhibitor. B16F10 melanoma cells, Mel-ab cells, human melanocytes, and a coculture were used to assess the anti-melanogenic activity of BCI-215. The molecular mechanisms were deciphered by assaying the melanin content and cellular tyrosinase activity via immunoblotting and RT-PCR. Results: BCI-215 was found to suppress basal and cAMP-stimulated melanin production and cellular tyrosinase activity in vitro through the downregulation of microphthalmia-associated transcription factor (MITF) protein and its downstream enzymes. The reduction in MITF expression caused by BCI-215 was found to be due to all three types of MAPK activation, including extracellular signal-regulated kinase (ERK), JNK, and p38. The degree of activation was greater in ERK. A phosphorylation of the β-catenin pathway was also demonstrated. The melanin index, expression of MITF, and downstream enzymes were well-reduced in UVB-irradiated ex vivo human skin by BCI-215. Conclusions: As BCI-215 potently inhibits UV-stimulated melanogenesis, small molecules of DUSP-related signaling modulators may provide therapeutic benefits against pigmentation disorders

Unique Changes in the Lung Microbiome following the Development of Chronic Lung Allograft Dysfunction

The importance of lung microbiome changes in developing chronic lung allograft dysfunction (CLAD) after lung transplantation is poorly understood. The lung microbiome–immune interaction may be critical in developing CLAD. In this context, examining alterations in the microbiome and immune cells of the lungs following CLAD, in comparison to the lung condition immediately after transplantation, can offer valuable insights. Four adult patients who underwent lung retransplantation between January 2019 and June 2020 were included in this study. Lung tissues were collected from the same four individuals at two different time points: at the time of the first transplant and at the time of the explantation of CLAD lungs at retransplantation due to CLAD. We analyzed whole-genome sequencing using the Kraken2 algorithm and quantified the cell fractionation from the bulk tissue gene expression profile for each lung tissue. Finally, we compared the differences in lung microbiome and immune cells between the lung tissues of these two time points. The median age of the recipients was 57 years, and most (75%) had undergone lung transplants for idiopathic pulmonary fibrosis. All patients were administered basiliximab for induction therapy and were maintained on three immunosuppressants. The median CLAD-free survival term was 693.5 days, and the median time to redo the lung transplant was 843.5 days. Bacterial diversity was significantly lower in the CLAD lungs than at transplantation. Bacterial diversity tended to decrease according to the severity of the CLAD. Aerococcus, Caldiericum, Croceibacter, Leptolyngbya, and Pulveribacter genera were uniquely identified in CLAD, whereas no taxa were identified in lungs at transplantation. In particular, six taxa, including Croceibacter atlanticus, Caldiserium exile, Dolichospermum compactum, Stappia sp. ES.058, Kinetoplastibacterium sorsogonicusi, and Pulveribacter suum were uniquely detected in CLAD. Among immune cells, CD8+ T cells were significantly increased, while neutrophils were decreased in the CLAD lung. In conclusion, unique changes in lung microbiome and immune cell composition were confirmed in lung tissue after CLAD compared to at transplantation

Safety of Surgical Tracheostomy during Extracorporeal Membrane Oxygenation

Background The risk of bleeding during extracorporeal membrane oxygenation (ECMO) is a potential deterrent in performing tracheostomy at many centers. To evaluate the safety of surgical tracheostomy (ST) in critically ill patients supported by ECMO, we reviewed the clinical correlation between preoperative coagulation status and bleeding complication-related ST during ECMO. Methods From April 1, 2012 to March 31, 2016, ST was performed on 38 patients supported by ECMO. We retrospectively reviewed and analyzed the medical records including complications related to ST. Results Heparin was administered to 23 patients (60.5%) for anticoagulation during ECMO, but 15 patients (39.5%) underwent ECMO without anticoagulation. Of the 23 patients administered anticoagulation therapy, heparin infusion was briefly paused in 13 prior to ST. The median platelet count, international normalized ratio, and activated partial thromboplastin time before ST were 126 × 109/L (range, 46 to 434 × 109/L), 1.2 (range, 1 to 2.3) and 62 seconds (27 to 114.2 seconds), respectively. No peri-procedural clotting complications related to ECMO were observed. Two patients (5.3%) suffering from ST-related major bleeding required surgical hemostasis. Minor bleeding after ST occurred in two cases (5.3%). No significant difference was found according to anticoagulation management (P = 0.723). No fatality was attributable to ST. Conclusions The complication rates of ST in the patients supported by ECMO were low. Therefore, ST performed by an experienced operator, and with careful optimization of coagulation status, is a relatively safe procedure; the use of ST with ECMO should thus not be dismissed on account of the potential for bleeding caused by the administration of anticoagulants