Erratum: Isoform requirement of clustered protocadherin for preventing neuronal apoptosis and neonatal lethality.

[This corrects the article DOI: 10.1016/j.isci.2022.105766.].

Clinical Impacts of Urinary Neutrophil Gelatinase-Associated Lipocalin in Patients With Chronic Kidney Disease Undergoing Percutaneous Coronary Intervention.

BACKGROUND: Chronic kidney disease (CKD) is associated with poor prognosis in patients undergoing percutaneous coronary intervention (PCI). Urinary neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker for renal injury. However, the association between urinary NGAL concentrations and renal and cardiovascular events in patients with CKD undergoing PCI has not been elucidated. This study investigated the clinical impact of urinary NGAL concentrations on renal and cardiovascular outcomes in patients with non-dialysis CKD undergoing PCI.Methods and Results: We enrolled 124 patients with non-dialysis CKD (estimated glomerular filtration rate <60 mL/min/1.73 m2) undergoing elective PCI. Patients were divided into low and high NGAL groups based on the median urinary NGAL concentration measured the day before PCI. Patients were monitored for renal and cardiovascular events during the 2-year follow-up period. Kaplan-Meier analyses showed that the incidence of renal and cardiovascular events was higher in the high than low NGAL group (log-rank P<0.001 and P=0.032, respectively). Multivariate Cox proportional hazards analyses revealed that urinary NGAL was an independent risk factor for renal (hazard ratio [HR] 4.790; 95% confidence interval [CI] 1.537-14.924; P=0.007) and cardiovascular (HR 2.938; 95% CI 1.034-8.347; P=0.043) events. CONCLUSIONS: Urinary NGAL could be a novel and informative biomarker for predicting subsequent renal and cardiovascular events in patients with CKD undergoing elective PCI.

Prognostic impact of polypharmacy and discharge medications in octogenarians and nonagenarian patients with acute heart failure.

With the increasing frequency of heart failure (HF) in elderly patients, polypharmacy has become a major concern owing to its adverse outcomes. However, reports on the clinical impact of polypharmacy and discharge medications in hospitalized super-aged patients with acute HF are rare. Data from 682 patients aged 80 years or older, hospitalized for treating acute HF, were analyzed. We recorded the number of medications at discharge and classified them into three groups: HF, non-HF cardiovascular, and non-cardiovascular medications. We investigated the correlation of polypharmacy, defined as daily administration of 10 or more medications at discharge, and the use of discharge medications with post-discharge prognosis. Polypharmacy was recorded in 24.3% of enrolled patients. Polypharmacy was not an independent predictor of all-cause mortality, the incidence of cardiac-related death, or HF-associated rehospitalization; however, the number of non-cardiovascular medications, multiple usage of potentially inappropriate medications, use of mineralocorticoid receptor antagonists, and doses of loop diuretics were associated with poor prognosis. Polypharmacy was significantly associated with higher mortality in patients with Barthel index ≥ 60 at discharge; hence, physical function at discharge was useful for the stratification of prognostic impacts of polypharmacy. The current study demonstrated that polypharmacy was not essentially associated with poor prognosis in super-aged patients with acute HF. Appropriate medications that consider the patient's physical function, rather than polypharmacy itself, are important for the management of HF.

The association between oral health status and physical function in elderly patients with acute heart failure.

OBJECTIVES: Oral health problems are common and are associated with various geriatric conditions in older adults. The importance of oral health has not been fully highlighted in the assessment and management of patients with heart failure. Here, we investigated the association between oral health status and the decline in physical function during hospitalization in elderly patients with acute heart failure. MATERIALS AND METHODS: We evaluated oral health using the revised oral assessment guide in 77 patients aged 65 years or older who were admitted to hospital for acute heart failure. Oral health problems were defined as a revised oral assessment guide score ≥9. RESULTS: Oral health problems were identified in 66.2% of the patients. Patients with oral health problems had high prevalence of decreased physical function, undernutrition, and cognitive impairment. A reduction in the Barthel Index, as an indicator of activities of daily living during hospitalization, was significant in the enrolled patients. The Barthel Index decreased more in patients with oral health problems than those with normal oral health. Furthermore, the revised oral assessment guide score on admission was found to be the only independent predictor of changes in the Barthel Index during hospitalization in the multivariate analyses. CONCLUSIONS: Oral assessment using the revised oral assessment guide during hospitalization could provide useful information for the management of elderly heart failure patients.

Two-step changes in paced QRS morphology suggest capturing at different levels of posterior fascicle fibers during left bundle branch area pacing: A case report.

Two-step changes in paced QRS morphology during the left bundle branch area pacing threshold test. It suggests that capturing occurs at multiple sites of the left bundle branch-Purkinje system.

Dimethyl-α-cyclodextrin induces capacitation by removing phospholipids from the plasma membrane of mouse sperm†.

Capacitation is an important event in the completion of fertilization by mammalian sperm. Cholesterol efflux is a trigger of capacitation. In general, cholesterol acceptors of albumin and ß-cyclodextrins are used to induce capacitation during in vitro fertilization. Previously, we reported that methyl-ß-cyclodextrin (MBCD), which is composed of seven glucoses, had a higher ability to induce capacitation than bovine serum albumin (BSA) in frozen-thawed mouse sperm. Comparison of albumin and cyclodextrins is helpful for understanding the mechanism of capacitation. In this study, we examined the effects of albumin, MBCD, and a different type of cyclodextrin, dimethyl-α-cyclodextrin (DMACD), which is composed of six glucoses, on several events of sperm capacitation. We showed that DMACD induced sperm capacitation and promoted fertilization ability. The time required to increase the fertilization rate differed among BSA, MBCD, and DMACD. BSA and MBCD enhanced cholesterol and phospholipid efflux, whereas DMACD enhanced only phospholipid efflux. BSA, MBCD, and DMACD increased sperm membrane fluidity, rearrangement of the lipid raft, and the acrosome reaction. These findings suggest that phospholipid efflux is a novel trigger of capacitation. Increasing the choice of sperm capacitation inducers may be useful for improving in vitro fertilization (IVF) techniques not only in mice, but also in various species in which it has been difficult to produce embryos by IVF.

Differences in clinical outcomes between octogenarian and nonagenarian patients with acute heart failure.

AIM: The number of hospitalized super-elderly patients with heart failure (HF) has increased with aging of the population. These patients are associated with poor clinical outcomes with the advance of age; however, few reports regarding acute HF have compared the clinical outcomes of nonagenarians with those of octogenarians. METHODS: This study enrolled 683 patients aged ≥80 years who were admitted to our institution for acute HF between 2016 and 2020. The outcomes of interest were the 1-year all-cause mortality, incidence of cardiac events (cardiac-related death or HF-related readmission), and physical function during hospitalization of patients with survival-to-discharge. Physical function was evaluated using the Barthel index. RESULTS: Post-discharge all-cause mortality, particularly non-cardiac mortality, was significantly higher in nonagenarians than octogenarians. Conversely, the incidence of cardiac death or rehospitalization for HF after discharge was comparable between the two groups. On admission, the Barthel index score was significantly lower in nonagenarians than octogenarians, and further decreased during hospitalization. Nonagenarians required social support at discharge more often than octogenarians (67.4% vs. 44.4%; P < 0.001). CONCLUSIONS: The current study demonstrated that nonagenarians have poorer non-cardiac outcomes and were more vulnerable regarding physical activities than octogenarians among patients with acute HF. Holistic medical care, including palliative care and social support, will be increasingly required with increasing age. Geriatr Gerontol Int 2023; 23: 227-233.

Long-term outcomes of percutaneous revascularization for internal mammary artery-left anterior descending artery bypass failure.

Despite the excellent long-term results of internal mammary artery (IMA)-left anterior descending (LAD) bypass, percutaneous revascularization of IMA is sometimes required for IMA-LAD bypass failure. However, its clinical outcomes have not been fully elucidated. The aim of this study was to investigate the long-term clinical outcomes, including target lesion revascularization (TLR) following contemporary percutaneous revascularization of failed IMA bypass graft. We examined data of 59 patients who had undergone percutaneous revascularization of IMA due to IMA-LAD bypass failure at nine hospitals. Patients with IMA graft used for Y-composite graft or sequential bypass graft were excluded. The incidence of TLR was primarily examined, whereas other clinical outcomes including cardiac death, myocardial infarction, and target vessel revascularization were also evaluated. Mean age of the enrolled patients was 67.4 ± 11.3 years, and 74.6% were men. Forty patients (67.8%) had anastomotic lesions, and 17 (28.8%) underwent revascularization within three months after bypass surgery. Procedural success was achieved in 55 (93.2%) patients. Stent implantation was performed in 13 patients (22.0%). During a median follow-up of 1401 days (interquartile range, 282-2521 days), TLR was required in six patients (8.5% at 1, 3, and 5 years). Patients who underwent percutaneous revascularization within 3 months after surgery tended to have a higher incidence of TLR. Clinical outcomes of IMA revascularization for IMA-LAD bypass failure were acceptable.

Isoform requirement of clustered protocadherin for preventing neuronal apoptosis and neonatal lethality.

Clustered protocadherin is a family of cell-surface recognition molecules implicated in neuronal connectivity that has a diverse isoform repertoire and homophilic binding specificity. Mice have 58 isoforms, encoded by Pcdhα, ß, and γ gene clusters, and mutant mice lacking all isoforms died after birth, displaying massive neuronal apoptosis and synapse loss. The current hypothesis is that the three specific γC-type isoforms, especially γC4, are essential for the phenotype, raising the question about the necessity of isoform diversity. We generated TC mutant mice that expressed the three γC-type isoforms but lacked all the other 55 isoforms. The TC mutants died immediately after birth, showing massive neuronal death, and γC3 or γC4 expression did not prevent apoptosis. Restoring the α- and ß-clusters with the three γC alleles rescued the phenotype, suggesting that along with the three γC-type isoforms, other isoforms are also required for the survival of neurons and individual mice.

A new fluorescent sensor mitoferrofluor indicates the presence of chelatable iron in polarized and depolarized mitochondria.

Mitochondrial chelatable iron contributes to the severity of several injury processes, including ischemia/reperfusion, oxidative stress, and drug toxicity. However, methods to measure this species in living cells are lacking. To measure mitochondrial chelatable iron in living cells, here we synthesized a new fluorescent indicator, mitoferrofluor (MFF). We designed cationic MFF to accumulate electrophoretically in polarized mitochondria, where a reactive group then forms covalent adducts with mitochondrial proteins to retain MFF even after subsequent depolarization. We also show in cell-free medium that Fe2+ (and Cu2+), but not Fe3+, Ca2+, or other biologically relevant divalent cations, strongly quenched MFF fluorescence. Using confocal microscopy, we demonstrate in hepatocytes that red MFF fluorescence colocalized with the green fluorescence of the mitochondrial membrane potential (ΔΨm) indicator, rhodamine 123 (Rh123), indicating selective accumulation into the mitochondria. Unlike Rh123, mitochondria retained MFF after ΔΨm collapse. Furthermore, intracellular delivery of iron with membrane-permeant Fe3+/8-hydroxyquinoline (FeHQ) quenched MFF fluorescence by ∼80% in hepatocytes and other cell lines, which was substantially restored by the membrane-permeant transition metal chelator pyridoxal isonicotinoyl hydrazone. We also show FeHQ quenched the fluorescence of cytosolically coloaded calcein, another Fe2+ indicator, confirming that Fe3+ in FeHQ undergoes intracellular reduction to Fe2+. Finally, MFF fluorescence did not change after addition of the calcium mobilizer thapsigargin, which shows MFF is insensitive to physiologically relevant increases of mitochondrial Ca2+. In conclusion, the new sensor reagent MFF fluorescence is an indicator of mitochondrial chelatable Fe2+ in normal hepatocytes with polarized mitochondria as well as in cells undergoing loss of ΔΨm.

A Comparative Study of Three Nutritional Risk/Screening Indices for Predicting Cardiac Events and Physical Functioning Among Patients with Acute Heart Failure.

Undernutrition is very common among patients with heart failure (HF). This study evaluated the prognostic values of three nutritional risk/screening indices among patients with acute HF. We retrospectively calculated scores for 465 patients with acute HF using the Controlling Nutritional Status (CONUT) tool, the Geriatric Nutritional Risk Index (GNRI), and the Mini-Nutritional Assessment Short Form (MNA-SF). The outcomes of interest were the 1-year rate of cardiac events (cardiac-related death or HF-related readmission) and the Barthel index as an index of physical function during hospitalization. The CONUT, GNRI, and MNA-SF scores were significantly correlated, although the proportions of a normal nutritional state varied (CONUT: 18.3%, GNRI: 32.9%, and MNA-SF: 43.9%). Kaplan-Meier estimates revealed that cardiac events were more common among patients with undernutrition based on the CONUT score, and multivariable regression analysis revealed that only the CONUT score independently predicted poor outcomes. Furthermore, changes in the Barthel index during hospitalization were significantly correlated with the CONUT score but not with the GNRI and MNA-SF scores. In receiver operating characteristic analyses, the CONUT score had the most powerful predictive values on both the postdischarge incidence of cardiac events and the decline of physical function during hospitalization compared with the GNRI and the MNA-SF. These results indicate that the CONUT score might provide useful information for predicting poor outcomes in patients with acute HF.

Clinical implications of severe sarcopenia in Japanese patients with acute heart failure.

AIM: Sarcopenia is a geriatric condition characterized by progressive loss of skeletal muscle mass and function. The definition and diagnosis of sarcopenia is inconsistent between different populations and is still evolving. Herein, we investigated the prevalence and clinical implications of severe sarcopenia using the Asian Working Group for Sarcopenia (AWGS) 2019 criteria in Japanese patients with acute heart failure (HF). METHODS: Overall, 272 patients admitted for acute HF were evaluated for sarcopenia using the AWGS 2019 criteria. RESULTS: There were 46 patients with severe sarcopenia, accounting for approximately 75% of patients who were diagnosed as having sarcopenia. A Kaplan-Meier analysis showed that patients with severe sarcopenia had a higher incidence of cardiac death or rehospitalization for HF 1 year post-discharge than those with non-severe sarcopenia or without sarcopenia (log-rank P = 0.006). A multivariate Cox regression analysis showed that severe sarcopenia was independently correlated with the occurrence of cardiac death or rehospitalization for HF after adjusting for other prognostic factors (hazard ratio 2.580, 95% confidence interval: 1.404-4.740, P = 0.002). CONCLUSIONS: Severe sarcopenia constituted most sarcopenia diagnoses using the AWGS 2019 cut-off values, and was independently associated with 1-year incidence of cardiac death or rehospitalization for HF post-discharge in Japanese patients with acute HF. The assessment of sarcopenia may provide useful information for HF management. Geriatr Gerontol Int 2022; 22: 477-482.

Mitochondrial depolarization after acute ethanol treatment drives mitophagy in living mice.

Ethanol increases hepatic mitophagy driven by unknown mechanisms. Type 1 mitophagy sequesters polarized mitochondria for nutrient recovery and cytoplasmic remodeling. In Type 2, mitochondrial depolarization (mtDepo) initiates mitophagy to remove the damaged organelles. Previously, we showed that acute ethanol administration produces reversible hepatic mtDepo. Here, we tested the hypothesis that ethanol-induced mtDepo initiates Type 2 mitophagy. GFP-LC3 transgenic mice were gavaged with ethanol (2-6 g/kg) with and without pre-treatment with agents that decrease or increase mtDepo-Alda-1, tacrolimus, or disulfiram. Without ethanol, virtually all hepatocytes contained polarized mitochondria with infrequent autophagic GFP-LC3 puncta visualized by intravital microscopy. At ~4 h after ethanol treatment, mtDepo occurred in an all-or-none fashion within individual hepatocytes, which increased dose dependently. GFP-LC3 puncta increased in parallel, predominantly in hepatocytes with mtDepo. Mitochondrial PINK1 and PRKN/parkin also increased. After covalent labeling of mitochondria with MitoTracker Red (MTR), GFP-LC3 puncta encircled MTR-labeled mitochondria after ethanol treatment, directly demonstrating mitophagy. GFP-LC3 puncta did not associate with fat droplets visualized with BODIPY558/568, indicating that increased autophagy was not due to lipophagy. Before ethanol administration, rhodamine-dextran (RhDex)-labeled lysosomes showed little association with GFP-LC3. After ethanol treatment, TFEB (transcription factor EB) translocated to nuclei, and lysosomal mass increased. Many GFP-LC3 puncta merged with RhDex-labeled lysosomes, showing autophagosomal processing into lysosomes. After ethanol treatment, disulfiram increased, whereas Alda-1 and tacrolimus decreased mtDepo, and mitophagy changed proportionately. In conclusion, mtDepo after acute ethanol treatment induces mitophagic sequestration and subsequent lysosomal processing.Abbreviations : AcAld, acetaldehyde; ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase; ALD, alcoholic liver disease; Alda-1, N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GFP, green fluorescent protein; LAMP1, lysosomal-associated membrane protein 1; LMNB1, lamin B1; MAA, malondialdehyde-acetaldehyde adducts; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; MPT, mitochondrial permeability transition; mtDAMPS, mitochondrial damage-associated molecular patterns; mtDepo, mitochondrial depolarization; mtDNA, mitochondrial DNA; MTR, MitoTracker Red; PI, propidium iodide; PINK1, PTEN induced putative kinase 1; PRKN, parkin; RhDex, rhodamine dextran; TFEB, transcription factor EB; Tg, transgenic; TMRM, tetramethylrhodamine methylester; TOMM20, translocase of outer mitochondrial membrane 20; VDAC, voltage-dependent anion channel.

Initiation and long-term use of tolvaptan for patients with worsening heart failure through hospital and clinic cooperation.

Worsening heart failure (WHF) has a negative impact on the prognosis of patients with heart failure. Adequate management of non-hospitalized episodes of WHF, regarded as "outpatient WHF", may reduce the frequency of emergent/urgent hospitalization for acute heart failure; thus, the patients' cardiac parameters return to their clinical baseline. This study aimed to investigate the efficacy of tolvaptan initiation during planned hospitalization of patients with "outpatient WHF" through hospital and clinic cooperation. The data from 28 patients with outpatient WHF referred by general practitioners to hospital were assessed. Tolvaptan administration was initiated during planned hospitalization and continued in the clinics. Patients were followed-up for 12 months. None of the patients required withdrawal of tolvaptan due to adverse effects. During the follow-up period, the loop diuretic dosage significantly decreased. There were significant favorable changes in the levels of serum creatinine, estimated glomerular filtration rate, natriuretic peptide and body weight. Kaplan-Meier survival analysis revealed that the cardiac death- and HF-related hospitalization-free survival rates were significantly higher among the patients who were administered tolvaptan for the outpatient WHF than the propensity score-matched patients who were administered tolvaptan for acute heart failure requiring emergent/urgent hospitalization. In conclusion, tolvaptan may be safe and effective for the long-term management of outpatient WHF through hospital and clinic cooperation.

Improved Renal Function After Percutaneous Coronary Intervention in Non-Dialysis Patients With Acute Coronary Syndrome and Advanced Renal Dysfunction.

BACKGROUND: The deterioration of renal function is a strong prognostic predictor in patients with coronary artery disease. Although percutaneous coronary intervention (PCI) has sometimes resulted in improved renal function (IRF) in acute coronary syndrome (ACS) patients, its clinical implications have not been fully elucidated. This study aimed to investigate the prevalence and predictors of IRF after PCI and its relationship with long-term renal outcomes. METHODS: In this retrospective observational cohort study, we examined data from 177 ACS patients with non-dialysis advanced renal dysfunction (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2) who underwent PCI. Patients with and without IRF were compared in terms of baseline demographic, clinical, and procedural characteristics and renal outcomes. IRF was defined as a 20% increase in eGFR from baseline at 7 or 30 days after the index PCI. RESULTS: IRF was observed in 66 (37.3%) patients. ST-elevation myocardial infarction and shock during PCI were independent predictors of IRF. Patients were followed up for a median of 695 days. Kaplan-Meier analyses demonstrated that patients with IRF had the lower incidence of initiation of permanent dialysis than those without IRF (Log-rank P = 0.015). CONCLUSIONS: IRF was relatively common in non-dialysis patients with ACS and advanced renal dysfunction who underwent PCI. ST-elevation myocardial infarction and shock, which may be indicative of hemodynamic instability during PCI, were independent predictors of IRF. Further, IRF was associated with favorable renal outcomes. Hemodynamic stabilization may be important for improving the short-term and long-term renal outcomes of high-risk patients.

Clinical impacts of cerebral microbleeds in patients with established coronary artery disease.

OBJECTIVE: Although cerebral microbleeds predict the occurrence and recurrence of cerebrovascular events in stroke patients, their clinical impacts are unclear in coronary artery disease patients. We aimed to investigate the clinical effect of the presence of cerebral microbleeds in patients with coronary artery disease receiving antithrombotic treatment. METHODS: We included 447 coronary artery disease patients taking at least one thrombotic agent who underwent brain MRI. The association between the presence of cerebral microbleeds and incidence of major adverse cardiac and cerebrovascular events was investigated. RESULTS: Cerebral microbleeds were identified in 18.7% of patients. Median follow-up duration was 1055 (interquartile range, 781-1172) days. Kaplan-Meier survival analysis demonstrated that patients with cerebral microbleeds had a higher incidence of major adverse cardiac and cerebrovascular events than those without (log-rank P = 0.003). A multivariate Cox regression analysis revealed that the presence of cerebral microbleeds was independently correlated with the occurrence of major adverse cardiac and cerebrovascular events after adjusting for other classical risk factors of coronary artery disease (hazard ratio 1.965, 95% confidence interval 1.086-3.556, P = 0.026). Hypertension was associated with the presence of cerebral microbleeds. The cut-off values to maximize the predictive power of SBP and DBP were 132 and 74 mmHg, respectively (P < 0.001). CONCLUSION: The presence of cerebral microbleeds predicts major adverse cardiac and cerebrovascular events in coronary artery disease patients receiving antithrombotic treatment. Evaluation of cerebral microbleeds and hypertension treatment complying with the established guidelines may be beneficial in the management of coronary artery disease patients.

Clinical outcomes following percutaneous coronary intervention for bifurcation lesions: kissing balloon inflation vs. sequential dilation.

Percutaneous coronary intervention for bifurcation lesions remains challenging, with there being several debatable issues, including the requirement for kissing balloon inflation (KBI). The objective of this study was to assess the clinical outcomes following single crossover stent implantation with KBI or sequential dilation alone. Data were examined for 255 non-left main bifurcation lesions (246 patients) treated with single crossover stent implantation, followed by side branch (SB) strut dilation with KBI (n = 74 lesions) or sequential dilation (n = 181 lesions) in three hospitals. Target lesion revascularization (TLR) was the primary endpoint. There was no significant difference in the pre-procedural reference diameter of both the main vessel (MV) and SB between the KBI and sequential dilation groups. However, MV post-dilation balloon size was smaller with lower pressure and post-procedural minimal lumen diameter was significantly smaller in the KBI group. During the median follow-up period of approximately 3 years, TLR incidence was significantly higher in the KBI group than in the sequential dilation group; in particular, the TLR rate at the distal MV was higher in the former. For bifurcation lesions treated with single crossover stent implantation, the TLR rate was higher after KBI than after sequential dilation; this was mainly due to higher revascularization in the distal MV. For bifurcation lesions treated with KBI, MV post-dilation balloon diameter tended to be smaller with lower pressure, which might lead to poorer stent expansion and a higher TLR rate.

Aldehyde dehydrogenase-2 activation decreases acetaminophen hepatotoxicity by prevention of mitochondrial depolarization.

Oxidative stress contributes to acetaminophen (APAP) hepatotoxicity. Since lipid peroxidation produces reactive aldehydes, we investigated whether activation of mitochondrial aldehyde dehydrogenase-2 (ALDH2) with Alda-1 decreases liver injury after APAP. Male C57BL/6 mice fasted overnight received Alda-1 (20 mg/kg, i.p.) or vehicle 30 min before APAP (300 mg/kg, i.p.). Blood and livers were collected 2 or 24 h after APAP. Intravital multiphoton microscopy of rhodamine 123 (Rh123) and propidium iodide (PI) fluorescence was conducted 6 h after APAP administration to detect mitochondrial polarization status and cell death. 4-Hydroxynonenal protein adducts were present in 0.1% of tissue area without APAP treatment but increased to 7% 2 h after APAP treatment, which Alda-1 blunted to 1%. Serum alanine and aspartate aminotransferases increased to 7594 and 9768 U/L at 24 h respectively, which decreased ≥72% by Alda-1. Alda-1 also decreased centrilobular necrosis at 24 h after APAP from 47% of lobular areas to 21%. N-acetyl-p-benzoquinone imine protein adduct formation and c-Jun-N-terminal kinase phosphorylation increased after APAP as expected, but Alda-1 did not alter these changes. Without APAP, no mitochondrial depolarization was detected by intravital microscopy. At 6 h after APAP, 62% of tissue area showed depolarization, which decreased to 33.5% with Alda-1. Cell death as detected by PI labeling increased from 0 to 6.8 cells per 30× field 6 h after APAP, which decreased to 0.6 cells by Alda-1. In conclusion, aldehydes are important mediators of APAP hepatotoxicity. Accelerated aldehyde degradation by ALDH2 activation with Alda-1 decreases APAP hepatotoxicity by protection against mitochondrial dysfunction.

Utility of the Nutritional Screening in Predicting Adverse Outcome of Patients With Overweight/Obesity and Acute Heart Failure.

BACKGROUND: Undernutrition is a negative predictor of adverse outcomes in patients with heart failure (HF). Despite the survival advantage of elevated body mass index (BMI) in patients with HF, BMI does not necessarily reflect a favorable nutritional status. In the present study, we investigated the clinical impact of nutritional screening in patients with HF and overweight/obesity. METHODS: We examined the data from 170 patients with overweight or obesity status (defined as BMI ≥ 25 kg/m2) who admitted for acute HF. Their controlling nutritional status (CONUT) score was calculated on admission. The CONUT score is regarded as an index of the nutritional status. RESULTS: The median duration of follow-up was 1096 days (interquartile range, 805-1096 days). Undernutrition was identified in 66.5% of the patients. Kaplan-Meier survival analysis demonstrated that patients with undernutrition had a higher incidence of all-cause death and readmission due to HF than those without undernutrition. Multivariate Cox regression analysis revealed that the CONUT score, but not BMI and the geriatric nutritional risk index, was independently correlated with poor prognosis. CONCLUSIONS: Undernutrition is highly prevalent and independently predicts poor outcomes in patients with overweight/obesity and acute HF.