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The opportunities to treat elderly patients with aneurysmal subarachnoid hemorrhage (aSAH) are increasing globally, but the outcome remains poor. This study seeks to investigate treatment-related factors that can modify functional outcomes in patients with aSAH aged ≥75 years. A total of 202 patients with aSAH aged ≥75 years prospectively enrolled in 9 primary stroke centers from 2013 to 2021 were retrospectively analyzed. Clinical variables including treatments for hydrocephalus, angiographic vasospasm, and delayed cerebral ischemia were compared between patients with good (modified Rankin Scale [mRS] score 0–2) and poor (mRS score 3–6) outcomes at 90 days from onset, followed by multivariate analyses to find independent outcome determinants. A modifiable treatment-related variable was evaluated after propensity score matching with adjustments for age, sex, pre-onset mRS score, aSAH severity, and treatment modality. More than half of patients showed World Federation of Neurological Societies grades IV–V on admission. Univariate analyses showed that advanced age, worse pre-onset mRS score, more severe neurologic status on admission, higher modified Fisher grade on admission computed tomography scans, and acute and chronic hydrocephalus were associated with poor outcomes. In contrast, administration of a phosphodiesterase type III inhibitor, cilostazol, was associated with good outcomes in both univariate (P = 0.036) and multivariate analyses (adjusted odds ratio, 0.305; 95% confidence interval, 0.097–0.955; P = 0.042). Propensity score matching analyses showed that patients treated with cilostazol had better outcomes (P = 0.016) with fewer incidences of delayed cerebral infarction (P = 0.008). Even in patients with aSAH aged ≥75 years, cilostazol administration may lead to better outcomes by suppressing the development of delayed cerebral infarction. [Display omitted] [ABSTRACT FROM AUTHOR]

• The Japanese version of Inventory of Creative Activities and Achievements (ICAA-J) was developed. • Validity and reliability of the ICAA-J were confirmed with little-c and pro-c samples. • The Japanese characteristics of responses to the ICAA-J were discussed. Measurement of real-life creativity across various countries serves as the foundation for the cultural psychology of creativity. Although studies have suggested differences in creativity between Western and East Asian countries, the underlying factors remain insufficiently understood. This study focused on Japan, an East Asian country, that was perceived to have high creativity yet exhibited negative self-perceptions of creativity. We translated the Inventory of Creative Activities and Achievements (ICAA), a comprehensive measure of real-life creativity from activities and achievements. Data were collected from various participants, who included creative activity experts and non-experts and spanned from university students to general adults (pro-c: n = 489 and little-c: n = 1485). Validity and reliability of the Japanese version of the ICAA was confirmed. However, the Japanese version revealed that Japanese individuals' mean score of creative activities and achievements, even among professionals, was only approximately half of that reported among Western or Chinese university students. Reasons for lower creativity and achievements among the Japanese population have been discussed. [ABSTRACT FROM AUTHOR]

Subarachnoid hemorrhage (SAH) is a devastating cerebrovascular disease. Neuronal apoptosis plays an important pathological role in early brain injury after SAH. Galanin receptor 1 (GalR1) activation was recently shown to be anti-apoptotic in the setting of ischemic stroke. This study aimed to explore the anti-neuronal apoptosis effect of GalR1 activation after SAH, as well as the underlying mechanisms. GalR1 CRISPR and GalR1 selective agonist, M617, was administered, respectively. Extracellular-signal-regulated kinase (ERK) inhibitor (U0126) and glycogen synthase kinase 3-beta (GSK3-β) CRISPR were administered to investigate the involvement of the ERK/GSK3-β pathway in GalR1-mediated neuroprotection after SAH. Outcome assessments included neurobehavioral tests, western blot, and immunohistochemistry. The results showed that endogenous ligand galanin (Gal) and GalR1 were markedly increased in the ipsilateral brain hemisphere at 12 h and 24 h after SAH. GalR1 were expressed mainly in neurons, but expression was also observed in some astrocytes and microglia. GalR1 CRISPR knockdown exacerbated neurological deficits and neuronal apoptosis 24 h after SAH. Moreover, activation of GalR1 with M617 significantly improved short- and long-term neurological deficits but decreased neuronal apoptosis after SAH. Furthermore, GalR1 activation dysregulated the protein levels of phosphorylated ERK and GSK-3β, but downregulated the phosphorylated Tat-interactive protein 60 (TIP60) and cleaved caspase-3 at 24 h after SAH. GalR1 CRISPR, U0126, and GSK-3β CRISPR abolished the beneficial effects of GalR1 activation at 24 h after SAH in rats. Collectively, the present study demonstrated that activation of GalR1 using M617 attenuated neuronal apoptosis through the ERK/GSK-3β/TIP60 pathway after SAH in rats. GalR1 may serve as a promising therapeutic target for SAH patients. [ABSTRACT FROM AUTHOR]

Brain edema is a vital contributor to early brain injury after subarachnoid hemorrhage (SAH), which is responsible for prolonged hospitalization and poor outcomes. Pharmacological therapeutic targets on edema formation have been the focus of research for decades. Pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to participate in neural development and brain injury. Here, we used PACAP knockout CRISPR to demonstrate that endogenous PACAP plays an endogenous neuroprotective role against brain edema formation after SAH in rats. The exogenous PACAP treatment provided both short- and long-term neurological benefits by preserving the function of the blood–brain barrier and glymphatic system after SAH. Pretreatment of inhibitors of PACAP receptors showed that the PACAP-involved anti-edema effect and neuroprotection after SAH was facilitated by the selective PACAP receptor (PAC1). Further administration of adenylyl cyclase (AC) inhibitor and sulfonylurea receptor 1 (SUR1) CRISPR activator suggested that the AC–cyclic adenosine monophosphate (cAMP)–protein kinase A (PKA) axis participated in PACAP signaling after SAH, which inhibited the expression of edema-related proteins, SUR1 and aquaporin-4 (AQP4), through SUR1 phosphorylation. Thus, PACAP may serve as a potential clinical treatment to alleviate brain edema in patients with SAH. [ABSTRACT FROM AUTHOR]

We previously reported that the patients with cholesteryl ester transfer protein (CETP) deficiency (CETP-D) show marked changes in the size and lipid compositions of high-density lipoprotein (HDL) and that they are not protected from atherosclerotic cardiovascular diseases, despite increased serum HDL-cholesterol (HDL-C) levels. HDL particles carry a variety of proteins, some of which are known to have antiatherogenic functions. This study aimed to investigate the protein composition of HDL particles in patients with CETP-D. Eight patients with complete deficiency of CETP and 8 normolipidemic healthy subjects were enrolled. We performed shotgun proteomic analysis to investigate the proteome of ultracentrifugally isolated HDL. We identified 79 HDL-associated proteins involved in lipid metabolism, protease inhibition, complement regulation, and acute-phase response, including 5 potential newly identified HDL-associated proteins such as angiopoietin-like3 (ANGPTL3). Spectral counts of apolipoprotein (apo) E were increased in patients with CETP-D compared with controls (60.3 ± 6.9 vs 43.7 ± 2.5, P <.001), which is concordant with our previous report. Complement regulatory proteins such as C3, C4a, C4b, and C9 were also significantly enriched in HDL from patients with CETP-D. Furthermore, apoC-III and ANGPTL3, both of which are now known to associate with increased atherosclerotic cardiovascular diseases, were enriched in patients with CETP-D compared with normolipidemic subjects (35.9 ± 5.3 vs 27.1 ± 3.7, 2.3 ± 1.1 vs 0.4 ± 1.1, respectively; P <.01). We have characterized HDL-associated proteins in patients with CETP-D. We identified a significant increase in the amount of apoE, apoC-III, ANGPTL3, and complement regulatory proteins. These proteomic changes might be partly responsible for the enhanced atherogenicity of patients with CETP-D. • We have characterized the proteome of HDL in healthy subjects and patients with CETP-D. • We identified 79 HDL-associated proteins, 5 of which were newly identified. • ApoE, apoC-III, and complement C3 and C4b were significantly increased in HDL of CETP-D. • We identified ANGPTL3 as an HDL-associated protein, which was increased in CETP-D. • These proteomic changes might be partly responsible for atherogenicity of CETP-D. [ABSTRACT FROM AUTHOR]

Aims CD36 is an important transporter of long-chain fatty acids (LCFAs) in the myocardium. As we have reported previously, CD36-deficient patients demonstrate a marked reduction in myocardial uptake of 123 I-15-(p-iodophenyl)-(R, S)-methyl pentadecanoic acid (BMIPP), which is an analog of LCFAs, while myocardial 18 F-fluorodeoxy-glucose (FDG) uptake is increased. However, it has not been clarified whether energy provision is preserved in patients with CD36 deficiency. The aims of the current study were to investigate the myocardial uptake of glucose and alterations in myocardial metabolites in wild-type (WT) and CD36 knockout (KO) mice. Methods and results High-resolution positron emission tomography (PET) demonstrated markedly enhanced glucose uptake in KO mouse hearts compared with those of WT mice in real-time. The myocardial protein expression of glucose transporter protein 1 (GLUT1) was significantly enhanced in KO mice compared to WT mice, whereas that of GLUT4 was not altered. While the myocardial expression of genes involved in fatty acid metabolism did not increase in KO mice, that of genes related to glucose utilization compensatorily increased in KO mice. The metabolomic analysis of cardiac tissues revealed that the myocardial concentrations of ATP and phosphocreatine were maintained, even in KO mice. The concentration of 3-hydroxybutyric acid and mRNA expression of hydroxybutyrate dehydrogenase in the heart were significantly higher in KO than in WT mice. Conclusion These data suggest that high-energy phosphate might be preserved by the increased utilization of glucose and ketone bodies in CD36KO mouse hearts under conditions of deficient LCFA uptake. [ABSTRACT FROM AUTHOR]

Background It is controversial whether taking antiplatelet agents (APs) or anticoagulant agents (ACs) could influence clinical outcome after intracerebral hemorrhage (ICH). Methods We retrospectively investigated 557 ICH patients between September 2008 and August 2013. We reviewed patients' characteristics, hematoma volume, deterioration (hematoma expansion, surgical hematoma evacuation, or death), and clinical outcome in modified Rankin Scale. Results A total of 397 were classified as neither AP nor AC ("Nothing"), 81 as single AP (44 as aspirin [ASA], 22 as clopidogrel or ticlopidine [CLP/TIC], 7 as cilostazol, 8 as dual antiplatelet therapy), 43 as single AC (40 as warfarin, 2 as rivaroxaban, 1 as dabigatran), and 36 as both AP and AC (AP + AC). The clinical outcome was worse in APs than in "Nothing" (P = .021). Among APs, CLP/TIC showed poorer clinical outcome than ASA (P = .020). Deterioration was observed more frequently in AC than in "Nothing" (P < .001) and the clinical outcome was also worse in AC than in "Nothing" (P < .001). AP + AC use resulted in deterioration more frequently than "Nothing" (P < .001) and in poorer outcome than in "Nothing" (P < .001). Conclusions The use of antithrombotic agents could be associated with the deterioration after admission and the poor clinical outcome. CLP/TIC use may affect the poor outcome compared with ASA use. [ABSTRACT FROM AUTHOR]

• Constraints are both beneficial and detrimental to creativity. • Prior knowledge is considered to be a kind of constraint. • Compared with experts who take approaches to overcome negative effects of prior knowledge, novices are usually unconscious of such effects. • Novices' creativity in drawing is enhanced through interventions that aim to mitigate the negative effects of prior knowledge. • This enhancement of creativity is more effective if novices become conscious of what is restraining them and construct their own perspectives. Constraints may facilitate or inhibit creativity. When confronting the negative influence of constraints on artistic creation, artists usually modify the process of creating to achieve a breakthrough that aids the development of creative ideas. However, novices are often not conscious of this negative influence, and therefore, may be restrained by it. The present study examined whether novices can be made conscious of what restrains them, and if this realization can then enable them to draw more creatively. An experiment was conducted with 33 university students assigned to three groups. Two interventions were implemented, and their effects were examined. Findings revealed that the intervention that involved interfering with access to prior knowledge enhanced novices' creativity in drawing. However, this improvement could not be transferred to drawing on a distinctive theme when participants were not provided the second intervention, which involved a reflective session instructing the participants on how prior knowledge restrains creativity, further making them reflect upon their own experiences of facing interference when accessing prior knowledge. Possible explanations for the different effects of the two interventions are discussed. [ABSTRACT FROM AUTHOR]

In response to the question of how actors can perform truthfully in imaginary settings, the present study focuses on the characteristics of changes in actors in a role through an acting training process, which emphasizes paying attention to a partner and communicating. The characteristics of changes in actors are captured by the pattern of utterances during the training. Statistical analyses are conducted on temporal changes, individual differences, and the granularity of utterances. The influence on utterances of attention to partners is discussed, which reflects an integrated perspective from which to view creative action, as is referred to in the five A's framework. In addition, by explaining the interrelation of words and context in acting through the theory of constructed emotion, the results provide a demonstration of how real emotion may be born in acting. [ABSTRACT FROM AUTHOR]

Abstract: Sodium zinc dihydrolipoylhistidinate (DHLHZn) is a compound of Zn2+/dihydrolipoic acid derivate complex, which was developed for cosmetic/medical use. To characterize DHLHZn as a novel skin-lightening agent, inhibitory actions of DHLHZn on tyrosinase (including its reaction pathway) have been elucidated in this study. In a B16 melanoma cell system, DHLHZn was active in suppressing the synthesis of melanins as well as α-arbutin, well known as a depigmenting drug. Furthermore, in a tyrosinase assay, DHLHZn showed stronger inhibitory effect on DOPAchrome formation than other tyrosinase inhibitors such as kojic acid. Our previous report demonstrated that the sulfhydryl groups of lipoyl motif react with DOPAquinone to form lipoyl DOPA conjugates. We therefore postulated that conjugated products between DHLHZn and DOPAquinone might be formed. Upon reaction of DHLHZn with l-DOPA following tyrosinase-catalyzed oxidation, the formation of DHLH DOPA conjugated products was confirmed by HPLC-tandem mass spectrometry using reserpine as the internal standard. In addition, the inhibitory kinetics analyzed by a Lineweaver–Burk plot exhibited the reversibility of DHLHZn as a competitive inhibitor with a K I value of 0.35μM. These results indicate that this covalent reaction might contribute to alternating DOPAquinone, which is a tyrosinase reaction product, and result in the competitive inhibitory effect of DHLHZn on DOPAchrome formation. DHLHZn may thus serve as a potentially effective skin-lightening agent, an effectiveness that is based on the compound’s covalent scavenging of DOPAquinone resulting in depigmentation. [Copyright &y& Elsevier]

Oxidative stress and neuronal apoptosis play important roles in the pathogenesis of early brain injury (EBI) after subarachnoid hemorrhage (SAH). The activation of TGR5, a novel membrane-bound bile acid receptor, possesses anti-oxidative stress and anti-apoptotic effects in hepatobiliary disease and kidney disease. The present study aimed to explore the neuroprotective effect of TGR5 activation against EBI after SAH and the potential underlying mechanisms. The endovascular perforation model of SAH was performed on 199 Sprague Dawley rats to investigate the beneficial effects of TGR5 activation after SAH. INT-777, a specific synthetic TGR5 agonist, was administered intranasally at 1 h after SAH induction. TGR5 CRISPR and ALDH2 CRISPR were administered intracerebroventricularly at 48 h before SAH to illuminate potential mechanisms. The SAH grade, short-term and long-term neurobehavioral tests, TUNEL staining, Fluoro-Jade C staining, Nissl staining, immunofluorescence staining, and western blots were performed at 24 h after SAH. The expressions of endogenous TGR5 and ALDH2 gradually increased and peaked at 24 h after SAH. TGR5 was expressed primarily in neurons, as well as in astrocytes and microglia. The activation of TGR5 with INT-777 significantly improved the short-term and long-term neurological deficits, accompanied by reduced the oxidative stress and neuronal apoptosis at 24 h after SAH. Moreover, INT-777 treatment significantly increased the expressions of TGR5, cAMP, phosphorylated PKCε, ALDH2, HO-1, and Bcl-2, while downregulated the expressions of 4-HNE, Bax, and Cleaved Caspase-3. TGR5 CRISPR and ALDH2 CRISPR abolished the neuroprotective effects of TGR5 activation after SAH. In summary, the activation of TGR5 with INT-777 attenuated oxidative stress and neuronal apoptosis via the cAMP/PKCε/ALDH2 signaling pathway after SAH in rats. Furthermore, TGR5 may serve as a novel therapeutic target to ameliorate EBI after SAH. • The TGR5 receptors were increased and were primarily expressed in neurons after SAH in rats. • TGR5 activation improved neurological deficits, accompanied by reduced oxidative stress and neuronal apoptosis after SAH. • TGR5 attenuated oxidative stress and neuronal apoptosis, at least in part, via cAMP/PKCε/ALDH2 pathway after SAH. [ABSTRACT FROM AUTHOR]

We conducted a prospective study to determine whether a bolus injection of sodium bicarbonate before emergent coronary procedures in patients with chronic kidney disease (CKD) might prevent contrast-induced nephropathy (CIN). We enrolled 59 patients with CKD, defined by a serum creatinine concentration of >1.1 mg/dl or an estimated glomerular filtration rate of <60 ml/min, who were scheduled at admission to undergo an emergent coronary procedure. The patients were randomized to receive a bolus intravenous injection of 154 mEq/L of sodium bicarbonate (n = 30) or sodium chloride (n = 29) at the dose of 0.5 ml/kg, before contrast administration, followed by infusion of 154 mEq/L sodium bicarbonate at 1 ml/kg/hour for 6 hours in both groups. The primary end point was the occurrence of CIN, defined as an increase by >25% or >0.5 mg/dl of the serum creatinine level within 2 days after the procedure. In the sodium bicarbonate group, the serum creatinine concentration remained unchanged within 2 days of contrast administration (from 1.32 ± 0.46 to 1.38 ± 0.60 mg/dl, p = 0.33). In contrast, it had increased in the sodium chloride group (1.51 ± 0.59 to 1.91 ± 1.19 mg/dl, p = 0.006). The incidence of CIN was significantly lower in the sodium bicarbonate group than in the sodium chloride group (3.3% vs 27.6%, p = 0.01). In conclusion, rapid alkalization by bolus injection of sodium bicarbonate was effective for the prevention of CIN in patients with CKD undergoing emergent procedures. [ABSTRACT FROM AUTHOR]

The Seattle Heart Failure Model (SHFM) is a validated prediction model that estimates the mortality in patients with chronic heart failure (CHF) using commonly obtained information, including clinical data, laboratory test results, medication use, and device implantation. In addition, cardiac iodine-123 meta-iodobenzylguanidine (MIBG) imaging provides prognostic information for patients with CHF. However, the long-term predictive value of combining the SHFM and cardiac MIBG imaging in patients with CHF has not been elucidated. To prospectively investigate whether cardiac iodine-123 MIBG imaging provides additional prognostic value to the SHFM in patients with CHF, we studied 106 outpatients with CHF who had radionuclide left ventricular ejection fraction <40% (30 ± 8%). The SHFM score was obtained at enrollment, and the cardiac MIBG washout rate (WR) was calculated from anterior chest images obtained at 20 and 200 minutes after isotope injection. During a mean follow-up of 6.8 ± 3.5 years (range 0 to 13), 32 of 106 patients died from cardiac causes. A multivariate Cox analysis revealed that the WR (p = 0.0002) and SHFM score (p = 0.0091) were independent predictors of cardiac death. Kaplan-Meier analysis showed that patients with an abnormal WR (>27%) had a significantly greater risk of cardiac death than did those with a normal WR for both those with a SHFM score of ≥1 (relative risk 3.3, 95% confidence interval 1.2 to 9.7, p = 0.01) and a SHFM score of ≤0 (relative risk 3.4, 95% confidence interval 1.2 to 9.6, p = 0.004). In conclusion, the cardiac MIBG WR provided additional prognostic information to the SHFM score for patients with CHF. [ABSTRACT FROM AUTHOR]