Surgical Management of Cardiac Implantable Electronic Device Complications in Patients Unsuitable for Transvenous Lead Extraction.

BACKGROUND: Although surgical approaches for infected or failing cardiac implantable electronic device (CIED) leads are more invasive than transvenous approaches, they are still required for patients considered unsuitable for transvenous procedures. In this study, surgical management with transvenous equipment for CIED complications was examined in patients unsuitable for transvenous lead extraction.Methods and Results: We retrospectively examined 152 consecutive patients who underwent CIED extraction between April 2009 and December 2021 at the Department of Cardiovascular Surgery, Nippon Medical School. Nine patients (5.9%; mean [±SD] age 61.7±16.7 years) who underwent open heart surgery were identified as unsuitable for the isolated transvenous approach. CIED types included 5 pacemakers and 4 implantable cardioverter-defibrillators; the mean [±SD] lead age was 19.5±7.0 years. Indications for surgical management according to Heart Rhythm Society guidelines included failed prior to transvenous CIED extraction (n=6), intracardiac vegetation (n=2), and severe lead adhesion (n=1). Transvenous CIED extraction tools were used in all patients during or before surgery. Additional surgical procedures with CIED extraction included epicardial lead implantation (n=4) and tricuspid valve repair (n=3). All patients were discharged; during the follow-up period (mean 5.7±3.7 years), only 1 patient died (non-cardiac cause). CONCLUSIONS: Surgical procedures and transvenous extraction tools were combined in the removal strategy for efficacious surgical management of CIED leads. Intensive surgical procedures were safely performed in patients unsuitable for transvenous extraction.

Change in static standing balance ability of community-residing elderly females after the onset of COVID-19 pandemic in Japan.

[Purpose] This study aimed to examine the changes in the balance ability of community-residing elderly females between 2017 and 2020. [Participants and Methods] The participants included 202 females with ≥65 years of age (average age, 78.3 ± 5.88 years), living independently in the community and attending the salon. The balance ability was measured through a one-legged standing test by keeping the participants' eyes open. The measurement duration was a maximum of 120 s while standing still. Each participant underwent the measurement twice, and the best attempt was recorded. The survey period was from 2017 to 2020, and the measurements were conducted once a year. [Results] The 2020 records showed a statistically significant difference compared to those of the other 3 years. The degree of decline was higher in the old-old than that in the young-old. [Conclusion] The balance ability of the elderly females was found to reduce significantly during the COVID-19 pandemic. Specifically, supporting physical activities in the old-old females is necessary to improve their balance ability.

[Overwhelming Postsplenectomy Infection after Cardiac Surgery in a Patient with Immune Thrombocytopenia;Report of a Case].

Splenectomy for immune thrombocytopenia (ITP) can increase the number of platelets. However, patients without functioning spleen become vulnerable to bacteria. Overwhelming post-splenectomy infection( OPSI), its most fulminant form, is rapidly progressive and is highly fatal. A 76-year-old male, who had undergone splenectomy for refractory ITP and taken a vaccination for treptococcus pneumoniae 4 years previously, was admitted to undergo cardiac surgery for severe aortic regurgitation and coronary disease. Prior to operation, high dose intravenous immunoglobulin therapy (400 mg/kg/day) for 5 days successfully increased platelet count. Surgery and early postoperative course were satisfactory. However, on 6th postoperative day, the patient had sudden high fever and became septic. After adequate antibiotic treatment for OPSI, the patient recovered well. Blood culture yielded methicillin-susceptible Staphylococcus aureus (MSSA). The patient discharged in good condition 30 days after the operation.

Effects of an exercise program with video: targeting older female residents in a remote island.

[Purpose] This study aimed to consider the influence of a three-month video exercise program on the physical function of older females. [Participants and Methods] Nineteen older females (aged 72.9 ± 3.64 years) participated in this study. We formed two groups-an experimental group that exercised (n=9) and a control group that did not exercise (n=10). Our study's exercise program focused on leg training. We conducted physical and cognitive tests before and after the program to determine the effects of the exercise program. [Results] The results of the second physical (post-intervention) test showed that the exercise group recorded significant improvement in the one-leg balance test with eyes open. However, no improvement was observed in cognitive function. [Conclusion] The static balance capacity of the exercise group improved. Thus, the three-month video exercise practice was effective for physical function improvement.

A thermomechanical coupling in cholesteric liquid crystals: Unidirectional rotation of double-twist cylinders driven by heat flux.

We made aggregates of cholesteric liquid crystalline Cylinders with Double-Twist orientational structure (DTC) and investigated their rigid-body rotation under a temperature gradient, focusing on how the rotational speed should depend on the cylinder size. The experimental results showed that the angular velocity of the DTC aggregates linearly increased with the height of the cylinders and was inversely proportional to the base area. With a phenomenological equation, we analyzed the torque caused by the heat flux and its balance with the viscous friction, and found that the simple analysis well explained the size-dependence of the rotation of the DTC aggregates. The coupling constant between the heat flux and the torque to drive the rigid-body rotation was in the same order of magnitude as that for the director rotation.

Long-term impact of critical silent cerebrovascular disease in patients undergoing coronary artery bypass surgery: a propensity score and multivariate analyses.

BACKGROUND: Cerebrovascular disease (CVD) with brain hypoperfusion is a strong risk factor for stroke. However, how this pathology influences long-term outcomes after coronary artery bypass graft (CABG) surgery is not known. METHODS: Magnetic resonance imaging/angiography (MRI/A) of the neck and brain was performed in 318 out of 575 consecutive CABG patients between May 2005 and April 2018. Critical CVD with chronic hypoperfusion was defined as multiple severe stenoses (⩾70%) and/or occlusion in the carotid and/or vertebral systems associated with reduced collateral flow due to severe contralateral and/or circle of Willis lesion. Fifty patients were identified to have this pathology (early results were previously reported). The entire cohort was followed up for 83.6 ± 53.7 months. Carotid endarterectomy was considered for symptomatic patients. Propensity matching was performed to compare long-term outcomes between patients with and without critical CVD. RESULTS: Patients with critical CVD at follow-up displayed significantly higher incidences of stroke than those without critical CVD (p=0.007), with an extremely high final incidence (approximately 40% at 8 years). However, survival (p=0.623) and incidences of major adverse cardiac events (MACE: myocardial infarction, coronary revascularization and all causes of death) (p=0.881) were similar. The Cox hazard model revealed that critical CVD was the strongest risk factor for stroke (p=0.000; hazard ratio 6.572; 95% confidence interval 2.657-16.258) while not affecting survival and MACE. CONCLUSION: Critical CVD was the strongest risk factor for long-term stroke after CABG. However, survival and MACE-free rates were equivalent in patients with critical CVD and those without critical CVD.

Formation and dynamics of the aggregates of cholesteric double-twist cylinders.

We succeeded in driving the unidirectional rigid-body rotation of cholesteric (Ch) double-twist cylinder (DTC) droplets under a heat flux along the cylindrical symmetry axis. To directly observe the rigid-body rotation of DTC droplets, in each of which the center of the rotation and the symmetry axis of the structure correspond, we fabricated DTC aggregates that comprise several DTCs with intact structures. Given a steady heat flux, the DTC aggregates metastabilized by the shape and the surface anchoring show a unidirectional rigid-body rotation with a constant angular velocity. The rotational direction is determined by the molecular chirality and the direction of the heat flux, and the rotational velocity increases with the temperature gradient and decreases with the aggregation number N of the DTCs as 1 + 2/sin2(π/N). The behavior agrees with a simple model based on the linear phenomenological equation.

Effects of tolvaptan on urine output in hospitalized heart failure patients with hypoalbuminemia or proteinuria.

Hypoalbuminemia is an independent prognostic factor in hospitalization for heart failure (HHF). Hypoalbuminemia or proteinuria is related to resistance to loop diuretics. Tolvaptan is an oral non-peptide, competitive antagonist of vasopressin receptor-2. It has been used for the treatment of volume overload in HHF patients in several Asian countries. Several studies have demonstrated marked improvement in congestion in HHF patients. However, whether tolvaptan is useful for HHF patients with hypoalbuminemia or proteinuria (both of which are related to resistance to loop diuretics) has not been clarified. We examined the diuretic response to tolvaptan in HHF patients with hypoalbuminemia or proteinuria. We defined hypoalbuminemia as a serum level of albumin < 2.6 g/dl. Fifty-one HHF patients who received additional tolvaptan upon therapies with loop diuretics were divided into the hypoalbuminemia group (n = 24) or control group (n = 27). The changes in urine output per day were not different between the two groups [610 (range 100-1032); 742 (505-1247) ml, P = 0.313]. There was no difference in diuretic responses between patients with and without proteinuria. The serum level of albumin did not correlate with changes in urine output per day after tolvaptan treatment (P = 0.276, r = 0.156). Thus, additional administration of tolvaptan elicited a good diuretic response in HHF patients with hypoalbuminemia or proteinuria. These data suggest that tolvaptan might be beneficial for such HHF patients.

[Coronary artery bypass grafting for cardiovascular sequelae in Kawasaki disease].

There are several issues regarding surgical revascularization for Kawasaki coronary disease including (1) the choice of conduits and (2) the optimal timing and correct indication for coronary artery bypass grafting(CABG). The internal thoracic artery(ITA) is the best conduit in terms of growth potential for pediatric CABG and for excellent long-term patency. The use of saphenous vein graft should be avoided unless an ITA is unavailable. The indication of CABG for Kawasaki coronary disease has not been established. In principle, coronary aneurysms should be observed continuously for 1 to 2 years under restrictive anticoagulation therapy, because regression of coronary aneurysm often occurs in 50 % within 1 to 2 years. The presence of severe ischemia in giant coronary aneurysms involving either the left main trunk or left anterior descending coronary artery is an absolute indicator for CABG. In addition, giant aneurysms with recurrent thrombosis under restrictive anticoagulation therapy or with severe delayed flow without significant localized stenosis may be an indication for CABG.

[Left apical tumor extirpation via left ventriculotomy with the aid of epicardial echocardiography].

We reported a rare case of cardiac lipoma in the left ventricular apex. A 67-year-old woman who was diagnosed with cardiac tumor in the left ventricular apex was underwent the extirpation of the tumor via left ventriculotomy with the aid of intraoperative epicardiac ultra-sound. An intraoperative epicardiac ultra-sound is a very useful tool to document a location of the tumor, and a left ventriculotomy approach for the extirpation of the tumor provides a good operative field.

Saphenous vein characteristics evaluated using three-dimensional contrastless computed tomography before coronary artery bypass grafting.

OBJECTIVE: Saphenous vein (SV) grafts are occasionally unsuitable for grafting owing to anatomic variants. However, there is some concern regarding preoperative SV evaluation. We used contrastless 3D-CT to investigate the anatomical SV characteristics before CABG. METHODS: Contrastless 3D-CT was used to preoperatively evaluate the SV anatomy in 102 consecutive patients undergoing elective first-time CABG. The external diameter of the SV was measured at the mid-level of the thigh and calf segments on both sides. Abnormal branches of the SV were classified into three categories; (1) partial duplication, which was defined as double SVs; (2) large accessory SVs, which were larger than the great SV; and (3) complicated branches of the SV, which resulted in the great SV being undetected. The existence of varicose veins was assessed. RESULTS: The size distribution of the SV (< 3 mm/3-5 mm/5 mm <) was 9/142/53 and 17/154/33 in the thigh and calf segments, respectively. Abnormal branches of the SV were found in 47 patients (46%): (1) partial duplication was noted in 40 patients; (2) large accessory SV was observed in eight patients; and (3) complicated branches were identified in five patients. Varicose veins were detected in 15 patients. SV was harvested in 74 patients, and no additional skin incision was required. CONCLUSIONS: Contrastless 3D-CT is an objective, less time-consuming modality to preoperatively evaluate the SV, and may be less invasive in terms of avoiding unnecessary skin incision. This technique is useful for defining atypical anatomical variations, such as partial duplications, large accessory SVs, and varicose veins.

Temporal and Microbiological Analysis of Cardiac Implantable Electrical Device Infections　- A Retrospective Study.

Background: Although the causative pathogens in cardiac implantable electronic device (CIED) infections are well known, the relationship between time after implantation and infection patterns has not been sufficiently investigated. This study investigated the microbiology and onset of CIED infections according to infection patterns. Methods and Results: This retrospective study included 97 patients who underwent CIED removal due to device-related infections between April 2009 and December 2018. After device implantation, infections peaked in the first year and declined gradually over 10 years. Most infections (>60%) occurred within 5 years. Staphylococcal infections, the predominant form of CIED infections, occurred throughout the study period. CIED infections were categorized as systemic (SI; n=26) or local (LI; n=71) infections according to clinical presentation, and as CIED pocket-related (PR; n=85) and non-pocket-related (non-PR; n=12) infections according to the pathogenic pathway. The main causative pathogen in SI was Staphylococcus aureus, whereas coagulase-negative staphylococci were mainly related to LI. Both SI and LI peaked in the first year after implantation and then decreased gradually. There was no significant microbiological difference between PR and non-PR infections. PR infections showed the same temporal distribution as the overall cohort. However, non-PR infections exhibited a uniform temporal distribution after the first year. Conclusions: The severity of CIED infections depends on the causative pathogen, whereas their temporal distribution is affected by the microbiological intrusion pathway.

Postoperative Changes in Pulmonary Function after Valve Surgery: Oxygenation Index Early after Cardiopulmonary Is a Predictor of Postoperative Course.

OBJECTIVE: To determine pulmonary functional changes that predict early clinical outcomes in valve surgery requiring long cardiopulmonary bypass (CPB). METHODS: This retrospective study included 225 consecutive non-emergency valve surgeries with fast-track cardiac anesthesia between January 2014 and March 2020. Blood gas analyses before and 0, 2, 4, 8, and 14 h after CPB were investigated. RESULTS: Median age and EuroSCORE II were 71.0 years (25-75 percentile: 59.5-77.0) and 2.46 (1.44-5.01). Patients underwent 96 aortic, 106 mitral, and 23 combined valve surgeries. The median CPB time was 151 min (122-193). PaO2/FiO2 and AaDO2/PaO2 significantly deteriorated two hours, but not immediately, after CPB (both p < 0.0001). Decreased PaO2/FiO2 and AaDO2/PaO2 were correlated with ventilation time (r2 = 0.318 and 0.435) and intensive care unit (ICU) (r2 = 0.172 and 0.267) and hospital stays (r2 = 0.164 and 0.209). Early and delayed extubations (<6 and >24 h) were predicted by PaO2/FiO2 (377.2 and 213.1) and AaDO2/PaO2 (0.683 and 1.680), measured two hours after CPB with acceptable sensitivity and specificity (0.700-0.911 and 0.677-0.859). CONCLUSIONS: PaO2/FiO2 and AaDO2/PaO2 two hours after CPB were correlated with ventilation time and lengths of ICU and hospital stays. These parameters suitably predicted early and delayed extubations.

Heat-Driven Rigid-Body Rotation of a Mixture of Cholesteric Liquid Crystal Droplets and Colloids.

We show that cholesteric (Ch) liquid crystal droplets with cylindrically symmetric orientation dispersing in an isotropic (Iso) phase exhibited unidirectional rotation under a heat flux along the symmetry axis. By introducing colloidal particle adhesive to the Ch droplet surface, we traced the translational motion of the colloids and found that the colloids rotated unidirectionally around the center of each Ch droplet. The director configuration of the droplets was not distorted either spatially or temporally, while the colloids rotated constantly. The results suggest that the Ch droplets under the heat flux should rotate as a rigid body. Using this heat-driven rotation of the Ch droplets, we designed new geometries of various composites of Ch droplets and colloids and succeeded in driving intriguing complex dynamics.

Early extubation in current valve surgery requiring long cardiopulmonary bypass: Benefits and predictive value of preoperative spirometry.

BACKGROUND: Early extubation (EEx) after cardiac surgery has been essentially studied in patients with short cardiopulmonary bypass (CPB). Whether preoperative spirometry can predict EEx remains controversial. OBJECTIVES: To investigate whether EEx can be a goal and predicted by preoperative spirometry in valve surgery requiring long CPB. METHODS: Nonemergent consecutive 210 patients who underwent valve surgery from January 2014 to August 2019 were investigated retrospectively. RESULTS: EEx (<8 h) was achieved in 93 (44.3%) patients without increasing adverse events. Patients with EEx had shorter ICU and hospital stays than those without EEx. Multivariate analysis showed that higher estimated glomerular filtration rate and mitral valve repair were significant protective factors for EEx. Conversely, moderate and severe chronic obstructive pulmonary disease defined by spirometry, longer operation, CPB, and aortic cross-clamp time were significant risk factors. CONCLUSIONS: EEx should be the goal in current valve surgery. Preoperative spirometry is a significant predictor.

Risk factors for de novo hepatitis B during solid cancer treatment.

BACKGROUND: Reactivation of hepatitis B virus (HBV) during anticancer treatment is a critical issue. When treating patients with solid tumors, it is unclear whether specific cancer types or treatments affect HBV reactivation in hepatitis B surface antigen (HBsAg)-negative and hepatitis B core antibody (HBcAb)-positive patients, so-called de novo hepatitis B patients. The risk of de novo hepatitis B may vary based on different background factors. AIM: To determine the frequency and risk factors for de novo hepatitis B during solid tumor treatment. METHODS: This retrospective cohort study comprised 1040 patients without HBsAgs and with HBcAbs and/or hepatitis B surface antibodies (HBsAbs). The patients were treated for solid cancer from 2008 to 2018 at the National Kyushu Cancer Center and underwent HBV DNA measurements. Patient characteristics and disease and treatment information were investigated. HBV DNA measurements were performed using TaqMan polymerase chain reaction (PCR). To identify the risk factors associated with HBV DNA expression, the age, sex, original disease, pathology, treatment method, presence or absence of hepatitis C virus (HCV), and HBsAb and/or HBcAb titers of all subjects were investigated. In patients with HBV DNA, the time of appearance, presence of HBsAgs and HBsAbs at the time of appearance, and course of the subsequent fluctuations in virus levels were also investigated. RESULTS: Among the 1040 patients, 938 were HBcAb positive, and 102 were HBcAb negative and HBsAb positive. HBV DNA expression was observed before the onset of treatment in nine patients (0.9%) and after treatment in 35 patients (3.7%), all of whom were HBcAb positive. The HBV reactivation group showed significantly higher median HBcAb values [9.00 (8.12-9.89) vs 7.22 (7.02-7.43), P = 0.0001] and significantly lower HBsAb values (14 vs 46, P = 0.0342) than the group without reactivation. Notably, the reactivated group showed a significantly higher proportion of cancers in organs related to digestion and absorption (79.0% vs 58.7%, P = 0.0051). A high HBcAb titer and cancers in organs involved in digestion and absorption were identified as independent factors for HBV reactivation (multivariate analysis, P = 0.0002 and P = 0.0095). The group without HBsAbs tended to have a shorter time to reactivation (day 43 vs day 193), and the frequency of reactivation within 6 mo was significantly higher in this group (P = 0.0459) than in the other group. CONCLUSION: A high HBcAb titer and cancers in organs involved in digestion and absorption are independent factors that contribute to HBV reactivation during solid tumor treatment.

Long-term outcomes of endovascular aortic aneurysm repair with the Zenith AAA endovascular graft: a single-center study.

PURPOSE: To present long-term results obtained with endovascular abdominal aortic aneurysm (AAA) repair (EVAR) using the Zenith AAA endovascular graft from a single institution. MATERIALS AND METHODS: Between 2007 and 2013, 95 consecutive patients (median age 77 years) underwent EVAR using Zenith. Data were prospectively collected and retrospectively analyzed until 2019. Primary outcomes were overall survival, freedom from AAA rupture, and freedom from AAA-related death. Secondary outcomes were freedom from late (> 30 days) re-intervention and surgical conversion, and freedom from aneurysm sac growth (> 5 mm). RESULTS: The initial technical success rate was 96.8%. There were no deaths or intraoperative conversions. Overall survival at 1, 3, 5, and 10 years was 90.8%, 81.7%. 74.3%, and 57.2%, respectively. AAA rupture occurred in one patient (1.1%). Freedom from AAA-related death was 100% during the follow-up period. Freedom from aneurysm sac growth at 1, 3, 5, and 10 years was 98.8%, 86.4%, 76.9%, 53.0%, respectively. Freedom from late re-intervention and open surgical conversion at 1, 3, 5, and 10 years was 98.9%, 88.9%, 86.7, and 57.9%, respectively. CONCLUSION: EVAR with Zenith endografts represents a safe and durable means of AAA repair, and risk of rupture and aneurysm-related death are low.

Differences in pharmacological property between combined therapy of the vasopressin V2-receptor antagonist tolvaptan plus furosemide and monotherapy of furosemide in patients with hospitalized heart failure.

BACKGROUND: Tolvaptan has been shown to improve congestion in heart failure patients. The purpose of this study was to evaluate the pharmacology and clinical efficacy of combined tolvaptan and furosemide therapy. METHODS: This study included 40 patients with systemic volume overload who were hospitalized for heart failure. Patients who showed no improvement in the condition after receiving 20 mg intravenous furosemide were included and were randomly selected to receive tolvaptan as an add-on to furosemide or to receive an increased dose of furosemide. We evaluated the bioelectrical impedance analyzer parameters, the parameters of the inferior vena cava using echocardiography, vital signs, body weight, urine output, and laboratory data for 5 days. RESULTS: In the changes from baseline between intracellular water volume (ICW) and extracellular water volume (ECW) after additional use of tolvaptan or furosemide from Day 1 to Day 5, there were no significant differences observed between ICW and ECW over 5 days in the tolvaptan + furosemide group, although differences were found in the furosemide group from Day 2 onward. Changes in the respiratory collapse of inferior vena cava increased significantly, and systolic blood pressure decreased significantly only in the furosemide group. CONCLUSIONS: The present study clearly demonstrates that combined therapy with tolvaptan and furosemide removed excess ICW and ECW to an equal extent, while furosemide alone primarily removed ECW, including intravascular water.

Clinical significance of arterial stiffness as a factor for hospitalization of heart failure with preserved left ventricular ejection fraction: a retrospective matched case-control study.

BACKGROUND: Previous studies have been conducted to identify characteristics of patients with heart failure with preserved ejection fraction (HFpEF), but the risk factors of HFpEF remain unclear. We investigated the associations between arterial stiffness and the risk of hospitalization for HFpEF patients. METHODS: For the case group, we enrolled patients with preserved EF who had been hospitalized for HF from April 2013 to March 2015 and examined the cardio-ankle vascular index (CAVI). For the control group, we enrolled outpatients with preserved EF and with hypertension, diabetes mellitus, dyslipidemia, and/or coronary artery disease but who did not present with HF symptoms and had never been diagnosed or treated for HF during the same period. The control group matched with the case group for age and sex. The association between hospitalized HFpEF and clinical variables was analyzed using conditional logistic regression models. RESULTS: The CAVI value was significantly higher in patients with hospitalized HFpEF compared with patients with the control [10.4 (9.8-11.0) vs. 9.2 (8.1-10.0), p < 0.001). On the multivariate conditional logistic regression analysis, high CAVI (OR 6.76, 95% CI 2.28-20.10, p < 0.001) and anemia (OR 3.91, 95% CI 1.47-10.40, p = 0.006) were independently associated with hospitalization of HFpEF patients. CONCLUSIONS: The present study has demonstrated that the high value of CAVI was independently associated with the hospitalization of HFpEF patients.

4'-Demethylnobiletin, a bioactive metabolite of nobiletin enhancing PKA/ERK/CREB signaling, rescues learning impairment associated with NMDA receptor antagonism via stimulation of the ERK cascade.

The biochemical and pharmacological activities of nobiletin, including neurotrophic and memory-enhancing action, in both in vitro and in vivo systems are well established. However, whether its metabolites do have such beneficial effects like nobiletin remains to be examined. Here we, for the first time, report that 2-(4-hydroxy-3-methoxyphenyl)-5,6,7,8-tetramethoxychromen-4-one (4'-demethylnobiletin), a major metabolite of nobiletin identified in the urine of rats and mice, stimulates the phosphorylation of ERK and CREB and enhances CRE-mediated transcription by activating a PKA/MEK/ERK pathway, like nobiletin, in cultured hippocampal neurons. Since NMDA receptor-mediated ERK signaling is involved in memory processing, including associative memories, we also examined whether 4'-demethylnobiletin, by activating ERK signaling, could restore learning impairment. Chronic intraperitoneal (ip) treatment of the mice with 10 or 50 mg of 4'-demethylnobiletin/kg rescued the NMDA receptor antagonist MK-801-induced learning impairment, accompanied by improvement of the MK-801-induced decrease in the level of ERK phosphorylation in the hippocampus of the animals. Consistently, 4'-demethylnobiletin also restored MK-801-induced inhibition of NMDA-stimulated phosphorylation of not only ERK but also PKA substrates in cultured rat hippocampal neurons. Moreover, we actually detected 4'-demethylnobiletin in the brain of mice following acute ip administration, demonstrating that the metabolite can cross the blood-brain barrier to reach the brain and thereby exert its effects to reverse learning impairment. Therefore, these results suggest that 4'-demethylnobiletin, a bioactive metabolite of nobiletin, may serve as a potential therapeutic agent, at least, for memory disorders associated with a dysregulated NMDA receptor ERK signaling, like nobiletin.