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A 13-year-old neutered male Maltese dog presented to our hospital with lethargy and anorexia. Laboratory abnormalities included severe non-regenerative anemia (hematocrit, 12.9%; reticulocyte count 12.8 K/μL). The cytology of bone marrow revealed erythroid hypercellularity with mild myelofibrosis. Therefore, late-stage precursor-targeted immune-mediated anemia (PIMA) was diagnosed. Multimodal treatment including 2 immunosuppressant drugs (prednisolone and mycophenolate mofetil), antithrombic drug (clopidogrel), and blood transfusion was performed. The dog showed complete remission from PIMA, and the total duration of follow-up was 622 days. This is the first case report of canine PIMA managed successfully with prednisolone and mycophenolate mofetil in Korea.
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Recently, ex-vivo gene therapy has emerged as a promising approach to enhance the therapeutic potential of mesenchymal stem cells (MSCs) by introducing functional genes in vitro. Here, we explored the need of using selection markers to increase the gene delivery efficiency and evaluated the potential risks associated with their use in the manufacturing process. We used MSCs/CD that carry the cytosine deaminase gene (CD) as a therapeutic gene and a puromycin resistance gene (PuroR) as a selection marker. We evaluated the correlation between the therapeutic efficacy and the purity of therapeutic MSCs/CD by examining their anti-cancer effect on co-cultured U87/GFP cells. To simulate in vivo horizontal transfer of the PuroR gene in vivo, we generated a puromycin-resistant
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Therapeutic efficacy of mesenchymal stem cells (MSCs) is determined by biodistribution and engraftment in vivo.Compared to intravenous infusion, biodistribution of locally transplanted MSCs are partially understood. Here, we performed a pharmacokinetics (PK) study of MSCs after local transplantation. We grafted human MSCs into the brains of immune-compromised nude mice. Then we extracted genomic DNA from brains, lungs, and livers after transplantation over a month. Using quantitative polymerase chain reaction with human Alu-specific primers, we analyzed biodistribution of the transplanted cells. To evaluate the role of residual immune response in the brain, MSCs expressing a cytosine deaminase (MSCs/CD) were used to ablate resident immune cells at the injection site. The majority of the Alu signals mostly remained at the injection site and decreased over a week, finally becoming undetectable after one month. Negligible signals were transiently detected in the lung and liver during the first week. Suppression of Iba1-positive microglia in the vicinity of the injection site using MSCs/CD prolonged the presence of the Alu signals.After local transplantation in xenograft animal models, human MSCs remain predominantly near the injection site for limited time without disseminating to other organs. Transplantation of human MSCs can locally elicit an immune response in immune compromised animals, and suppressing resident immune cells can prolong the presence of transplanted cells. Our study provides valuable insights into the in vivo fate of locally transplanted stem cells and a local delivery is effective to achieve desired dosages for neurological diseases.
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Background@#Left bundle branch area pacing (LBBAP) has emerged as a novel form of physiological pacing. However, few physicians have used stylet-driven pacing leads with a steerable delivery sheath for left fascicular bundle pacing.Case presentation A 75-year-old man with a history of heart valve surgery and atrial fibrillation arrived at the emergency department complaining of exertional dyspnea and general weakness. Twelve-lead electrocardiography showed atrial fibrillation with regular RR intervals with escape beats of 41 beats per minutes, which suggested complete atrioventricular block. Two-dimensional echocardiography showed global hypokinesia and a huge atrium. Given the impaired left ventricular (LV) function and the deleterious effects of right ventricular apical pacing, conduction system pacing was attempted. Mapping of His bundle and left bundle potential using a steerable delivery sheath was attempted; however, it did not appear prominent. Several attempts to deploy the lead failed because the sheath was malpositioned such that the lead could not move perpendicularly. Reshaping the sheath allowed for an extended reach so that the pacing lead could be positioned inferior to the previously attempted site toward the apex, deep inside the septum, where the distal left septal fascicle was captured rather than the left bundle branch trunk. During the 6-month follow-up period, the patient was free of any symptoms. Capture threshold and sensing value were stable and follow-up echocardiography showed slightly improved LV function. @*Conclusions@#Left fascicular bundle pacing may be an alternative strategy when conventional pacing using styletdriven pacing leads with a steerable delivery sheath fails to capture the left branch bundle in patients with challenging anatomy.
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Background/Aims@#Administrative databases provide valuable information for large-cohort studies. This study aimed to evaluate the diagnostic accuracy of an administrative database for resected gastric adenomas. @*Methods@#Data of patients who underwent endoscopic resection for benign gastric lesions were collected from three hospitals. Gastric adenoma cases were identified in the hospital database using International Classification of Diseases (ICD) 10-codes. The non-adenoma group included patients without gastric adenoma codes. The diagnostic accuracy for gastric adenoma was analyzed based on the pathological reports of the resected specimen. @*Results@#Among 5,095 endoscopic resections with codes for benign gastric lesions, 3,909 patients were included in the analysis. Among them, 2,831 and 1,078 patients were allocated to the adenoma and non-adenoma groups, respectively. Regarding the overall diagnosis of gastric adenoma with ICD-10 codes, the sensitivity, specificity, positive predictive value, and negative predictive value were 98.7%, 88.5%, 95.2%, and 96.8%, respectively. There were no significant differences in these parameters between the tertiary and secondary centers. @*Conclusions@#Administrative codes of gastric adenoma, according to ICD-10 codes, showed good accuracy and can serve as a useful tool to study prognosis of these patients in real-world data studies in the future.
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Purpose@#To examine the refractive errors, retinal manifestations, and genotype in tuberous sclerosis complex (TSC) patients in a Korean population. @*Materials and Methods@#A total of 98 patients with TSC were enrolled in Severance Hospital for a retrospective cohort study. The number of retinal astrocytic hamartoma and retinal achromic patch within a patient, as well as the size, bilaterality, and morphological type were studied. In addition, the refractive status of patients and the comorbidity of intellectual disability and epilepsy were also examined. @*Results@#Retinal astrocytic hamartoma was found in 37 patients, and bilateral invasion was observed in 20 patients (54%). TSC1 mutation was associated with myopia (p=0.01), while TSC2 mutation was associated with emmetropia (p=0.01). Retinal astrocytic hamartoma was categorized into three morphological types and examined as follows: type I (87%), type II (35%), and type III (14%). Single invasion of retinal astrocytic hamartoma was identified in 32% of the patients, and multiple invasions in 68%. The TSC1/ TSC2 detection rate was 91% (41/45). Among them, TSC1 variant was detected in 23 patients (54%), whereas TSC2 variant was detected in 18 patients (40%). The results showed that TSC2 mutations are correlated with a higher rate of retinal astrocytic hamartoma involvement (all p<0.05), and multiple and bilateral involvement of retinal hamartomas (all p<0.05). However, the size of retinal astrocytic hamartomas, comorbidity of epilepsy, or intellectual disability did not show correlation with the genetic variant. @*Conclusion@#TSC1 variant patients were more myopic, while TSC2 variant patients showed association with more extensive involvement of retinal astrocytic hamartoma.
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Chronic right ventricular (RV) pacing can exacerbate heart failure in patients with a low left ventricular ejection fraction (LVEF). Left bundle branch area pacing (LBBAP) has emerged as a novel physiological pacing technique; however, information remains limited on its use among patients with a low EF. This study investigated the safety and short-term clinical outcomes of LBBAP among patients with impaired left ventricular (LV) function. This retrospective analysis of pacemakers at Chosun University Hospital, South Korea, included all patients with impaired LV function (EF＜50%) who underwent pacemaker implantation for atrioventricular blockage from 2019-2022. Clinical characteristics, 12-lead electrocardiography findings, echocardiography findings, and laboratory parameters were evaluated. Composite outcomes were defined as all-cause mortality, cardiac death, and hospitalization due to heart failure during the 6-month follow-up. Altogether 57 patients (25 men; mean age, 77.4±10.8 y; LVEF, 41.5±3.8%) were divided into LBBAP (n=16), biventricular pacing (BVP; n=16), and conventional RV pacing (RVP; n=25) groups. In the LBBAP group, the mean paced QRS duration (pQRSd) was narrower (119.5±14.7 vs. 140.2±14.3 vs. 163.2±13.9; p＜0.001) and cardiac troponin I level was elevated post-pacing (1.14±1.29 vs. 0.20±0.29 vs.0.24±0.51, p=0.001). Lead parameters were stable. One patient was hospitalized, and four died (one patient each from heart failure admission, myocardial infarction, unexplained death, and pneumonia in RVP vs. one from intracerebral hemorrhage in BVP) during the follow-up period. In conclusion, LBBAP is feasible in patients with impaired LV function without acute or significant complications and provides a remarkably narrower pQRSd with a stable pacing threshold.
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A 76-year-old female visited the emergency department with complaining of dizziness and syncope. She had a history of paroxysmal atrial fibrillation (AF) and had been prescribed flecainide 50 mg and apixaban 5 mg 12-hourly in another hospital 1 day before the presentation. Upon admission, her electrocardiogram showed profound bradycardia and extremely long sinus arrest, which required temporary cardiac pacing. Within 24 hours, her intrinsic rhythm was restored, and the temporary pacemaker was removed. Transthoracic and transesophageal echocardiography revealed no structural heart disease or thrombus in the left atrial appendage. Cardiac computed tomography showed no coronary artery stenosis, but a pulmonary thrombus in the right pulmonary artery. She underwent an electrophysiology study, and four pulmonary vein (PV) isolations were attempted to treat the paroxysmal AF. A bidirectional PV conduction block was acquired in all PVs despite spontaneous dissociation of PV potential in the right PV. Programmed stimulation following ablation resulted in sinus node dysfunction. After the procedure, the patient did not complain of dizziness and syncope for 72 hours of telemetry monitoring. She was discharged with anticoagulant and did not show any further symptoms for 6 months. Flecainide acetate is a class Ic antiarrhythmics, and its clinical efficacy has been confirmed in several clinical trials. However, it can unmask sinus node dysfunction in asymptomatic patients with paroxysmal AF. Clinicians should screen candidates for sinus nodal diseases when prescribing flecainide.
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Background@#This study examined the relationship between alcohol consumption and total testosterone deficiency based on facial flushing among Korean men. @*Methods@#A total of 314 men were included in this study and divided into non-drinkers (n=78) and drinkers (n=236). Drinkers were also divided into flushers (n=96) and non-flushers (n=140). Flushers and non-flushers were separated into two groups based on the amount of alcohol consumed: moderate drinkers (≤8 standard drinks per week) and heavy drinkers (>8 standard drinks per week). Total testosterone 8 drinks per week) who flush compared to that in non-drinkers.
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Background@#Chronic right-ventricular (RV) pacing can exacerbate heart failure in patients with a low ejection fraction (EF). There is little information on the effects of diastolic dysfunction (DD) in patients with preserved EF undergoing permanent pacemaker (PPM) placement. We aimed to investigate the clinical outcomes in these patients. @*Methods@#This multicenter, retrospective analysis of PPM use in Chonnam, South Korea, included all patients with preserved EF undergoing transvenous PPM implantation for atrioventricular blockage from 2017 to 2019. Patients were divided into two groups according to DD, which were assessed by including mitral flow velocities (E′ velocity, E/E′ ratio), peak velocity of the tricuspid regurgitant, and left atrial maximum volume index. Composite outcomes were defined as (1) cardiovascular death, and (2) hospitalization by heart failure during the follow-up period. @*Results@#One hundred sixty-seven patients (66 men; overall mean age, 75.3 ± 11.9 years) were divided into two groups: 125 normal versus 42 DD. Compared with normal subjects, the DD group included older patients (mean age, 79.1 ± 9.9 vs. 74.0 ± 12.3; p = 0.016), and had longer paced QTc interval (pQTc, 168.5 ± 20.1 vs. 159.1 ± 16.3 ms; p < 0.001). Fifteen patients were hospitalized and two died. In a Cox proportional regression analysis, DD (hazard ratio [HR], 7.343; 95% confidence interval [CI], 2.035–26.494; p = 0.002) and pQRSd (HR, 1.046; 95% CI, 1.004–1.091; p = 0.033) were independent predictors of composite outcomes. @*Conclusion@#In patients with DD, RV pacing raised the risk of pacing-induced heart failure despite preserved leftventricular function. Thus, patients with DD should be monitored intensively.
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Background/Aims@#Globally, the population aged 80 years or older is growing faster due to the rising life expectancy. Korea has already entered into an advanced aged society, and a post-aged society is expected in 2025. This study evaluated the patterns of gastrointestinal disease in the population aged 80 years or older during the recent decade in Korea.Method: This study retrospectively reviewed the medical records of patients admitted to the gastrointestinal department of Suwon St. Vincent’s hospital, Incheon St. Mary’s hospital, and Uijeongbu St. Mary's Hospital ― general hospitals of Seoul-Gyeonggi province in Korea. It was a repeated cross-sectional study in 2009 and 2019. @*Results@#The number of admitted patients aged 80 years or older increased from 549 (9.0%) in 2009 to 1,073 (14.4%) in 2019 (p<0.01). As for the in-hospital mortality, there was no significant difference (p=0.25). On the other hand, the combined morbidities increased, and the duration of admission also increased (7.2±7.8 days vs. 8.1±8.2 days, p=0.03). The number of upper gastrointestinal hemorrhage and patients who are bleeding associated with drugs users increased (p<0.01). The proportion of lower gastrointestinal disease decreased (p<0.01) because of the decrease in procedure-related admissions (p<0.01). The number of those with pancreaticobiliary tract disease increased markedly (p<0.01), and the rate of cases that could not perform the procedure decreased (p=0.04). @*Conclusion@#The patterns of gastrointestinal disease in the population aged 80 years or older have changed in the recent decade in Korea. Hence, more preparation for this medical environment is needed.
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Purpose@#To evaluate the therapeutic effects and safety of oral spironolactone (SPRL) in patients with central serous chorioretinopathy (CSC). @*Materials and Methods@#The medical records and imaging data of patients diagnosed with CSC and treated with SPRL were retrospectively reviewed. Central macular thickness (CMT), subretinal fluid (SRF) height, subfoveal choroidal thickness (SFCT), and best-corrected visual acuity (BCVA) at baseline, at 1, 3, and 6 months, and at the last visit after the treatment were analyzed. @*Results@#In total, 103 patients with 107 eyes were included. The mean age of the patients was 51.5±9.3 years, and 77 (72.0%) were male. The mean follow-up duration was 48.6±40.2 weeks. The mean duration of oral SPRL therapy was 15.5±13.4 weeks. CMT, SRF height, and SFCT improved significantly at 1, 3, and 6 months after SPRL therapy and at the last follow-up. BCVA, however, showed no significant change at any time point. The rate of complete resolution of SRF at 1 month was higher in those with chronic CSC than in those with acute CSC (21.1% vs. 6.0%, respectively). Recurrence occurred in 14 (13.1%) eyes after the complete resolution of SRF. Older age (p=0.001), a greater number of previous intravitreal bevacizumab injections (p=0.006), and poor initial visual acuity (p=0.048) were associated with recurrence. No permanent adverse effects were observed. @*Conclusion@#Oral SPRL showed therapeutic benefits in patients with CSC in terms of SRF resolution, but relatively frequent recurrence was observed, especially in older patients.
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Background/Aims@#While switching strategies of P2Y12 receptor inhibitors (RIs) have sometimes been used in acute myocardial infarction (AMI) patients, the current status of in-hospital P2Y12RI switching remains unknown. @*Methods@#Overall, 8,476 AMI patients who underwent successful revascularization from Korea Acute Myocardial Infarction Registry-National Institute of Health (KAMIR-NIH) were divided according to in-hospital P2Y12RI strategies, and net adverse cardiovascular events (NACEs), defined as a composite of cardiac death, non-fatal myocardial infarction (MI), stroke, or thrombolysis in myocardial infarction (TIMI) major bleeding during hospitalization were compared. @*Results@#Patients with in-hospital P2Y12RI switching accounted for 16.5%, of which 867 patients were switched from clopidogrel to potent P2Y12RI (C-P) and 532 patients from potent P2Y12RI to clopidogrel (P-C). There were no differences in NACEs among the unchanged clopidogrel, the unchanged potent P2Y12RIs, and the P2Y12RI switching groups. However, compared to the unchanged clopidogrel group, the C-P group had a higher incidence of non-fatal MI, and the P-C group had a higher incidence of TIMI major bleeding. In clinical events of in-hospital P2Y12RI switching, 90.9% of non-fatal MI occurred during pre-switching clopidogrel administration, 60.7% of TIMI major bleeding was related to pre-switching P2Y12RIs, and 71.4% of TIMI major bleeding was related to potent P2Y12RIs. Only 21.6% of the P2Y12RI switching group switched to P2Y12RIs after a loading dose (LD); however, there were no differences in clinical events between patients with and without LD. @*Conclusions@#In-hospital P2Y12RI switching occurred occasionally, but had relatively similar clinical outcomes compared to unchanged P2Y12RIs in Korean AMI patients. Non-fatal MI and bleeding appeared to be mainly related to pre-switching P2Y12RIs.
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Purpose@#To investigate the interocular difference of axial length (AL), mean keratometry (K), corneal astigmatism and anterior chamber depth (ACD) according to AL without history of ocular surgery. @*Methods@#This study was performed on 16,411 patients (32,825 eyes) who were measured AL, K, corneal astigmatism and ACD by IOL Master® from April 2007 to September 2016, excluding patients with missing values and extreme values in AL. After, patients were divided into four groups based on AL; AL < 24 mm, 24 mm ≤ AL < 26 mm, 26 mm ≤ AL < 28 mm, AL ≥ 28 mm, we investigated which variables were associated according to AL. To compensate for age and sex, 1:1:1:1 random matching was performed for age and sex. @*Results@#The longer the average AL of both eyes, the greater the difference between the AL, ACD and mean corneal K of both eyes. The longer AL group had the deeper ACD, the flatter mean corneal K, the higher corneal astigmatism. The older age group had the more shallow ACD, the steeper mean corneal K, lower corneal astigmatism. @*Conclusions@#Ophthalmologists have to be careful in setting fellow eye as control in treating or studying patients with long AL or axial myopia. Because, the longer the average AL of both eyes, the greater the difference between the AL, the ACD and the mean corneal K of both eyes.
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Purpose@#This study aimed to investigate the relationship between femoral offset (FO) and clinical outcomes of patients with femoral neck fracture following bipolar hip arthroplasty (BHA). @*Materials and Methods@#Records for a total of 520 patients who underwent BHA for a femoral neck fracture between December 1, 2003, and September 30, 2018, were reviewed retrospectively. Patients with unclear medical records, a congenital deformity and preoperative trauma history of the hip, high-energy multiple trauma, or a history of neurodegenerative disease or cerebrovascular disease were excluded. The remaining 77 patients included in the analysis had a minimum follow-up period of one year. For clinical assessment, the postoperative pain visual analogue scale (VAS) and Harris hip score (HHS) were analyzed at each follow-up period. For radiological assessment, the difference in leg length discrepancy (LLD) and FO were measured. @*Results@#The difference in mean FO postoperatively was 6.7±4.8 mm, and the difference in mean postoperative LLD was 4.9±3.4 mm. The mean HHS was 77.1±7.7, 82.3±8.6, 83.4±7.7, and 86.4±6.7 at 1, 3, 6, and 12 months postoperative, respectively. The correlation coefficient between FO and HHS in 1-year follow-up was –0.38, and a statistically significant outcome was found (P=0.001). For the HHS domain, the correlation coefficient for function at 1-year follow-up was –0.42, revealing a statistically significant outcome (P=0.0001). @*Conclusion@#There was a statistically significant correlation between clinical outcomes and FO difference at 1 year after BHA in patients over 65 years of age with femoral neck fractures.
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Objective@#High disease activity of ankylosing spondylitis (AS) is associated with poor sleep quality. The purpose of this study was to identify which of the representative tools for evaluating the disease activity of AS best reflect the quality of sleep. @*Methods@#A total of 107 AS patients were enrolled in the study and the sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). Age, sex, concomitant medication, erythrocyte sedimentation rate (ESR), serum C-reactive protein (CRP) level, Beck Depression Inventory second edition (BDI-II), Bath ankylosing spondylitis disease activity index (BASDAI), ankylosing spondylitis disease activity score (ASDAS)-ESR, ASDAS-CRP, pain visual analog scale, Insomnia Severity Index (ISI), and Epworth Sleepiness Scale (ESS) were analyzed as covariates. @*Results@#Overall, 65% (70/107) of subjects reported poor sleep quality (PSQI＞5). There was a positive correlation between the sleep quality and disease activity as measured by the BASDAI, ASDAS-ESR, and ASDAS-CRP. In addition, the BASDAI demonstrated good correlations with ISI, ESS, and BDI-II, respectively. However, only BASDAI showed reliable correlation with PSQI among the disease activity parameters of AS (adjusted odd ratio 5.36, p=0.023). @*Conclusion@#BASDAI is the most reliable parameter of disease activity associated with the sleep quality in patients with AS.
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Background@#Patient-centered management is becoming increasingly important in gout, but there are limited studies exploring patients' perspectives and preferences. We aimed to investigate patients' perspectives and preferences regarding gout and gout management, and their impacts on adherence to urate lowering therapy (ULT). @*Methods@#A paper-based survey was performed in patients with gout seen at the rheumatology outpatient clinics of 16 tertiary hospitals. The survey included questions regarding demographics, comorbidities, gout attacks, current treatment and adherence, and patients' perspectives and preferences regarding gout and gout management. Multivariate regression analysis was performed to determine the factors associated with ULT adherence. @*Results@#Of 809 surveyed patients with gout, 755 (94.5%) were using ULT. Among those using ULT, 89.1% had ≥ 80% adherence to ULT. Majority of the patients knew management strategies to some extent (94.8%), perceived gout as a life-long disease (91.2%), and were making efforts toward practicing at least one lifestyle modification (89.2%). Most patients (71.9%) obtained information about gout management during their clinic visits.Approximately half of the patients (53.6%) preferred managing their disease with both ULT and lifestyle modification, 28.4% preferred ULT only, and 17.4% preferred lifestyle modification only. Adherence was better in patients with older age (odds ratio [OR], 1.03), those with better knowledge of gout management strategies (OR, 3.56), and those who had preference for ULT (OR, 2.07). @*Conclusion@#Patients' perspectives and management preferences had high impacts on adherence to ULT in gout. Consideration of patients' perspectives and preferences is important for achieving the desired clinical outcome in gout.
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The inducible Cre-loxP system provides a useful tool for inducing the selective deletion of genes that are essential for proper development and enables the study of gene functions in properly developed animals. Here, we show that inducible Cre-loxP driven by the Gli1-promoter can induce cell-type-specific deletion of target genes in cerebellar cortical neurons. We used reporter mice containing the YFP (yellow fluorescence protein) gene at the Gt(ROSA)26Sor locus with a loxP -flanked transcriptional stop sequence, in which successful Cre-mediated excision of the stop sequence is indicated by YFP expression in Cre-expressing cells. Administration of tamoxifen during early postnatal days (P4~7) induces Cre-dependent excision of stop sequences and allows YFP expression in proliferating neuronal progenitor cells in the external granule layer and Bergmann glia in the Purkinje cell layer. A substantial number of YFP-positive progenitor cells in the external granule layer migrated to the internal granule cell layer and became granule cell neurons. By comparison, injection of tamoxifen during late postnatal days (P19~22) induces YFP expression only in Bergmann glia, and most granule cell neurons were devoid of YFP expression. The results indicate that the Gli1 promoter is temporarily active in progenitor cells in the external granule layer during the early postnatal period but constitutively active in Bergmann glia. We propose that the Gli1-mediated CreER system can be applied for the conditional deletion of genes of interest from cerebellar granule cell neurons and/or Bergmann glia.
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Following acute myocardial infarction (AMI), early use of beta-blockers (BBs) reduced the incidences of ventricular arrhythmia (VA) and death in the pre reperfusion era.However, some studies have reported a worsening of clinical outcomes and therefore, this study used a porcine model of AMI to evaluate the efficacy of bisoprolol on VAs and mortality. Twenty pigs were divided into two groups with one group using oral bisoprolol which was given for 3 hours before the experiment and then maintained for 7 days. A loop recorder was implanted, AMI was induced by balloon occlusion for 60 min, and then, reperfusion. One week later, the echocardiography and loop recorder data were analyzed in the surviving animals. Bisoprolol did not increase the heart rate (62.9±14.5 vs 79.0±20.3; p=0.048), lower the rate of premature ventricular contractions (PVC) (0.8±0.8 vs 11.0±12.8; p=0.021) or tend to lower recurrent VA (0.6±0.5 vs 1.1±1.1;p=0.131) during coronary artery occlusion. After reperfusion, bisoprolol did reduce VA in the early AMI period (0.1±0.3 vs 4.2±4.6; p=0.001) and it was not associated with the extent of myocardial recovery. In this porcine model, early oral bisoprolol might help reduce the incidences of PVC and recurrent VA and determine whether effects are more pronounced during the early AMI period. Our results suggest that bisoprolol might help reduce lethal VA and cardiac death following AMI in this reperfusion era.
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The sleep-wake cycle is regulated by the alternating activity of sleep- and wake-promoting neurons. The dorsal raphe nucleus (DRN) secretes 5-hydroxytryptamine (5-HT, serotonin), promoting wakefulness. Melatonin secreted from the pineal gland also promotes wakefulness in rats. Our laboratory recently demonstrated that daily changes in nitric oxide (NO) production regulates a signaling pathway involving with-no-lysine kinase (WNK), Ste20-related proline alanine rich kinase (SPAK)/oxidative stress response kinase 1 (OSR1), and cation-chloride co-transporters (CCC) in rat DRN serotonergic neurons. This study was designed to investigate the effect of melatonin on NO-regulated WNK-SPAK/OSR1-CCC signaling in wake-inducing DRN neurons to elucidate the mechanism underlying melatonin’s wake-promoting actions in rats. Ex vivo treatment of DRN slices with melatonin suppressed neuronal nitric oxide synthase (nNOS) expression and increased WNK4 expression without altering WNK1, 2, or 3. Melatonin increased phosphorylation of OSR1 and the expression of sodium-potassium-chloride co-transporter 1 (NKCC1), while potassium-chloride cotransporter 2 (KCC2) remained unchanged. Melatonin increased the expression of tryptophan hydroxylase 2 (TPH2, serotonin-synthesizing enzyme). The present study suggests that melatonin may promote its wakefulness by modulating NO-regulated WNK-SPAK/OSR1-KNCC1 signaling in rat DRN serotonergic neurons.