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Objective: A significant number of patients experience early recurrence after surgical resection for pancreatic ductal adenocarcinoma (PDAC), negating the benefit of surgery. The present study conducted clinicopathologic and metabolomic analyses to explore the factors associated with the early recurrence of PDAC., Materials and Methods: Patients who underwent pancreatectomy for PDAC at Kagawa University Hospital between 2011 and 2020 were enrolled. Tissue samples of PDAC and nonneoplastic pancreas were collected and frozen immediately after resection. Charged metabolites were quantified by capillary electrophoresis-mass spectrometry. Patients who relapsed within 1 year were defined as the early recurrence group., Results: Frozen tumor tissue and nonneoplastic pancreas were collected from 79 patients. The clinicopathologic analysis identified 11 predictive factors, including preoperative carbohydrate antigen 19-9 levels. The metabolomic analysis revealed that only hypotaurine was a significant risk factor for early recurrence. A multivariate analysis, including clinical and metabolic factors, showed that carbohydrate antigen 19-9 and hypotaurine were independent risk factors for early recurrence ( P = 0.045 and P = 0.049, respectively). The recurrence-free survival rate 1 year after surgery with both risk factors was only 25%., Conclusions: Our results suggested that tumor hypotaurine is a potential metabolite associated with early recurrence. Carbohydrate antigen 19-9 and hypotaurine showed a vital utility for predicting early recurrence., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

No accepted standard for the correction of medial ectropion has been established. The most critical part of the surgical treatment for medial ectropion is the tightening of both horizontal and vertical laxity. To correct this ectropion, we have applied a combination procedure which includes tightening of the conjunctiva and the eyelid retractors (posterior lamellae) and the lateral tarsal strip procedure. Our imitation of the 'Lazy-T', a surgical operation performed on the medial ectropion, is tentatively named 'Invisible Lazy-T'. It is a versatile technique with a less visible scar than alternative techniques because skin incision is made along the crease line of the 'the crow's feet'. Results suggest a satisfactory solution to this problem and with better outcomes than by other techniques. We propose this novel combination technique is the best strategy for the medial ectropion, and it does not require specialized surgical skill, so ectropion can be managed by craniofacial surgeons., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by Mutaz B. Habal, MD.)

Background: Rare protein-altering variants in SCN5A , KCNQ1 , and KCNH2 are major causes of Brugada syndrome and the congenital long QT syndrome. While splice-altering variants lying outside 2-bp canonical splice sites can cause these diseases, their role remains poorly described. We implemented 2 functional assays to assess 12 recently reported putative splice-altering variants of uncertain significance and 1 likely pathogenic variant without functional data observed in Brugada syndrome and long QT syndrome probands., Methods: We deployed minigene assays to assess the splicing consequences of 10 variants. Three variants incompatible with the minigene approach were introduced into control induced pluripotent stem cells by CRISPR genome editing. We differentiated cells into induced pluripotent stem cell-derived cardiomyocytes and studied splicing outcomes by reverse transcription-polymerase chain reaction. We used the American College of Medical Genetics and Genomics functional assay criteria (PS3/BS3) to reclassify variants., Results: We identified aberrant splicing, with presumed disruption of protein sequence, in 8/10 variants studied using the minigene assay and 1/3 studied in induced pluripotent stem cell-derived cardiomyocytes. We reclassified 8 variants of uncertain significance to likely pathogenic, 1 variant of uncertain significance to likely benign, and 1 likely pathogenic variant to pathogenic., Conclusions: Functional assays reclassified splice-altering variants outside canonical splice sites in Brugada Syndrome- and long QT syndrome-associated genes.

Background: The adherence to home exercise is generally low despite its well-known effect on knee osteoarthritis. Therefore, we developed a home exercise application, LongLifeSupport, to provide patients with daily basic exercise videos and an automatic recording calendar. We hypothesized that this application would encourage patients to exercise and help maintain their motivation; this pilot study aimed to determine their exercise adherence rates. Using outcome measures, we also aimed to determine the effect of home exercise using this application and the factors for its continuation., Methods: Twenty patients with knee osteoarthritis were included. The participants exercised for 12 weeks. Using pre- and post-tests, we examined their satisfaction with continuation (only in the post-test), Japanese knee osteoarthritis measure score, short physical performance battery score, bilateral knee extension muscle strength, and short test battery for locomotive syndrome. Furthermore, we investigated correlations between adherence rates and pretest scores of Japanese knee osteoarthritis measure and short test battery and between pretest scores and variations in Japanese knee osteoarthritis measure and short test battery., Results: The mean adherence rate was 82.4%. The participants showed ease of continuation (100%) and significant improvements in the degree of knee pain, pain, and stiffness, and daily life conditions using the Japanese knee osteoarthritis measure score, total score, walk seconds, and chair stand seconds of the short physical performance battery, as well as the extension muscle strength of the right- and pain-side knee. No significant correlations were identified between the adherence rate and the pretest or variation., Conclusion: The adherence rate to the application was over 80%. Participants with knee osteoarthritis showed almost full satisfaction, reduced pain, and improved physical ability. Therefore, the use of this application provided a safe exercise program and maintained the exercise motivation of participants. Thus, it may be useful for unsupervised home exercise., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Sequencing Mendelian arrhythmia genes in individuals without an indication for arrhythmia genetic testing can identify carriers of pathogenic or likely pathogenic (P/LP) variants. However, the extent to which these variants are associated with clinically meaningful phenotypes before or after return of variant results is unclear. In addition, the majority of discovered variants are currently classified as variants of uncertain significance, limiting clinical actionability., Methods: The eMERGE-III study (Electronic Medical Records and Genomics Phase III) is a multicenter prospective cohort that included 21 846 participants without previous indication for cardiac genetic testing. Participants were sequenced for 109 Mendelian disease genes, including 10 linked to arrhythmia syndromes. Variant carriers were assessed with electronic health record-derived phenotypes and follow-up clinical examination. Selected variants of uncertain significance (n=50) were characterized in vitro with automated electrophysiology experiments in HEK293 cells., Results: As previously reported, 3.0% of participants had P/LP variants in the 109 genes. Herein, we report 120 participants (0.6%) with P/LP arrhythmia variants. Compared with noncarriers, arrhythmia P/LP carriers had a significantly higher burden of arrhythmia phenotypes in their electronic health records. Fifty-four participants had variant results returned. Nineteen of these 54 participants had inherited arrhythmia syndrome diagnoses (primarily long-QT syndrome), and 12 of these 19 diagnoses were made only after variant results were returned (0.05%). After in vitro functional evaluation of 50 variants of uncertain significance, we reclassified 11 variants: 3 to likely benign and 8 to P/LP., Conclusions: Genome sequencing in a large population without indication for arrhythmia genetic testing identified phenotype-positive carriers of variants in congenital arrhythmia syndrome disease genes. As the genomes of large numbers of people are sequenced, the disease risk from rare variants in arrhythmia genes can be assessed by integrating genomic screening, electronic health record phenotypes, and in vitro functional studies., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier; NCT03394859.

Background: Multiple reports associate the cardiac sodium channel gene ( SCN5A ) variants S1103Y and R1193Q with type 3 congenital long QT syndrome and drug-induced long QT syndrome. These variants are too common in ancestral populations to be highly arrhythmogenic at baseline, however: S1103Y allele frequency is 8.1% in African Americans and R1193Q 6.1% in East Asians. R1193Q is known to increase late sodium current ( I Na-L ) in cardiomyocytes derived from induced pluripotent stem cells but the role of these variants in modulating repolarization remains poorly understood., Methods: We determined the effect of S1103Y on QT intervals among African-American participants in a large electronic health record. Using cardiomyocytes derived from induced pluripotent stem cells carrying naturally occurring or genome-edited variants, we studied action potential durations (APDs) at baseline and after challenge with the repolarizing potassium current ( I Kr ) blocker dofetilide and I Na-L and I Kr at baseline., Results: In 1479 African-American participants with no confounding medications or diagnoses of heart disease, QT intervals in S1103Y carriers was no different from that in noncarriers. Baseline APD was no different in cells expressing the Y allele (SY, YY cells) compared with isogenic cells with the reference allele (SS cells). However, I Na-L was increased in SY and YY cells and the I Na-L blocker GS967 shortened APD in SY/YY but not SS cells ( P <0.001). I Kr was increased almost 2-fold in SY/YY cells compared with SS cells (tail current: 0.66±0.1 versus 1.2±0.1 pA/pF; P <0.001). Dofetilide challenge prolonged APD at much lower concentrations in SY (4.1 nmol/L [interquartile range, 1.5-9.3]; n=11) and YY (4.2 nmol/L [1.7-5.0]; n=5) than in SS cells (249 nmol/L [22.3-2905]; n=14; P <0.001 and P <0.01, respectively) and elicited afterdepolarizations in 8/16 SY/YY cells but only in 1/14 SS cells. R1193Q cells similarly displayed no difference in baseline APD but increased I Kr and increased dofetilide sensitivity., Conclusions: These common ancestry-specific variants do not affect baseline repolarization, despite generating increased I Na-L . We propose that increased I Kr serves to maintain normal repolarization but increases the risk of manifest QT prolongation with I Kr block in variant carriers. Our findings emphasize the need for inclusion of diverse populations in the study of adverse drug reactions.

Objective: To examine the validity of head roll-tilt subjective visual vertical (HT-SVV) in diagnosing persistent postural-perceptual dizziness (PPPD)., Study Design: Retrospective review., Setting: Tertiary referral center., Patients: Sixty-one patients with PPPD, 10 with unilateral vestibular hypofunction (UVH), and 11 with psychogenic dizziness (PD), showing chronic vestibular symptoms for >3 months., Interventions: Head-tilt perception gain (HTPG, i.e., mean perceptual gain [perceived/actual tilt angle]) during right or left head tilt of approximately 30° (HT-SVV) and conventional head-upright SVV (UP-SVV) were measured. Bithermal caloric testing, cervical and ocular vestibular-evoked myogenic potentials (cVEMP and oVEMP), and posturography were conducted., Main Outcome Measures: Multiple comparisons were performed for the HT-SVV and other vestibular tests among the disease groups. A receiver operating characteristic curve was created to predict PPPD using HTPG., Results: HTPG was significantly greater in the PPPD group than in the UVH and PD groups. There were no significant differences in UP-SVV, cVEMP, oVEMP, and posturography (foam ratio and Romberg ratio on foam) among the disease groups, while the UVH group had the highest canal paresis compared to the other two groups. The area under the curve of the receiver operating characteristic curve for predicting PPPD was 0.764, and the HTPG value of 1.202 had a specificity of 95.2% for diagnosing PPPD., Conclusions: While conventional vestibular tests including UP-SVV, VEMPs, and posturography did not show abnormalities in PPPD, high HTPG in the HT-SVV test, an excessive perception of head tilt, can be a specific marker for discriminating PPPD from other chronic vestibular diseases., Competing Interests: The authors disclose no conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of Otology & Neurotology, Inc.)

Abstract: Recently, activities of daily living (ADL) were identified as a prognostic factor among elderly patients with heart disease; however, a specific association between ADL and prognosis after cardiac and aortic surgery is not well established. We aimed to clarify the impact of ADL capacity at discharge on prognosis in elderly patients after cardiac and aortic surgery.This retrospective cohort study included 171 elderly patients who underwent open operation for cardiovascular disease in a single center (median age: 74 years; men: 70%). We used the Barthel Index (BI) as an indicator for ADL. Patients were classified into 2 groups according to the BI at discharge, indicating a high (BI ≥ 85) or low (BI < 85) ADL status. All-cause mortality and unplanned readmission events were observed after discharge.Thirteen all-cause mortality and 44 all-cause unplanned readmission events occurred during the median follow-up of 365 days. Using Kaplan-Meier analysis, a low ADL status was determined to be significantly associated with all-cause mortality and unplanned readmission. In the multivariable Cox proportional hazard models, a low ADL status was an independent predictor of all-cause mortality and unplanned readmission after adjusting for age, sex, length of hospital stay, and other variables (including preoperative status, surgical parameter, and postoperative course).A low ADL status at discharge predicted all-cause mortality and unplanned readmission in elderly patients after cardiac and aortic surgery. A comprehensive approach from the time of admission to postdischarge to improve ADL capacity in elderly patients undergoing cardiac and aortic surgery may improve patient outcomes., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The proliferation of genetic profiling has revealed many associations between genetic variations and disease. However, large-scale phenotyping efforts in largely healthy populations, coupled with DNA sequencing, suggest variants currently annotated as pathogenic are more common in healthy populations than previously thought. In addition, novel and rare variants are frequently observed in genes associated with disease both in healthy individuals and those under suspicion of disease. This raises the question of whether these variants can be useful predictors of disease. To answer this question, we assessed the degree to which the presence of a variant in the cardiac potassium channel gene KCNH2 was diagnostically predictive for the autosomal dominant long QT syndrome., Methods: We estimated the probability of a long QT diagnosis given the presence of each KCNH2 variant using Bayesian methods that incorporated variant features such as changes in variant function, protein structure, and in silico predictions. We call this estimate the posttest probability of disease. Our method was applied to over 4000 individuals heterozygous for 871 missense or in-frame insertion/deletion variants in KCNH2 and validated against a separate international cohort of 933 individuals heterozygous for 266 missense or in-frame insertion/deletion variants., Results: Our method was well-calibrated for the observed fraction of heterozygotes diagnosed with long QT syndrome. Heuristically, we found that the innate diagnostic information one learns about a variant from 3-dimensional variant location, in vitro functional data, and in silico predictors is equivalent to the diagnostic information one learns about that same variant by clinically phenotyping 10 heterozygotes. Most importantly, these data can be obtained in the absence of any clinical observations., Conclusions: We show how variant-specific features can inform a prior probability of disease for rare variants even in the absence of clinically phenotyped heterozygotes.

Objective: Several software-based quantitative computed tomography (CT) analysis methods have been developed for assessing emphysema and interstitial lung disease. Although the texture classification method appeared to be more successful than the other methods, the software programs are not commercially available, to our knowledge. Therefore, this study aimed to investigate the usefulness of a commercially available software program for quantitative CT analyses., Methods: This prospective cohort study included 80 patients with chronic obstructive pulmonary disease (COPD) or idiopathic pulmonary fibrosis (IPF)., Results: The percentage of low attenuation volume and high attenuation volume had high sensitivity and high specificity for detecting emphysema and pulmonary fibrosis, respectively. The percentage of diseased lung volume (DLV%) was significantly correlated with the lung diffusion capacity for carbon monoxide in all patients with COPD and IPF patients., Conclusions: The quantitative CT analysis may improve the precision of the assessment of DLV%, which itself could be a useful tool in predicting lung diffusion capacity in patients with the clinical diagnosis of COPD or IPF., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Abstract: In principle, reconstruction in macrostomia requires symmetry and accurate positioning of the newly reconstructed commissure. The proper position of the new commissure can be determined by several methods. In the determination of the new commissure of bilateral cases, generally the average length of the lips or the distance from anatomical landmarks other than the lips, such as the pupils or tragi, has been used. A new approach was reported by Tse et al in 2018: the anatomic approximation approach. Macrostomia repair refers to anatomical landmarks in the lips to determine the new commissure. The authors performed surgery using this anatomic approximation approach for bilateral macrostomia and achieved the good results., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by Mutaz B. Habal, MD.)

Competing Interests: The authors have no funding and conflicts of interests to disclose.

Purpose: The aim of this study was to investigate advantages of the left-handed ultrasonic shears technique in robotic gastrectomy for gastric cancer., Methods: We retrospectively analyzed 67 consecutive gastric cancer patients who underwent robotic gastrectomy. Fifty-six patients underwent gastrectomy with the left-handed ultrasonic shears technique (the left hand group), and 11 patients underwent surgery with the conventional approach (the conventional group). Intraoperative and postoperative outcomes were compared between the 2 groups., Results: Operative blood loss, morbidity, and mortality were similar between the 2 groups. We observed a trend toward a shorter operation time and higher number of retrieved lymph nodes in the left hand group compared with the conventional group. Console time (docking-gastrectomy) in the left hand group was significantly shorter than in the conventional group (192.20 vs. 218.36 min, P<0.05). In robotic distal gastrectomy, both operation time and console time in the left hand group were significantly shorter than in the conventional group (276.10 vs. 354.80 min, 176.43 vs. 209.20 min, P<0.05 for both). The postoperative intra-abdominal infectious complication (Clavien Dindo≥1) rate in the left hand group was significantly lower than that in the conventional group (0% vs. 20%, P<0.05)., Conclusions: Use of the left-handed ultrasonic shears technique is safe and provides a technically superior operative environment with satisfactory postoperative results., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: We aimed to determine whether responsive insulin-producing cells (IPCs) could be generated from adipose-derived stem cells (ADSCs) isolated from patients with type 1 diabetes mellitus (T1DM)., Methods: We isolated ADSCs from adipose tissue of 4 patients (one patient with T1DM and 3 nondiabetic patients), who underwent surgery and differentiated them into IPCs with using a 2-step xeno-antigen free, 3-dimensional culture method. Characteristics of isolated ADSCs, in vitro cell quality, programmed cell death ligand-1 (PDL-1) expression, and transplantation into streptozotocin induced diabetic nude mice were investigated., Results: Adipose-derived stem cells from T1DM patients and commercially obtained ADSCs showed the same surface markers; CD31CD34CD45CD90CD105CD146. Moreover, the generated IPCs at day 21 demonstrated appropriate autonomous insulin secretion (stimulation index, 3.5; standard deviation, 0.8). Nonfasting blood glucose concentrations of IPC-transplanted mice were normal at 30 days. The normalized rate of IPC-transplanted mice was significantly higher than that of the sham-operated group (P < 0.05). Insulin-producing cells generated from T1DM adipose tissue expressed high levels of PDL-1., Conclusions: Insulin-producing cells obtained from adipose tissue of T1DM patients are capable of secreting insulin long-term and achieve normoglycemia after transplantation. Expression of PDL-1 suggests the potential for immune circumvention.

Purpose of Review: Human milk contains a variety of bioactive proteins, and some of the bioactivities are exerted only after proteins are digested in the gastrointestinal tract. This review aims to overview recent studies on bioactive peptides in human milk and gastric digesta of breast-fed infants., Recent Findings: Milk protein-derived peptides are endogenously present in human milk, and some of them have been reported to be bioactive peptides, such as a homologue of caseinophosphopeptide, an antimicrobial peptide, and an immunomodulatory peptide. A larger number of peptides are identified in gastric aspirates from breast-fed infants, and bioactive peptides such as angiotensin I-converting enzyme-inhibitory peptides, an antioxidative peptide, opioid agonist peptides are only found in the digesta of human milk but not in human milk per se. Casein is the greatest source of released bioactive peptides., Summary: Technological advances have considerably increased our capability to identify and characterize peptides derived from human milk proteins. However, their physiological significance and the roles of these bioactive peptides in growth and development of breast-fed infants have not yet been sufficiently elucidated, and further in-vivo experiments and clinical trials are warranted.

Background: Risk stratification in catecholaminergic polymorphic ventricular tachycardia remains ill defined. Heart rate recovery (HRR) immediately after exercise is regulated by autonomic reflexes, particularly vagal tone, and may be associated with symptoms and ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. Our objective was to evaluate whether HRR after maximal exercise on the exercise stress test (EST) is associated with symptoms and ventricular arrhythmias., Methods: In this retrospective observational study, we included patients ≤65 years of age with an EST without antiarrhythmic drugs who attained at least 80% of their age- and sex-predicted maximal HR. HRR in the recovery phase was calculated as the difference in heart rate (HR) at maximal exercise and at 1 minute in the recovery phase (ΔHRR1')., Results: We included 187 patients (median age, 36 years; 68 [36%] symptomatic before diagnosis). Pre-EST HR and maximal HR were equal among symptomatic and asymptomatic patients. Patients who were symptomatic before diagnosis had a greater ΔHRR1' after maximal exercise (43 [interquartile range, 25-58] versus 25 [interquartile range, 19-34] beats/min; P <0.001). Corrected for age, sex, and relatedness, patients in the upper tertile for ΔHRR1' had an odds ratio of 3.4 (95% CI, 1.6-7.4) of being symptomatic before diagnosis ( P <0.001). In addition, ΔHRR1' was higher in patients with complex ventricular arrhythmias at EST off antiarrhythmic drugs (33 [interquartile range, 22-48] versus 27 [interquartile range, 20-36] beats/min; P =0.01). After diagnosis, patients with a ΔHRR1' in the upper tertile of its distribution had significantly more arrhythmic events as compared with patients in the other tertiles ( P =0.045)., Conclusions: Catecholaminergic polymorphic ventricular tachycardia patients with a larger HRR following exercise are more likely to be symptomatic and have complex ventricular arrhythmias during the first EST off antiarrhythmic drug.

Background: Variants in ion channel genes have classically been studied in low throughput by patch clamping. Deep mutational scanning is a complementary approach that can simultaneously assess function of thousands of variants., Methods: We have developed and validated a method to perform a deep mutational scan of variants in SCN5A , which encodes the major voltage-gated sodium channel in the heart. We created a library of nearly all possible variants in a 36 base region of SCN5A in the S4 voltage sensor of domain IV and stably integrated the library into HEK293T cells., Results: In preliminary experiments, challenge with 3 drugs (veratridine, brevetoxin, and ouabain) could discriminate wild-type channels from gain- and loss-of-function pathogenic variants. High-throughput sequencing of the pre- and postdrug challenge pools was used to count the prevalence of each variant and identify variants with abnormal function. The deep mutational scan scores identified 40 putative gain-of-function and 33 putative loss-of-function variants. For 8 of 9 variants, patch clamping data were consistent with the scores., Conclusions: These experiments demonstrate the accuracy of a high-throughput in vitro scan of SCN5A variant function, which can be used to identify deleterious variants in SCN5A and other ion channel genes.

A surgical approach to zygomaticomaxillary complex (ZMC) fracture has not been standardized. The authors reviewed 15 cases of ZMC fractures treated with the swinging eyelid approach and evaluated the effectiveness of the technique by an observational study of Japanese patients. Results were assessed from authentic and functional perspectives: the presence of entropion/ectropion, external canthal malposition and chemosis of the conjunctiva. After a minimum follow-up of 10 months, no patients had lower eyelid ectropion, entropion or retraction. Wounds appeared inconspicuous, and a lateral canthal shape was preserved. No post-operative chemosis of the conjunctiva was observed. Each case was evaluated based on patient satisfaction about their aesthetic outcomes. Patient self-assessment is classified into 4 groups (excellent, good, fair, and unsatisfactory). Thirteen patients were assessed to have an "excellent" outcome, and 2 patients were assessed to have a "good" outcome. No patients had "fair" or "unsatisfactory" outcomes. Avoidance of scarring is a goal of every craniofacial surgeon. The swinging eyelid approach to ZMC fractures offers a simple alternative to the conventional technique. It is versatile and provides sufficient exposure to surgical fields with less visible scar because skin incision is made along the natural crease line, "the crow's feet."

Background and Purpose: Eosinophil counts are thought to be associated with atherosclerosis and aortic arch plaques. However, whether these associations exist among patients with acute ischemic stroke remains unclear. We aimed to evaluate the association between absolute eosinophil count (AEC) and aortic arch plaques among these patients., Methods: Consecutive acute ischemic stroke patients undergoing transesophageal echocardiography were retrospectively analyzed. Complex aortic arch plaques (CAPs) were defined as plaques ≥4 mm in thickness, with ulcer, or with mobile component., Results: A total of 430 patients (289 male, mean age 69.8±11.4 years) were enrolled. Patients with CAPs (n=169) showed higher mean AEC than those without (167±174/µL versus 127±127/µL; P =0.007). Multivariate analysis showed that increased AEC was independently associated with the presence of CAPs (odds ratio, 2.09; 95% confidence interval, 1.21-3.65)., Conclusions: Among patients with acute ischemic stroke, increased AEC was independently associated with the presence of CAPs. Our results suggest that AEC may be a useful predictor for the presence of CAPs in these patients., (© 2017 American Heart Association, Inc.)

Background and Purpose: Brain infarct patterns that are observed via diffusion-weighted imaging are useful for classifying stroke subtypes. However, it is unclear whether infarct patterns can predict long-term outcomes in cryptogenic stroke patients. Herein, we investigated the association between acute brain infarct patterns and long-term stroke outcomes in cryptogenic stroke patients., Methods: Acute cryptogenic stroke patients were consecutively enrolled between April 2008 and March 2012. Diffusion-weighted imaging ischemic lesion patterns were classified as single lesions, scattered lesions in one vascular territory, or multiple lesions in multiple vascular territories. Survivors (at discharge) were followed up for 3 years after stroke onset., Results: A total of 272 cryptogenic stroke patients (132 women; aged 72±13 years) were enrolled. Among these patients, 169 (62.1%) had a single lesion, 38 (14.0%) had scattered lesions, and 65 (23.9%) had multiple lesions. Next, 261 patients (96.0%) were evaluated to assess right-to-left shunting, and 61 patients (23.4%) exhibited right-to-left shunting. On patient admission, right-to-left shunting and increased D-dimer levels were independently associated with multiple lesions but not single or scattered lesions. During the follow-up period (median, 1093 days), 30 patients (11.0%) developed recurrent stroke and 35 patients (12.9%) died. Multivariate Cox proportional hazard analyses showed that multiple infarcts were independently associated with recurrent stroke and all-cause mortality (hazard ratio, 3.79; 95% confidence interval, 2.24-6.37; P<0.001)., Conclusions: Multiple brain infarcts on diffusion-weighted imaging were independently associated with long-term stroke outcomes in cryptogenic stroke patients., (© 2016 American Heart Association, Inc.)

There are many different operations to correct involutional blepharoptosis (IB); however, the outcome of the corrective surgery is rather unpredictable, regardless of the procedure employed. A reasonably predictable outcome can be achieved with careful intraoperative evaluation of the condition, with measuring of the margin reflex distance-1 (MRD-1) in supine position of the patients. With these prepositions, we collected data that indicated that our approach can achieve a predictable outcome. This was a prospective study of 21 consecutive patients (8 men and 13 women) involving 42 eyelids with IB. IB was defined as an MRD-1 of <2  mm. All 21 patients were informed of the purposes of the study, and underwent levator aponeurosis advancement. The MRD-1 was measured intraoperatively with the patients in a supine position and in the 3-month postoperative inspection with the patients in a sitting position. Statistical analyses using paired t-tests were performed. From intraoperative measurement, mean MRD-1 values were 4.31  mm on the right side (range 3.0-4.5) and 4.29  mm on the left side (range 3.5-5.0). Three months after the operations, mean MRD-1 values were 3.07  mm on the right side (range 1.5-4.0) and 3.07  mm on the left side (range 2.0-4.0). Compared with the intraoperative MRD-1 measurements, those of the postoperatives were significantly 1.2  mm reduced (right: P < 0.01, left: P < 0.01). The intraoperative measurement of MRD-1 without changing position of patients could result in successful outcome of the operation.

Objectives: Food or supplement-derived L-carnitine is changed to trimethylamine (TMA) by interstinal microbiota, which is further metabolized to trimethylamine-N-oxide (TMAO), being involved in the promotion of atherosclerosis in animal models. Meanwhile, carnitine deficiency has played a role in accelerated atherosclerosis in hemodialysis (HD) patients. However, effects of oral L-carnitine supplementation on circulating levels of TMAO and markers of vascular injury and oxidative stress in patients on HD remain unclear. In this study, we addressed the issue., Methods: Thirty-one HD patients with carnitine deficiency were treated with oral L-carnitine (900 mg/d) for 6 months. At baseline and after treatment, clinical variables including circulating levels of carnitine fractions, TMA, TMAO, advanced glycation end products (AGE), soluble forms of intracellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), and malondialdehyde (MDA) were measured., Results: Oral L-carnitine supplementation significantly increased total, free, acyl carnitine, and plasma TMA and TMAO levels, whereas it decreased markers of vascular injury and oxidative stress such as sICAM-1, sVCAM-1, and MDA levels. TMA and TMAO levels at baseline were correlated with each other, and free carnitine was independently associated with TMAO levels. Furthermore, change in AGE values from baseline ([INCREMENT]AGE) was positively correlated with [INCREMENT]sICAM-1 (P = 0.043) and was a sole independent determinant of [INCREMENT]sICAM-1 (R = 0.133, P = 0.043)., Conclusions: This study demonstrated that although oral L-carnitine supplementation was associated with increased TMAO levels, it might be beneficial on vascular injury in patients on HD. Vasculoprotective properties of L-carnitine supplementation in HD patients might be ascribed partly to its inhibitory actions on AGE.

Background: Subjects with autism spectrum disorders (ASDs) often exhibit behavioral symptoms such as aggressiveness and irritability. The purpose of this study was to examine the efficacy and the tolerability of aripiprazole switched from risperidone in children and adolescents with ASD., Methods: This prospective, 12-week, open-label study included 9 male subjects with ASD (age range, 9-22 years; mean ± SD age, 14.8 ± 4.0 years) followed up for 12 weeks after switching to aripiprazole from risperidone. The primary outcome measures were the Clinical Global Impression-Improvement scales and the irritability subscale of the Aberrant Behavior Checklist., Results: The mean ± SD maintenance dosages of risperidone and aripiprazole were 0.6 ± 0.4 mg/d and 4.8 ± 4.0 mg/d, respectively. The mean ± SD scores of the irritability subscale of the Aberrant Behavior Checklist before switching to aripiprazole (baseline) and 12 weeks after switching to aripiprazole (end point) were 14.8 ± 7.6 and 13.1 ± 8.0, respectively. The mean ± SD Clinical Global Impression-Improvement score, a comparison from baseline to end point, was 2.4 ± 0.7. Mild somnolence was observed only in 1 subject. No significant changes in vital signs, weight, electrocardiogram, or laboratory measures occurred during switching to aripiprazole. Serum prolactin levels decreased significantly from 17.3 ± 9.4 ng/mL (baseline) to 2.3 ± 1.7 ng/mL (end point)., Conclusions: The results show that aripiprazole might be generally well tolerated and might constitute an alternative treatment of subjects with ASD who experience poor efficacy or tolerability issues with risperidone treatment. Additional long-term controlled studies are needed to evaluate the efficacy and the safety of switching to aripiprazole from other antipsychotics in subjects with ASD.

Study Design: Prospective consecutive series., Objective: To evaluate the post-traumatic disc degeneration and range of motion 10 years after short-segment fixation without fusion for thoracolumbar burst fractures with neurological deficit., Summary of Background Data: Early clinical results of short-segment fixation without fusion for thoracolumbar burst fractures were satisfactory. However, the long-term results have not been reported, and post-traumatic disc degeneration and preservation of thoracolumbar motion have not been elucidated., Methods: Twelve patients who had thoracolumbar burst fractures and associated incomplete neurological deficit, operatively treated within 4 days of admission and had their implants removed within 1 year, were prospectively followed for at least 10 years. Following indirect reduction and pedicle screw fixation, transpedicular intracorporeal hydroxyapatite grafting to the fractured vertebrae was performed., Results: Sagittal alignment was improved from a mean preoperative kyphosis of 17° to -2° (lordosis) by operation, but was found to have slightly deteriorated to 2° at the final follow-up observation. With respect to back pain, 8 patients did not report back pain. Three reported occasional minimal pain, and 1 reported moderate pain. None reported severe pain or needed daily dosages of analgesics.Regarding disc degeneration, the shape of the disc adjacent to the fractured vertebra had not changed from the preoperative to the 10-year postoperative magnetic resonance image (MRI). Although signal intensity of the disc had decreased by 1 grade from the preoperative to the 2-year postoperative MRI, the intensity had not changed from the 2-year postoperative MRI to the 10-year postoperative MRI. At the 10-year follow-up, flexion-extension radiographs revealed that a mean range of motion at the disc adjacent to the fractured vertebra was 12º (range; 5-19)., Conclusion: This unprecedented 10-year follow-up study demonstrated that posterior indirect reduction, transpedicular hydroxyapatite grafting, and pedicle screw fixation does not require fusion to a segment, thereby preserves thoracolumbar motion without resulting in post-traumatic disc degeneration., Level of Evidence: 4.

In an earlier study in rodents, we showed that the aromatase that converts androgens to estrogens in the preoptic area and bed nucleus of stria terminalis was significantly increased in concentration after exposure to anabolic-androgenic steroids. To confirm whether this occurs in primates, we conducted a positron emission tomographic study using macaque monkeys. Male rhesus monkeys were treated with nandrolone decanoate for 3 weeks. To measure aromatase concentrations, we performed positron emission tomographic imaging using a 11C-labeled specific aromatase inhibitor, [11C]vorozole. After treatment with nandrolone, significant increase in [11C]vorozole binding was observed in the hypothalamus but not other areas including the amygdala, which is also aromatase enriched. These findings in monkeys are consistent with those we obtained earlier in rats. These findings strongly suggest that aromatase in the hypothalamus may play a crucial role in the emotional instability of anabolic-androgenic steroids abusers.

Objective: This study was undertaken to evaluate a modified form of Estimation of Physiologic Ability and Surgical Stress (E-PASS) for surgical audit comparing with other existing models., Background: Although several scoring systems have been devised for surgical audit, no nation-wide survey has been performed yet., Methods: We modified our previous E-PASS surgical audit system by computing the weights of 41 procedures, using data from 4925 patients who underwent elective digestive surgery, designated it as mE-PASS. Subsequently, a prospective cohort study was conducted in 43 national hospitals in Japan from April 1, 2005, to April 8, 2007. Variables for the E-PASS and American Society of Anesthesiologists (ASA) status-based model were collected for 5272 surgically treated patients. Of the 5272 patients, we also collected data for the Portsmouth modification of Physiologic and Operative Severity Score for the enUmeration of Mortality and morbidity (P-POSSUM) in 3128 patients. The area under the receiver operative characteristic curve (AUC) was used to evaluate discrimination performance to detect in-hospital mortality. The ratio of observed to estimated in-hospital mortality rates (OE ratio) was defined as a measure of quality., Results: The numbers of variables required were 10 for E-PASS, 7 for mE-PASS, 20 for P-POSSUM, and 4 for the ASA status-based model. The AUC (95% confidence interval) values were 0.86 (0.79-0.93) for E-PASS, 0.86 (0.79-0.92) for mE-PASS, 0.81 (0.75-0.88) for P-POSSUM, and 0.73 (0.63-0.83) for the ASA status-based model. The OE ratios for mE-PASS among large-volume hospitals significantly correlated with those for E-PASS (R = 0.93, N = 9, P = 0.00026), P-POSSUM (R = 0.96, N = 6, P = 0.0021), and ASA status-based model (R = 0.83, N = 9, P = 0.0051)., Conclusion: Because of its features of easy use, accuracy, and generalizability, mE-PASS is a candidate for a nation-wide survey.

The purpose of this study was to determine whether high-speed treadmill training improved the gait velocity of patients whose maximum walking speed was assumed to have reached a plateau level. The subjects included seven patients with hemiplegia after stroke. The high-speed treadmill training was performed as the maximum gait velocity of each patient was presumed to have reached a plateau level. The patients walked 20% faster than their maximum gait velocity of the day for 5 days (phase I). Then they walked 20% slower than maximum gait velocity of the day for 5 days, and they repeated the fast treadmill walking for further 5 days (phase II). Before phase I, mean maximum gait velocity of the day was 0.84 m/sec before phase I, 1.08 m/sec after phase I, and 1.24 m/sec after phase II. These results demonstrated that training at a speed 20% faster than the maximum gait velocity of the day on the treadmill for 5 days could further increase a patient's gait velocity.

Rationale: The (pro)renin receptor [(P)RR], encoded in ATP6AP2, plays a key role in the activation of local renin-angiotensin system (RAS). A truncated form of (P)RR, termed M8.9, was also found to be associated with the vacuolar H(+)-ATPase (V-ATPase), implicating a non-RAS-related function of ATP6AP2., Objective: We investigated the role of (P)RR/ATP6AP2 in murine cardiomyocytes., Methods and Results: Cardiomyocyte-specific ablation of Atp6ap2 resulted in lethal heart failure; the cardiomyocytes contained RAB7- and lysosomal-associated membrane protein 2 (LAMP2)-positive multivesicular vacuoles, especially in the perinuclear regions. The myofibrils and mitochondria remained at the cell periphery. Cardiomyocyte death was accompanied by numerous autophagic vacuoles that contained undigested cellular constituents, as a result of impaired autophagic degradation. Notably, ablation of Atp6ap2 selectively suppressed expression of the V(O) subunits of V-ATPase, resulting in deacidification of the intracellular vesicles. Furthermore, the inhibition of intracellular acidification by treatment with bafilomycin A1 or chloroquine reproduced the phenotype observed for the (P)RR/ATP6AP2-deficient cardiomyocytes., Conclusions: Genetic ablation of Atp6ap2 created a loss-of-function model for V-ATPase. The gene product of ATP6AP2 is considered to act as in 2 ways: (1) as (P)RR, exerting a RAS-related function; and (2) as the V-ATPase-associated protein, exerting a non-RAS-related function that is essential for cell survival.

Experimentally induced changes in the central visual pathway were studied by using positron emission tomography in monkeys with unilateral hypertension glaucoma. In 2-[18F]fluoro-2-deoxy-glucose studies, monocular visual stimulation of the affected eye yielded significantly reduced neural responses in the occipital visuocortical areas. The response reduction was limited to the visual cortex ipsilateral to the affected eye, indicating the unique vulnerability of ipsilateral visual cortex in experimental unilateral glaucoma. In addition, in [11C]PK11195 positron emission tomography and immunohistochemical studies, selective accumulation of activated microglia, a sign of neural degeneration, was found bilaterally in lateral geniculate nuclei. The present findings establish the usefulness of noninvasive molecular imaging for early diagnosis of glaucoma by providing a sharper surrogate end point for an early phase of glaucoma.

Study Design: Prospective consecutive series., Objective: To analyze supine and standing radiographs and the association of back pain using subjective pain criteria., Summary of Background Data: It has been considered that there is little correlation between the degree of collapse of the vertebral body and the level of pain. In previous studies, however, measurements have only been based on supine radiographs. Although there were 2 authors who reported the results of supine lateral and standing lateral radiographs in patients with thoracolumbar vertebral fractures, as far as we know, there has not been any detailed report concerning the correlation between radiologic findings using supine and standing lateral radiographs and back pain., Methods: We examined 100 consecutively treated patients, prospectively. Back pain and the supine and standing radiographs were assessed 1 month after injury. Changes in vertebral wedging rate (WR) from supine to standing position (Delta WR) was reported by the following equation: Delta WR = WR(standing)-WR(supine)., Results: The median age of the cohort was 75 years (range, 60-89 years). The median VAS of back pain at supine position, at standing position, and when standing erect was 13, 33, and 41, respectively. The median wedging rate on the supine and standing radiographs were 28% and 37%, respectively (P < 0.001). There was a significant correlation between Delta WR and back pain when standing erect (r = 0.79, P < 0.001)., Conclusion: Changes in vertebral wedging rate between supine and standing position and its association with back pain may give a clue to the pathogenesis of pain from osteoporotic thoracolumbar vertebral compression fractures.

We conducted this animal study to demonstrate whether exposing the acetabulum in immature rabbits to extracorporeal shock waves induces bone formation in the acetabulum. Five thousand shock waves of 100 MPa each were directed, from outside, at the acetabular roof of eight immature rabbits. At each of two time points (4 and 8 weeks) after treatment, the pelvises of four rabbits were removed and evaluated morphologically. Woven bone formation was observed on the lateral margin of the acetabular roof at 4 weeks after treatment, and the breadth of the acetabular roof in the coronal plane was significantly increased. Eight weeks after treatment, the woven bone disappeared; the breadth of the acetabular roof, however, was significantly increased. These findings demonstrated that extracorporeal shock waves induced acetabular augmentation in rabbits. We conclude that extracorporeal shock waves, perhaps, could be applied clinically for the treatment of acetabular dysplasia.

Objective: Heme oxygenase-1 (HO-1), the rate-limiting enzyme of heme degradation, has recently been considered to have protective roles against various pathophysiological conditions. Since we demonstrated that HO-1 overexpression inhibits atherosclerotic formation in animal models, we examined the effect of HO modulation on proinflammatory cytokine production, endothelial NO synthase (eNOS) expression, and endothelium-dependent vascular relaxation responses., Methods and Results: After HO-1 induction by heme arginate (HA), vascular endothelial cell cultures were exposed to oxidized low-density lipoprotein (oxLDL) or tumor necrosis factor-alpha (TNF-alpha). HA pretreatment significantly attenuated the production of vascular cell adhesion molecule-1, monocyte chemotactic protein-1, and macrophage colony-stimulating factor, suggesting that HO-1 induction attenuates proinflammatory responses. In addition, HO-1 overexpression also alleviated endothelial dysfunction as judged by restoration of attenuated eNOS expression after exposure to oxLDL and TNF-alpha. Importantly, impaired endothelium-dependent vascular relaxation responses in thoracic aortic rings from high-fat-fed LDL receptor knockout mice were also improved. These effects were observed by treatment with bilirubin not by carbon monoxide., Conclusions: These results suggest that the antiatherogenic properties of HO-1 may be mediated predominantly through the action of bilirubin by inhibition of vascular endothelial activation and dysfunction in response to proinflammatory stresses.

Purpose: To characterize the clinical features of two Japanese families with choroideremia associated with a 402delT and a 555-556delAG mutation in the choroideremia gene (CHM)., Methods: Four affected members and one obligate carrier from two Japanese families with choroideremia were studied. To detect mutations of the CHM gene, the products of polymerase chain reaction were directly sequenced in both directions. The ophthalmologic examination included best-corrected visual acuity, slit-lamp examination, fundus examination, kinetic perimetry, electroretinography, and fluorescein angiography., Results: A 402delT and a 555-556delAG mutation were found in two Japanese families with choroideremia. All affected members had night-blindness, progressive constriction of the visual field, chorioretinal atrophy, and mottled appearance of the retinal pigment epithelium. The obligate carrier had mild patchy areas of retinal pigment epithelial atrophy with no visual symptoms., Conclusion: The authors found a 402delT and a 555-556delAG mutation in the CHM gene, one of which (402delT) is a novel mutation. They conclude that these mutations cause choroideremia in Japanese families.

Background: Although treatment with immunosuppressive agents has contributed to overcoming acute rejection and improving the midterm survival of transplanted hearts, cardiac allograft vasculopathy (CAV) has remained the main cause of primary graft failure. Recent approaches have shown that hepatocyte growth factor (HGF) exhibits cardiotrophic functions. We therefore addressed whether HGF would regulate acute and chronic rejection in cardiac transplantation., Methods and Results: We used a murine heterotopic cardiac transplantation model between fully incompatible strains and administered 500 microg x kg(-1) x d(-1) HGF during the initial 14 days after transplantation. The HGF-treated allografts showed significantly prolonged survival (42.3+/-4.1 days, P<0.001) compared with the controls (11.1+/-0.6 days), with tolerance induction in 47.4%. Histopathologically, the number of infiltrating cells was significantly decreased and myocardial necrosis was less prominent with a reduction of apoptosis in the allografts by HGF treatment during acute rejection. In the long-term surviving allografts, HGF significantly inhibited the development of CAV and interstitial fibrosis. With respect to intragraft cytokine mRNA expression, HGF treatment reduced the early expression of interferon-gamma and enhanced the expression of transforming growth factor-beta1 during the acute phase and of interleukin-10 continuously through the acute phase to the chronic phase., Conclusions: Our findings demonstrate that HGF can prolong the survival of allografts by its cardioprotective and immunomodulative potencies. Thus, HGF administration may constitute a new therapeutic approach to preventing cardiac graft failure that has not been overcome by conventional immunosuppressive agents.

We hypothesized that extracorporeal shock waves induce overgrowth and local increases in bone mineral content (BMC) in immature long bones. Immature male rabbits (n=14; 9 weeks old) were randomized equally between group I, which received 1000 100 MPa shock waves on the femoral shaft and group II, which received 5000. Unexposed femurs were used as controls. No fractures occurred in group I; three occurred in group II. Six weeks after exposure, the length and width were significantly larger (1.0 and 14.9%, respectively), and the BMC was significantly higher (22.8%) than those of control femurs in group I. These results of differences in width and BMC might be clinically useful.