Crim1C140S mutant mice reveal the importance of cysteine 140 in the internal region 1 of CRIM1 for its physiological functions.

Cysteine-rich transmembrane bone morphogenetic protein regulator 1 (CRIM1) is a type I transmembrane protein involved in the organogenesis of many tissues via its interactions with growth factors including BMP, TGF-ß, and VEGF. In this study, we used whole-exome sequencing and linkage analysis to identify a novel Crim1 mutant allele generated by ENU mutagenesis in mice. This allele is a missense mutation that causes a cysteine-to-serine substitution at position 140, and is referred to as Crim1C140S. In addition to the previously reported phenotypes in Crim1 mutants, Crim1C140S homozygous mice exhibited several novel phenotypes, including dwarfism, enlarged seminal vesicles, and rectal prolapse. In vitro analyses showed that Crim1C140S mutation affected the formation of CRIM1 complexes and decreased the amount of the overexpressed CRIM1 proteins in the cell culture supernatants. Cys140 is located in the internal region 1 (IR1) of the N-terminal extracellular region of CRIM1 and resides outside any identified functional domains. Inference of the domain architecture suggested that the Crim1C140S mutation disturbs an intramolecular disulfide bond in IR1, leading to the protein instability and the functional defects of CRIM1. Crim1C140S highlights the functional importance of the IR1, and Crim1C140S mice should serve as a valuable model for investigating the functions of CRIM1 that are unidentified as yet.

Ultrasound-guided versus conventional femoral venipuncture for catheter ablation of atrial fibrillation: a multicentre randomized efficacy and safety trial (ULTRA-FAST trial).

Aims: Complications of catheter ablation for atrial fibrillation (AF) are frequently related to vascular access. We hypothesized that ultrasound-guided (USG) venipuncture may facilitate the procedure and reduce complication rates. Methods and results: We conducted a multicentre, randomized trial in patients undergoing catheter ablation for AF on uninterrupted anticoagulation therapy. The study enrolled consecutive 320 patients (age: 63 ± 8 years; male: 62%) and were randomized to USG or conventional venipuncture in 1:1 fashion. It was prematurely terminated due to substantially lower-than-expected complication rates, which doubled the population size needed to maintain statistical power. While the complication rates did not differ between two study arms (0.6% vs. 1.9%, P = 0.62), intra-procedural outcome measures were in favour of the USG approach (puncture time, 288 vs. 369 s, P < 0.001; first pass success, 74% vs. 20%, P < 0.001; extra puncture attempts 0.5 vs. 2.1, P < 0.001; inadvertent arterial puncture 0.07 vs. 0.25, P < 0.001; unsuccessful cannulation 0.6% vs. 14%, P < 0.001). Though these measures varied between trainees (49% of procedures) and expert operators, between-arm differences (except for unsuccessful cannulation) were comparably significant in favour of USG approach for both subgroups. Conclusions: Ultrasound-guided puncture of femoral veins was associated with preferable intra-procedural outcomes, though the major complication rates were not reduced. Both trainees and expert operators benefited from the USG strategy. (www.clinicaltrials.gov ID: NCT02834221).

[Papillary Fibroelastoma of the Left Ventricular Outflow Tract;Report of a Case].

Papillary fibroelastoma(PFE) is a rare and benign primary cardiac neoplasm. The incidence of PFE in the left ventricle is lower than that in other parts of the heart. A 67-year-old female was referred to our cardiology department for treatment of severe cardiac failure due to mitral regurgitation. Transthoracic and transesophageal echocardiography coincidently revealed a 1.0 cm highly mobile mass attached by a stalk to the outflow tract wall of the left ventricle. The mass was easily detected using endoscope and successfully removed without any postoperative complications and was pathologically diagnosed as a PFE. In this report, we discuss the echocardiographic character of PFE and the usefulness of endoscope for the identification and resection of a PFE in the left ventricle.

Distinct 1-monoacylglycerol and 2-monoacylglycerol kinase activities of diacylglycerol kinase isozymes.

Diacylglycerol kinase (DGK) consists of ten isozymes and is involved in a wide variety of patho-physiological events. However, the enzymological properties of DGKs have not been fully understood. In this study, we performed a comprehensive analysis on the 1-monoacylglycerol kinase (MGK) and 2-MGK activities of ten DGK isozymes. We revealed that type I (α, ß and γ), type II (δ, η and κ) and type III (ε) DGKs have 7.9-19.2% 2-MGK activity compared to their DGK activities, whereas their 1-MGK activities were <3.0%. Both the 1-MGK and 2-MGK activities of the type IV DGKs (ζ and ι) were <1% relative to their DGK activities. Intriguingly, type V DGKθ has approximately 6% 1-MGK activity and <2% 2-MGK activity compared to its DGK activity. Purified DGKθ exhibited the same results, indicating that its 1-MGK activity is intrinsic. Therefore, DGK isozymes are categorized into three types with respect to their 1-MGK and 2-MGK activities: those having (1) 2-MGK activity relatively stronger than their 1-MGK activity (types I-III), (2) only negligible 1-MGK and 2-MGK activities (type IV), and (3) 1-MGK activity stronger than its 2-MGK activity (type V). The 1-MGK activity of DGKθ and the 2-MGK activity of DGKα were stronger than those of the acylglycerol kinase reported as 1-MGK and 2-MGK to date. The presence or absence of 1-MGK and 2-MGK activities may be essential to the patho-physiological functions of each DGK isozyme.

Quantitative analysis of impact of awareness-raising activities on organic solid waste separation behaviour in Balikpapan City, Indonesia.

Many cities in Indonesia are under pressure to reduce solid waste and dispose of it properly. In response to this pressure, the Japan International Cooperation Agency and the Indonesian Government have implemented a solid waste separation and collection project to reduce solid waste in the target area (810 households) of Balikpapan City. We used a cluster randomised controlled trial method to measure the impact of awareness-raising activities that were introduced by the project on residents' organic solid waste separation behaviour. The level of properly separated organic solid waste increased by 6.0% in areas that conducted awareness-raising activities. Meanwhile, the level decreased by 3.6% in areas that did not conduct similar activities. Therefore, in relative comparison, awareness-raising increased the level by 9.6%. A comparison among small communities in the target area confirmed that awareness-raising activities had a significant impact on organic solid waste separation. High frequencies of monitoring at waste stations and door-to-door visits by community members had a positive impact on organic solid waste separation. A correlation between the proximity of environmental volunteers' houses to waste stations and a high level of separation was also confirmed. The awareness-raising activities introduced by the project led to a significant increase in the separation of organic solid waste.

Development and validation of a device for monitoring laryngeal motion during swallowing.

Objectives: Hyolaryngeal movement during swallowing is essential to airway protection and bolus clearance. Although palpation is widely used to evaluate hyolaryngeal motion, insufficient accuracy has been reported. The Bando Stretchable Strain Sensor for Swallowing (B4S™) was developed to capture hyolaryngeal elevation and display it as waveforms. This study compared laryngeal movement time detected by the B4S™ with laryngeal movement time measured by videofluoroscopy (VF). Methods: Participants were 20 patients without swallowing difficulty (10 men, 10 women; age 30.6 ± 7.1 years). The B4S™ was attached to the anterior neck and two saliva swallows were measured on VF images to determine the relative and absolute reliability of laryngeal elevation time measured on VF and that measured by the B4S™. Results: The intra-class correlation coefficient of the VF and B4S™ times was very high [ICC (1.1) = 0.980]. A Bland-Altman plot showed a strong positive correlation with a 95% confidence interval of 0.00-3.01 for the mean VF time and mean B4S™ time, with a fixed error detected in the positive direction but with no proportional error detected. Thus, the VF and B4S™ time measurements showed high consistency. Conclusion: The strong relative and absolute reliability suggest that the B4S™ can accurately detect the duration of superior-inferior laryngeal motion during swallowing. Further study is needed to develop a method for measuring the distance of laryngeal elevation. It is also necessary to investigate the usefulness of this device for evaluation and treatment in clinical settings.

Ultrasound evaluation of vagus nerve cross-sectional area in a community-dwelling elderly Japanese cohort.

OBJECTIVES: Although the vagus nerve (VN) is easily observed by ultrasonography, few studies have evaluated the cross-sectional area (CSA) of the VN in healthy older individuals from East Asia. In this study, we aimed to report reference values for the CSA of the VN in community-dwelling elderly Japanese individuals and to identify any associated medical history and/or lifestyle factors. METHODS: The present study included 336 participants aged ≥ 70 years from a prospective cohort study conducted in Yahaba, Japan from October 2021 to February 2022. The CSA of the VN was measured bilaterally at the level of the thyroid gland by ultrasonography. Simple linear regression analysis and generalized estimating equation were conducted to identify the associations between clinical and background factors and the CSA of the VN. RESULTS: In our cohort, the median CSA of the VN was 1.3 mm2 (interquartile range [IQR] 1.1-1.6) on the right side and 1.2 mm2 (IQR 1.0-1.4) on the left side. Generalized estimating equation showed that history of head injury (ß = 0.19, p < .01), current smoking habit (ß = -0.09, p = .03), and BMI (ß = 0.02, p < .01) were independently associated with the CSA of the VN. CONCLUSION: We have reported reference VN CSA values for community-dwelling elderly Japanese individuals. In addition, we showed that the CSA of the VN was positively associated with a history of head injury and BMI and inversely associated with current smoking habit.

Electrical isolation of the superior vena cava using upstream phrenic pacing to avoid phrenic nerve injury.

BACKGROUND: Phrenic nerve (PN) injury is a potential complication that can occur during superior vena cava (SVC) isolation to cure atrial fibrillation (AF). Avoiding radiofrequency (RF) energy delivery is the safer alternative but may result in failed isolation. High-output PN pacing above the ablation site (upstream PN pacing) to confirm whether the PN is intact is a promising technique to avoid PN injury. This study was conducted to elucidate the safety of delivering RF energy at the site of capture of the right PN using upstream high-output pacing during electrical SVC isolation. METHODS: SVC isolation was conducted in 41 drug-resistant AF patients. When high-output pacing (25 mA) from the distal tip of the ablation catheter captured the PN at the right atrial-SVC junction, upstream PN pacing (cycle length: 1000-1500 ms) was applied during RF delivery. The application of RF energy was stopped upon the failure or weakness of diaphragmatic twitching. The feasibility of SVC isolation using upstream PN pacing was investigated. RESULTS: In all 41 patients, SVC isolation was successfully achieved. RF energy was delivered at the PN capture site in 26 patients (154 ± 138 second, 18 ± 5 W), and upstream PN pacing was successfully applied in all of the patients. Out of 46 SVC isolations, including five repeated sessions, PN injury occurred in one patient, who recovered spontaneously within 2 weeks. CONCLUSIONS: Upstream PN pacing may be effective for the safe completion of SVC isolation and to reduce the severity of PN injury.

MPO-ANCA-positive Microscopic Polyangiitis Following COVID-19 Infection.

Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is a systemic disease that causes vasculitis in various organs. Although the cause of the onset is unknown, infection has been reported to be a causative factor. The subsequent cytokine storm triggered by the immune response against SARS-CoV-2 infection has been reported to lead to symptoms being more severe. We herein report our experience with the onset of AAV following COVID-19 infection. We also report the course of anti-SARS-CoV-2 serum antibody titers following induction therapy, which suggests that vaccination and education concerning standard precautions are necessary in patients who require immunosuppressive therapy, even after COVID-19 infection.

Transsylvian and trans-Heschl's gyrus approach for a left posterior insular lesion and functional analyses of the left Heschl's gyrus: illustrative case.

BACKGROUND: A common surgical approach for dominant insular lesions is to make a surgical corridor in asymptomatic cortices based on functional mapping. However, the surgical approach is difficult for posterior insular lesions in a dominant hemisphere because the posterior parts of the perisylvian cortices usually have verbal functions. OBSERVATIONS: We present the case of a 40-year-old male whose magnetic resonance images revealed the presence of contrast-enhancing lesions in the left posterior insula. Our surgical approach was to split the sylvian fissure as widely as possible, and partially resect Heschl's gyrus if the cortical mapping was negative for language tests. Because Heschl's gyrus did not have verbal functions, the gyrus was used as a surgical corridor. It was wide enough for the removal of the lesion; however, because intraoperative pathological diagnosis eliminated the possibility of brain tumors, further resection was discontinued. The tissues were histologically diagnosed as tuberculomas. Antituberculosis drugs were administered, and the residual lesions finally disappeared. According to the neurophysiological tests, the patient showed temporary impairment of auditory detection, but the low scores of these tests improved. LESSONS: The transsylvian and trans-Heschl's gyrus approach can be a novel surgical option for excising dominant posterior insular lesions.

A cross-sectional study of Parkinson's disease and the prodromal phase in community-dwelling older adults in eastern Japan.

Introduction: Parkinson's disease (PD) is more prevalent in the aging population, and epidemiological evidence must be constantly updated to provide an accurate understanding of PD prevalence. Various nonmotor symptoms of PD precede the onset of motor symptoms and prodromal PD. The detection of such symptoms is crucial yet remains challenging. In this study, we aimed to clarify the current prevalence of PD and prodromal PD. Methods: We enrolled 714 community-dwelling older adults (330 men and 384 women) aged ≥ 65 years (mean age 76.3 years). We used a self-administered questionnaire based on the International Parkinson and Movement Disorder Society prodromal PD criteria to obtain information on prodromes and calculate PD probability. Patients with a probability of ≥ 0.3 were considered as having prodromal PD. We analyzed the crude prevalence rates of PD and prodromal PD. Results: The crude prevalence rate of PD in our sample was 279.7 per 100,000 persons. The crude prevalence rate of prodromal PD and PD probability were 5034.5 per 100,000 persons and 0.057 ± 0.121, respectively. Never smoker (61.4%), physical inactivity (47.0%), regular pesticide exposure (30.7%), and urinary dysfunction (26.5%) were frequent positive prodromes. Subjects with higher PD probability possessed more variable prodromal markers than those with lower probability. Conclusion: We examined current prevalence rates of PD and prodromal PD in community-dwelling older adults aged ≥ 65 years in Japan. Our questionnaire-based approach to examine prodromal PD provided valuable evidence for the prevalence of prodromal PD in the aging population.

Epithelial-Myoepithelial Carcinoma of the Minor Salivary Glands: Case Series with Comprehensive Review.

Epithelial-myoepithelial carcinoma (EMC) is a rare salivary gland tumor that is histologically characterized by biphasic tubular structures composed of inner ductal and outer clear myoepithelial cells, which is especially uncommon in the minor salivary glands (MSG). Because of its histologic variety, complexity, and heterogeneity, it is sometimes challenging to make the accurate diagnosis. Here, we report a literature review of EMC of the MSGs with our experience of two cases. Incisional biopsy was suggestive of pleomorphic adenoma in Case 1 and pleomorphic adenoma or a low-grade salivary gland carcinoma in Case 2. Both cases were performed intraoral tumor resection, and they have good postoperative courses and are alive with no evidence of local recurrence or metastasis at 31 and 16 months, respectively. Considering that the anatomy, structure, and size of salivary glands are quite different from MSGs, it might be difficult to predict EMCs of the MSG similarly to EMCs of the major salivary glands. This comprehensive review also reports the features of EMC of the MSG cases and the trends of diagnosis and discusses treatment strategy.

Renal cell carcinoma metastasis to the maxillary bone successfully treated with surgery after vascular embolization: a case report.

BACKGROUND: Metastasis of renal cell carcinoma to the oral cavity is rare. Renal cell carcinoma metastases are regarded as radioresistant tumors and surgery is recommended. However, since metastatic renal cell carcinoma has poor prognosis and is composed of abundant blood vessels, it is sometimes difficult for clinicians to choose surgical therapy. Here, we report a case of a patient with renal cell carcinoma metastasis to the maxillary bone, which was successfully controlled by surgical therapy after vascular embolization, and provide a detailed literature review regarding the treatments and outcomes of renal cell carcinoma metastasis to the oral cavity. CASE PRESENTATION: An 89-year-old Japanese man presented with an 8 × 8-mm granulomatous tumor with palpable pulsation in the left upper gingiva, which had been clinically suspected as an arteriovenous malformation or neoplastic lesion with rich blood vessels. Our patient had undergone left nephrectomy for clear cell carcinoma 7 years prior. Pulmonary metastasis had appeared 3 years later. After intravascular embolization, our patient underwent tumor resection of the maxilla with little intraoperative blood loss. The tumor was diagnosed on histopathology as a metastasis of clear cell renal cell carcinoma to the maxillary bone. Seventeen months after surgery, he died because of pulmonary metastasis without evidence of recurrence in the oral cavity. CONCLUSIONS: Our literature review reveals that oral metastatic lesions of renal cancer often exhibit rapid enlargement and cause severe symptoms, such as dysphagia and bleeding. Although oral metastasis of renal cell carcinoma has a poor prognosis due to the presence of concurrent disseminated metastases, surgical therapy may be recommended because of its high local control rate and ability to maintain quality of life. Preoperative vascular embolization is considered to be effective to reduce intraoperative hemorrhage, which leads to safe surgery.

Protocol Optimization for the Production of the Non-Cytotoxic JΔNI5 HSV Vector Deficient in Expression of Immediately Early Genes.

Non-toxic herpes simplex virus (HSV) vectors can be generated by functional deletion of all immediate-early (IE) genes, providing a benign vehicle with potential for gene therapy. However, deletion of multiple IE genes raises manufacturing concerns and thus limits clinical application of these vectors. To address this issue, we previously developed a novel production cell line, called U2OS-ICP4/27, by lentiviral transduction of human osteosarcoma U2OS cells with two essential HSV IE genes, ICP4 and ICP27. To optimize the process of vector manufacturing on this platform, we evaluated several cell culture parameters of U2OS-ICP4/27 for high-titer and -quality production of non-toxic HSV vectors, revealing that the yields and functionality of these vectors can be significantly influenced by culturing conditions. We also found that several chemical compounds can enhance the replication of non-toxic HSV vectors and their release from producer cells into the supernatants. Notably, the vector produced by our optimized protocol displayed a greatly improved vector yield and quality and showed elevated transgene expression in cultures of primary dorsal root ganglion neurons. Taken together, our optimized production approach emerges as a relevant protocol for high-yield and high-quality preparation of non-toxic HSV-based gene therapy vectors.

Diagnosis and treatment of oral focal mucinosis: a case series.

BACKGROUND: Oral focal mucinosis, the oral counterpart of cutaneous focal mucinosis, is a rare disease. As it has no characteristic clinical or radiological features, diagnosis is established by histopathological and immunohistological examination. We present three cases of oral focal mucinosis occurring in the retromolar (which is extremely rare) and gingival regions. CASE PRESENTATION: Case 1 involved a 26-year-old Japanese man with radiolucency in the right retromolar region on panoramic radiograph and computed tomography; no obvious protrusion was observed in the region. This finding was clinically diagnosed as a tumor of the retromolar region. Case 2 involved a 60-year-old Japanese woman. A tumor-like mass of tissue was identified on the buccal gingiva at the maxillary right canine and first premolar region. The lesion measured 7 × 6 mm and exhibited elastic hardness and healthy-colored mucosa. The lesion was diagnosed as an epulis. Case 3 involved a 47-year-old Japanese woman. A tumor-like mass of tissue was identified on the buccal gingiva at the maxillary right canine and first premolar region. The lesion measured 10 × 10 mm and exhibited elastic hardness and redness of the surface mucosa. This lesion was also diagnosed as an epulis. Resection was performed in all three cases, and the lesions were histopathologically diagnosed as oral focal mucinosis. Postoperative courses were uneventful and, thus far, there have been no recurrences. CONCLUSIONS: Although it is difficult to diagnose oral focal mucinosis based on clinical symptoms and imaging findings, the disease should be considered a possibility when diagnosing benign oral tumors. We believe that an emphasis on histopathologic study is essential to confirm the clinical suspicion.

Incidence rate of cutaneous squamous cell carcinoma is rapidly increasing in Akita Prefecture: Urgent alert for super-aged society.

Incidence rates of cutaneous squamous cell carcinoma (SCC) are increasing in many countries. To estimate detailed trends of SCC incidence rates in the population of Akita Prefecture as the forerunner of super-aged societies, we conducted a retrospective analysis of patients diagnosed with SCC between 2007 and 2016 in Akita University Hospital. The crude SCC incidence rate increased rapidly between 2007 and 2016 from 2.5 to 10.0/100 000 people. Remarkably, the age-specific incidence rate of people aged 80 years or over increased between 2007 and 2016 from 14.7 to 51.6/100 000 people, suggesting that SCC incidence rates increase possibly due to not only the increased number of aged people but also because of unidentified cancer-prone environments. When the findings of the present study are generalized to other regions entering the era of super-aging, it is clear that we need to prepare for the economic disease burden together with careful monitoring to confirm future trends for SCC.

[Lymphoepithelial cyst arising in the parotid gland; a report of 3 cases].

Lymphoepithelial cysts occur mainly in the lateral cervical region, but rarely in the parotid gland. We report three cases of lymphoepithelial cysts arising in the parotid gland. These patients presented with a mass in the pre-auricular or infra-auricular region. All masses were mobile and non-tender. The lesions were removed by superficial partial parotidectomy. A definite diagnosis could not be made at initial evaluation, including clinical findings, ultrasound sonography, computed tomography, magnetic resonance imaging, nor radioisotope scintigraphy. Final diagnoses were made by histopathologic evaluation of the excised specimen. In these three cases, histopathologic examination of the mass showed a cystic lesion to be lined by stratified squamous or cuboidal epithelium that was surrounded by a lymphoid tissue with lymphoid follicles, leading to a histopathological diagnosis of lymphoepithelial cyst. The postoperative course was uneventful, and there has been no evidence of recurrence in any of the three cases reported. A review of 52 cases of lymphoepithelial cyst arising in the parotid gland reported in Japanese literature was also made together with the three cases of lymphoepithelial cyst arising in the parotid gland reported here. The results of this review were considered clinical presentation and histopathogenesis of the three cases of lymphoepithelial cyst arising in the parotid gland reported here.

Development of monomorphic ventricular tachycardia in a patient with fever-induced Brugada syndrome.

A 50-year-old woman visited the emergency department with a high fever due to pneumonia. Incessant monomorphic ventricular tachycardia occurred and was terminated by intravenous lidocaine. Her ECG during sinus rhythm demonstrated ST segment elevation suggestive of Brugada syndrome (BS). An intensive examination could not detect any structural disease, and typical coved-type ST elevation was unmasked by a pilsicainide injection leading to a diagnosis of BS. An ICD was implanted for secondary prevention of ventricular arrhythmia. The patient has been free from any recurrences of arrhythmia for 3 years.

Mottainai: a Japanese sense of anima mundi.

The Japanese expression 'Mottainai!' can be translated as 'What a waste!' or 'Don't be wasteful!' However, mottainai means much more than that. It expresses a sense of concern or regret for whatever is wasted because its intrinsic value is not properly utilized. Buddhism and Japan's indigenous religion, Shinto, are integral to the Japanese psyche, accordingly the other-than-human world is also experienced and lived in daily life. In the Japanese worldview everything in nature is endowed with spirit, every individual existence is dependent on others and all are connected in an ever-changing world. Mottainai offers a glimpse of the anima mundi inherent in this worldview. This contrasts with our anthropocentric Zeitgeist, which manifests outwardly as environmental crisis and inwardly as fixation upon social interactions, especially through communication technologies, to the exclusion of all else. Jung's statement, 'The decisive question for man is: Is he related to something infinite or not? That is the telling question of his life', has never been more pertinent. Encounters beyond the human world could be understood as touching this 'something infinite', and the apparent benefits of such experiences in the analytical process are illustrated with clinical vignettes from the author's practice.