The Relationship between Holter Electrocardiography and Atrial Fibrillation Diagnosis Using Real-World Data in Japan.

The relationship between Holter electrocardiography (ECG) and atrial fibrillation (AF) diagnosis in the real world has not been widely evaluated in Japan.This is a claims-based retrospective study using a health insurance claims database provided by DeSC Healthcare Corporation. We identified patients with at least one Holter for any purpose during the data period from April 2015 to November 2020 and without diagnosis of AF before the tests (n = 19,739). We obtained a whole picture of Holter and AF diagnosis after correcting for population distribution bias in the dataset. Based on this picture and the assumption that the patient had AF at the 1st Holter whose AF was detected for the first time at the second or subsequent Holter, we estimated the number of diagnosis with AF and overlooked AF by initial Holter. We conducted sensitivity analyses changing the definition of AF, the potential detection period, and the washout period (a period required to avoid including patients who have already been diagnosed with AF or who have already undergone several Holters) to confirm the validity of the base scenario.Among patients for analysis, 88.4% had only one Holter. The percentage of AF diagnosis by initial Holter was 7.6%. The percentage of AF overlooked by initial Holter was estimated to be 31.4% and this value did not change much by sensitivity analyses.It was estimated that approximately 30% of AF patients were overlooked by initial Holter, and reducing the overlooked rate will be a clinical challenge.

Segmental resection with partial mesopancreatic and mesojejunal excision (pMME) for duodenal carcinoma of the third or fourth portion.

INTRODUCTION: Pancreatoduodenectomy is the standard procedure for duodenal carcinoma of the third or fourth portion. As an alternative option, we developed a novel segmental resection (SR) with partial mesopancreatic and mesojejunal excision (pMME) that enhances radicality. In this report, the surgical technique with video and outcomes are described. METHOD: We performed SR with pMME on seven consecutive patients with third or fourth duodenal carcinoma between 2009 and 2021. We divided the procedure into four sections, including (1) wide Kocher's maneuver, (2) supracolic anterior artery-first approach, (3) dissection of the mesopancreas and mesojejunum, and (4) devascularization of the uncinate process and dissection of duodenum. RESULT: Median operative time was 348 min (range, 222-391 min), and median blood loss was 100 mL (range, 30-580 mL). Major complications of Clavien-Dindo classification grade 3a or more occurred in one patient. All patients achieved R0 resections with 10 mm or more proximal margin. Six cases (85%) were alive without recurrence. CONCLUSION: We developed a radical and safe procedure of SR with pMME as an alternative and less invasive approach for duodenal carcinoma of the third or fourth portion.

Parachute technique for portal vein reconstruction during pancreaticoduodenectomy with portal vein resection in patients with pancreatic head cancer.

BACKGROUND: The most appropriate venous reconstruction method remains debatable when a long section of portal vein (PV) and/or superior mesenteric vein (SMV) must be resected in patients undergoing a pancreaticoduodenectomy (PD). The aim of the present study was to describe the technical details of the parachute technique, a modified end-to-end anastomotic maneuver that can be used in the above-mentioned circumstances, and to investigate its safety and feasibility. STUDY DESIGN: Patients who underwent venous reconstruction using the parachute technique after receiving a PD with PV resection for pancreatic cancer between January 2014 and March 2019 were retrospectively reviewed. For the parachute technique, the posterior wall was sutured in a continuous fashion while the stitches were left untightened. The stitches were then tightened from both sides after the running suture of the posterior wall had been completed, thereby dispersing the tension applied to the stitched venous wall when the venous ends were brought together and solving any problems that would otherwise have been caused by over-tension. The postoperative outcomes and PV patency were then investigated. RESULTS: Fifteen patients were identified. The median length of the resected PV/SMV measured in vivo was 5 cm (range, 3-6 cm). The splenic vein was resected in all the patients and was reconstructed in 13 patients (87%). The overall postoperative complication rate (≥ Clavien-Dindo grade I) was 60%, while a major complication (≥ Clavien-Dindo grade IIIa) occurred in 1 patient (7%). No postoperative deaths occurred in this series. The PV patency at 1 year was 87%. CONCLUSION: The parachute technique is both safe and feasible and is a simple venous reconstruction procedure suitable for use in cases undergoing PD when the distance between the resected PV and SMV is relatively long.

Radiologically occult metastatic pancreatic cancer: how can we avoid unbeneficial resection?

PURPOSE: This study aimed to clarify the key factors for minimizing unsuitable surgical interventions for patients with radiologically occult metastatic pancreatic cancer (ROMPC), defined as a distant metastasis detected during surgery or within 6 months after resection. METHODS: This study involved 502 patients planned to undergo curative resection for pancreatic cancer between 2008 and 2015. Patients were divided into ROMPC and non-ROMPC groups and evaluated preoperative factors associated with ROMPC. RESULTS: Overall survival (OS) was significantly lower in the ROMPC group (n = 145) than the non-ROMPC group (n = 357, median survival time [MST] 10.8 vs. 35.3 months, P < 0.001). In the ROMPC group, OS tended to be worse for patients who had pancreatectomies (n = 84) than those who did not (n = 61, MST 10.1 vs. 13.2 months, P = 0.057), and the next chemotherapy started significantly later in patients who had pancreatectomies (P < 0.001). Moreover, OS was significantly lower for patients with (n = 82) than without (n = 63) liver metastases (MST 9.7 vs. 13.0 months, respectively, P = 0.020). The best indicator for patients at higher risk of ROMPC was a combination of carbohydrate antigen 19-9 concentration ≥ 300 U/ml and tumor size ≥ 30 mm. CONCLUSIONS: In the ROMPC group, patients who underwent pancreatectomy had a poorer prognosis than patients not undergoing pancreatectomy. Given that the liver was the most frequent distant metastatic site for ROMPC and had the poorest prognosis, establishing a strategy featuring new imaging modalities to detect radiologically occult liver metastases is necessary.

Mef2d is essential for the maturation and integrity of retinal photoreceptor and bipolar cells.

Mef2 transcription factors play a crucial role in cardiac and skeletal muscle differentiation. We found that Mef2d is highly expressed in the mouse retina and its loss causes photoreceptor degeneration similar to that observed in human retinitis pigmentosa patients. Electroretinograms (ERGs) were severely impaired in Mef2d-/- mice. Immunohistochemistry showed that photoreceptor and bipolar cell synapse protein levels severely decreased in the Mef2d-/- retina. Expression profiling by microarray analysis showed that Mef2d is required for the expression of various genes in photoreceptor and bipolar cells, including cone arrestin, Guca1b, Pde6h and Cacna1s, which encode outer segment and synapse proteins. We also observed that Mef2d synergistically activates the cone arrestin (Arr3) promoter with Crx, suggesting that functional cooperation between Mef2d and Crx is important for photoreceptor cell gene regulation. Taken together, our results show that Mef2d is essential for photoreceptor and bipolar cell gene expression, either independently or cooperatively with Crx.

TRPM1.

The transient receptor potential (TRP) channels play a wide variety of essential roles in the sensory systems of various species, both invertebrates and vertebrates. The TRP channel was first identified as a molecule required for proper light response in Drosophila melanogaster. We and another group recently revealed that TRPM1, the founding member of the melanoma-related transient receptor potential (TRPM) subfamily, is required for the photoresponse in mouse retinal ON-bipolar cells. We further demonstrated that Trpm1 is a component of the transduction cation channel negatively regulated by the metabotropic glutamate receptor 6 (mGulR6) cascade in ON-bipolar cells through a reconstitution experiment using CHO cells expressing Trpm1, mGluR6, and Goα. Furthermore, human TRPM1 mutations are associated with congenital stationary night blindness (CSNB), whose patients lack rod function and suffer from night blindness starting in early childhood. In addition to the function of transduction cation channel, TRPM1 is one of the retinal autoantigens in some paraneoplastic retinopathy (PR) associated with retinal ON-bipolar cell dysfunction. In this chapter, we describe physiological functions of the TRPM1 channel and its underlying biochemical mechanisms in retinal ON-bipolar cells in association with CSNB and PR.

Presynaptic dystroglycan-pikachurin complex regulates the proper synaptic connection between retinal photoreceptor and bipolar cells.

Dystroglycan (DG) is a key component of the dystrophin-glycoprotein complex (DGC) at the neuromuscular junction postsynapse. In the mouse retina, the DGC is localized at the presynapse of photoreceptor cells, however, the function of presynaptic DGC is poorly understood. Here, we developed and analyzed retinal photoreceptor-specific DG conditional knock-out (DG CKO) mice. We found that the DG CKO retina showed a reduced amplitude and a prolonged implicit time of the ERG b-wave. Electron microscopic analysis revealed that bipolar dendrite invagination into the photoreceptor terminus is perturbed in the DG CKO retina. In the DG CKO retina, pikachurin, a DG ligand in the retina, is markedly decreased at photoreceptor synapses. Interestingly, in the Pikachurin(-/-) retina, the DG signal at the ribbon synaptic terminus was severely reduced, suggesting that pikachurin is required for the presynaptic accumulation of DG at the photoreceptor synaptic terminus, and conversely DG is required for pikachurin accumulation. Furthermore, we found that overexpression of pikachurin induces formation and clustering of a DG-pikachurin complex on the cell surface. The Laminin G repeats of pikachurin, which are critical for its oligomerization and interaction with DG, were essential for the clustering of the DG-pikachurin complex as well. These results suggest that oligomerization of pikachurin and its interaction with DG causes DG assembly on the synapse surface of the photoreceptor synaptic terminals. Our results reveal that the presynaptic interaction of pikachurin with DG at photoreceptor terminals is essential for both the formation of proper photoreceptor ribbon synaptic structures and normal retinal electrophysiology.

Identification of G Protein-Coupled Receptors (GPCRs) in Primary Cilia and Their Possible Involvement in Body Weight Control.

Primary cilia are sensory organelles that harbor various receptors such as G protein-coupled receptors (GPCRs). We analyzed subcellular localization of 138 non-odorant GPCRs. We transfected GPCR expression vectors into NIH3T3 cells, induced ciliogenesis by serum starvation, and observed subcellular localization of GPCRs by immunofluorescent staining. We found that several GPCRs whose ligands are involved in feeding behavior, including prolactin-releasing hormone receptor (PRLHR), neuropeptide FF receptor 1 (NPFFR1), and neuromedin U receptor 1 (NMUR1), localized to the primary cilia. In addition, we found that a short form of dopamine receptor D2 (DRD2S) is efficiently transported to the primary cilia, while a long form of dopamine receptor D2 (DRD2L) is rarely transported to the primary cilia. Using an anti-Prlhr antibody, we found that Prlhr localized to the cilia on the surface of the third ventricle in the vicinity of the hypothalamic periventricular nucleus. We generated the Npy2r-Cre transgenic mouse line in which Cre-recombinase is expressed under the control of the promoter of Npy2r encoding a ciliary GPCR. By mating Npy2r-Cre mice with Ift80 flox mice, we generated Ift80 conditional knockout (CKO) mice in which Npy2r-positive cilia were diminished in number. We found that Ift80 CKO mice exhibited a body weight increase. Our results suggest that Npy2r-positive cilia are important for body weight control.

Rax Homeoprotein Regulates Photoreceptor Cell Maturation and Survival in Association with Crx in the Postnatal Mouse Retina.

The Rax homeobox gene plays essential roles in multiple processes of vertebrate retina development. Many vertebrate species possess Rax and Rax2 genes, and different functions have been suggested. In contrast, mice contain a single Rax gene, and its functional roles in late retinal development are still unclear. To clarify mouse Rax function in postnatal photoreceptor development and maintenance, we generated conditional knockout mice in which Rax in maturing or mature photoreceptor cells was inactivated by tamoxifen treatment (Rax iCKO mice). When Rax was inactivated in postnatal Rax iCKO mice, developing photoreceptor cells showed a significant decrease in the level of the expression of rod and cone photoreceptor genes and mature adult photoreceptors exhibited a specific decrease in cone cell numbers. In luciferase assays, we found that Rax and Crx cooperatively transactivate Rhodopsin and cone opsin promoters and that an optimum Rax expression level to transactivate photoreceptor gene expression exists. Furthermore, Rax and Crx colocalized in maturing photoreceptor cells, and their coimmunoprecipitation was observed in cultured cells. Taken together, these results suggest that Rax plays essential roles in the maturation of both cones and rods and in the survival of cones by regulating photoreceptor gene expression with Crx in the postnatal mouse retina.

Complete Surgical Resection of a Leiomyosarcoma Arising from the Inferior Vena Cava.

A 76-year-old Japanese man was referred to our hospital with chief complaint of right hypochondoralgia. Abdominal ultrasound showed a retroperitoneal tumor in the suprarenal region of the right kidney. Computed tomography revealed an enhanced lobular tumor with irregular, circumscribed, and indistinct border. Ultrasound-guided biopsy was performed. The tumor consisted of spindle-shaped cells with a giant nucleus and multinuclear cells. The diagnosis was leiomyosarcoma by immunohistochemical staining. The patient underwent surgery accessed by a right eighth intercostal thoracoabdominal incision. The tumor was completely resected, accompanied by removal of the posterosuperior segment of the right hepatic lobe, right adrenal gland, and a portion of the inferior vena cava (IVC). The histopathologic diagnosis was leiomyosarcoma arising from the IVC. We present a rare case of a successfully managed leiomyosarcoma of the IVC. This case suggests the importance of curative surgical resection of the tumor due to low efficacy of adjuvant chemotherapy for leiomyosarcoma.

Giant polypoid tumor expressing on the pyloric ring.

A 66-year-old Japanese man was referred to our hospital because of suspected duodenal cancer. Upper gastric endoscopy revealed a giant polypoid-type tumor that extended from the duodenum bulb to the pyloric ring. A computed tomography scan revealed a slightly enhanced lobular tumor protruding into the duodenum bulb. Positron emission tomography showed an accumulation of (18)F-fluorodeoxyglucose in the area extending from the antrum of the stomach to the duodenum bulb. Since an endoscopic ultrasound test suggested that the tumor might invade the muscular tunic, indications of endoscopic mucosal resection were not favored, and the tumor was curatively removed via distal gastrectomy. The histopathologic diagnosis was papillary adenocarcinoma, and the invasion depth was the mucosal layer without vascular invasion, which was different from the preoperative diagnosis. Our case suggests the difficulties in precise diagnosis of the invasion depth of the giant polypoid cancer.

Protein-4.1G-Mediated Membrane Trafficking Is Essential for Correct Rod Synaptic Location in the Retina and for Normal Visual Function.

In vertebrate retinal development, the axonal terminals of retinal neurons make synaptic contacts within narrow fixed regions, and these locations are maintained thereafter. However, the mechanisms and biological logic of the organization of these fixed synapse locations are poorly understood. We show here that a membrane scaffold protein, 4.1G, is highly expressed in retinal photoreceptors and is essential for the arrangement of their correct synapse location. The 4.1G-deficient retina exhibits mislocalization of photoreceptor terminals, although their synaptic connections are normally formed. The 4.1G protein binds to the AP3B2 protein, which is involved in neuronal membrane trafficking, and promotes neurite extension in an AP3B2-dependent manner. 4.1G mutant mice showed visual acuity impairments in an optokinetic response, suggesting that correct synapse location is required for normal visual function. Taken together, the data in this study provide insight into the mechanism and importance of proper synapse location in neural circuit formation.

miR-124a is required for hippocampal axogenesis and retinal cone survival through Lhx2 suppression.

MicroRNA-124a (miR-124a) is the most abundant microRNA expressed in the vertebrate CNS. Despite past investigations into the role of miR-124a, inconsistent results have left the in vivo function of miR-124a unclear. We examined the in vivo function of miR-124a by targeted disruption of Rncr3 (retinal non-coding RNA 3), the dominant source of miR-124a. Rncr3(-/-) mice exhibited abnormalities in the CNS, including small brain size, axonal mis-sprouting of dentate gyrus granule cells and retinal cone cell death. We found that Lhx2 is an in vivo target mRNA of miR-124a. We also observed that LHX2 downregulation by miR-124a is required for the prevention of apoptosis in the developing retina and proper axonal development of hippocampal neurons. These results suggest that miR-124a is essential for the maturation and survival of dentate gyrus neurons and retinal cones, as it represses Lhx2 translation.