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Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disease characterised by systemic hamartomas or benign tumours which affects multiple organs including brains, kidneys, heart, liver, eyes, lungs and skin due to inappropriate activation of mammalian target of rapamycin (mTOR)

Due to the COVID-19 pandemic, the 84thAnnual Meeting of the Japanese Circulation Society (JCS) was held in a web-based format for the first time in its history as "The Week for JCS 2020" from Monday, July 27 to Sunday, August 2, 2020. All sessions, including general abstracts, were streamed live or on-demand. The main theme of the meeting was "Change Practice!" and the aim was to organize the latest findings in the field of cardiovascular medicine and discuss how to change practice. The total number of registered attendees was over 16,800, far exceeding our expectations, and many of the sessions were viewed by far more people than at conventional face-to-face scientific meetings. At this conference, the power of online information dissemination was fully demonstrated, and the evolution of online academic meetings will be a direction that cannot be reversed in the future. The meeting was completed with great success, and we express our heartfelt gratitude to all affiliates for their enormous amount of work, cooperation, and support.

Low blood levels of vitamin D have been reported in children who have frequent respiratory tract infections. We measured serum concentrations of 25-hydroxy (OH) vitamin D in Japanese infants under 3 months of age who had respiratory syncytial virus (RSV) infection. Serum levels of 25-OH vitamin D in the 10 infants, excluding those with underlying diseases, were between < 4 and 29.8 ng/mL. In 8 out of 10 subjects (80.0%), serum 25-OH vitamin D levels were lower than 20 ng/mL. There was no statistically significant association between the levels of 25-OH vitamin D and age, duration of admission, respiratory severity score, white blood cell count, blood gas levels, and N-terminal pro-natriuretic peptide levels. Levels of serum 25-OH vitamin D in children who required hospitalization owing to RSV infection were low, indicating deficiency. These results suggest that vitamin D deficiency affects the susceptibility to RSV infection, but not the severity of the infection.

Salusin-β is an endogenous bioactive peptide that was identified in a human full-length enriched cDNA library using bioinformatics analyses. In our previous study, we found that synthetic salusin-β exhibits antibacterial activity against only Gram-positive microorganisms such as Staphylococcus aureus NBRC 12732. Salusin-β has an ability to depolarize the cytoplasmic membrane of this bacterium, and this phenomenon may be linked to the antibacterial activity of this peptide. A cell-penetrating peptide (CPP), human immunodeficiency virus (HIV)-1 transactivator of transcription (Tat) (49-57) is a short cationic peptide that can traverse cell membranes. In this report, synthetic peptide conjugates of salusin-β and HIV-1 Tat(49-57) showed potent antibacterial activities against both Gram-positive Staphylococcus aureus NBRC 12732 and Gram-negative Escherichia coli NBRC 12734. The synthetic peptides also depolarized the cytoplasmic membrane of Escherichia coli NBRC 12734 as well as Staphylococcus aureus NBRC 12732. These results suggested that HIV-1 Tat(49-57) is a protein transduction domain or CPP that changes the interaction mode between salusin-β and the cell membrane of Escherichia coli NBRC 12734. By binding to HIV-1 Tat(49-57), salusin-β showed a broad antibacterial spectrum regardless of whether the target was a Gram-positive or Gram-negative bacterium.

Few studies have investigated or verified the pressure resistance of anastomosis with circular staplers. We conducted end-to-end anastomoses with circular staplers and compared the pressure resistance with or without bioabsorbable material (Neoveil NanoⓇ). We conducted end-to-end anastomosis with or without Neoveil NanoⓇ (NN). Fresh pig small intestines were used. An end-to-end anastomosis was performed between two intestinal specimens using a circular stapler. The burst pressure of the anastomosis was recorded. The group with the highest pressure resistance was the group in which NN was attached only to the anvil, which was higher than the group in which NN was attached to the shaft and anvil. In contrast, no increase in pressure resistance occurred in the group using NN only for the shaft. Clinically, this method was used for various anastomoses using a circular stapler. In the absence of NN, a portion of the staple was often exposed at the anastomosis. When NN was used, however, only a small amount of the staple was exposed. There were no complications that were associated with NN. The usefulness of NN for pressure resistance of anastomosis with a circular stapler was demonstrated. The pressure resistance was highest by attaching NN only to the anvil of the stapler. Use of a circular stapler significantly reduces the complication associated with an anastomosis.

β-1,3-d-Glucan is a ubiquitous glucose polymer produced by plants, bacteria, and most fungi. It has been used as a diagnostic tool in patients with invasive mycoses via a highly-sensitive reagent consisting of the blood coagulation system of horseshoe crab. However, no method is currently available for measuring β-1,6-glucan, another primary β-glucan structure of fungal polysaccharides. Herein, we describe the development of an economical and highly-sensitive and specific assay for β-1,6-glucan using a modified recombinant endo-β-1,6-glucanase having diminished glucan hydrolase activity. The purified β-1,6-glucanase derivative bound to the β-1,6-glucan pustulan with a KD of 16.4 nm. We validated the specificity of this β-1,6-glucan probe by demonstrating its ability to detect cell wall β-1,6-glucan from both yeast and hyphal forms of the opportunistic fungal pathogen Candida albicans, without any detectable binding to glucan lacking the long β-1,6-glucan branch. We developed a sandwich ELISA-like assay with a low limit of quantification for pustulan (1.5 pg/ml), and we successfully employed this assay in the quantification of extracellular β-1,6-glucan released by >250 patient-derived strains of different Candida species (including Candida auris) in culture supernatant in vitro. We also used this assay to measure β-1,6-glucan in vivo in the serum and in several organs in a mouse model of systemic candidiasis. Our work describes a reliable method for β-1,6-glucan detection, which may prove useful for the diagnosis of invasive fungal infections.

Chitooligosaccharides exhibit several biomedical activities, such as inflammation and tumorigenesis reduction in mammals. The mechanism of the chitooligosaccharides’ formation in vivo has been, however, poorly understood. Here we report that mouse acidic chitinase (Chia), which is widely expressed in mouse tissues, can produce chitooligosaccharides from deacetylated chitin (chitosan) at pH levels corresponding to stomach and lung tissues. Chia degraded chitin to produce N-acetyl-d-glucosamine (GlcNAc) dimers. The block-type chitosan (heterogenous deacetylation) is soluble at pH 2.0 (optimal condition for mouse Chia) and was degraded into chitooligosaccharides with various sizes ranging from di- to nonamers. The random-type chitosan (homogenous deacetylation) is soluble in water that enables us to examine its degradation at pH 2.0, 5.0, and 7.0. Incubation of these substrates with Chia resulted in the more efficient production of chitooligosaccharides with more variable sizes was from random-type chitosan than from the block-type form of the molecule. The data presented here indicate that Chia digests chitosan acquired by homogenous deacetylation of chitin in vitro and in vivo. The degradation products may then influence different physiological or pathological processes. Our results also suggest that bioactive chitooligosaccharides can be obtained conveniently using homogenously deacetylated chitosan and Chia for various biomedical applications.

Introduction The occurrence of sporadic colonic neurofibroma particularly in a patient without neurofibromatosis type 1 has been rarely reported. Therefore, the clinical significance of this disease has not been fully elucidated. Presentation of case An 81-year-old woman with a positive fecal occult blood test result was referred to our institution for the evaluation of anemia. On colonoscopy, a 50-mm submucosal tumor-like mass was found in the hepatic flexure of the colon. Superficial biopsy and boring biopsy showed unspecific granulation tissues, and immunostaining revealed that the mesenchymal tumor was negative for CD34, c-kit, desmin, and S100 protein. The patient underwent laparoscopic right colectomy with complete mesocolic excision (CME). Pathologically, the tumor was diagnosed as neurofibroma. Discussion Gastrointestinal neurofibromas are known to cause clinical symptoms. No colonic neurofibroma has been diagnosed before resection. Moreover, neurofibromas, particularly large lesions, reportedly undergo malignant transformation. Surgical extirpation with clear margins is the primary treatment, and laparoscopic surgery is considered acceptable for colonic neurofibroma and colon cancer. Conclusion Based on our experience, a preoperative diagnosis was impossible for colonic neurofibroma. Laparoscopic surgery with CME is considered feasible for sporadic colonic neurofibroma.

Visual Abstract, Highlights • KUS121 was developed to selectively inhibit the adenosine triphosphatase activity of valosin-containing protein without affecting other cellular functions of valosin-containing protein. • KUS121 preserved adenosine triphosphate levels, reduced endoplasmic reticulum stress, and suppressed cell death in H9C2 rat cardiomyoblast cells, treated with tunicamycin or hydrogen peroxide, or cultured in glucose-free medium. • In murine ischemia and reperfusion injury models, KUS121 treatment after reperfusion attenuated the infarcted size and preserves cardiac function by maintaining adenosine triphosphate levels and reducing ER stress. • In porcine ischemia and reperfusion injury models, intracoronary administration of KUS121 also attenuated the infarcted area in a dose-dependent manner. • These results indicated that KUS121 is a promising novel therapeutic agent for myocardial infarction., Summary No effective treatment is yet available to reduce infarct size and improve clinical outcomes after acute myocardial infarction by enhancing early reperfusion therapy using primary percutaneous coronary intervention. The study showed that Kyoto University Substance 121 (KUS121) reduced endoplasmic reticulum stress, maintained adenosine triphosphate levels, and ameliorated the infarct size in a murine cardiac ischemia and reperfusion injury model. The study confirmed the cardioprotective effect of KUS121 in a porcine ischemia and reperfusion injury model. These findings confirmed that KUS121 is a promising novel therapeutic agent for myocardial infarction in conjunction with primary percutaneous coronary intervention.

Adaptive thermogenesis is essential for survival, and therefore is tightly regulated by a central neural circuit. Here, we show that microRNA (miR)-33 in the brain is indispensable for adaptive thermogenesis. Cold stress increases miR-33 levels in the hypothalamus and miR-33−/− mice are unable to maintain body temperature in cold environments due to reduced sympathetic nerve activity and impaired brown adipose tissue (BAT) thermogenesis. Analysis of miR-33f/f dopamine-β-hydroxylase (DBH)-Cre mice indicates the importance of miR-33 in Dbh-positive cells. Mechanistically, miR-33 deficiency upregulates gamma-aminobutyric acid (GABA)A receptor subunit genes such as Gabrb2 and Gabra4. Knock-down of these genes in Dbh-positive neurons rescues the impaired cold-induced thermogenesis in miR-33f/f DBH-Cre mice. Conversely, increased gene dosage of miR-33 in mice enhances thermogenesis. Thus, miR-33 in the brain contributes to maintenance of BAT thermogenesis and whole-body metabolism via enhanced sympathetic nerve tone through suppressing GABAergic inhibitory neurotransmission. This miR-33-mediated neural mechanism may serve as a physiological adaptive defense mechanism for several stresses including cold stress., 褐色脂肪細胞の燃焼を促す新たなメカニズムを解明 --体の熱産生にマイクロRNA-33が関与--. 京都大学プレスリリース. 2021-02-17.

One of the complications in laparoscopic surgery is port-site hernia. It is a rare but potentially dangerous complication. Especially when using ports with a size 10 mm or more, it is required to securely close the port site. However, this procedure is often difficult especially for obese patients. We herein devised a new closure method by using a device developed for port site. These techniques are methods that can close the port site by a combination of putting in and out of thread and port rotation without removing a port. The port-site closure with these techniques was done for 53 port sites of 41 patients. The port site was closed horizontally or vertically, depending on the shape of the port site for two patients. Modified Z-suture was done for other 37 patients. To date, we have not noted any complications from this new method, including port-site hernia. With our technique, we could save operation time and reduce stress of us especially for obese patients. We would like to increase the number of patients and verify the safety and usefulness in further study.

The use of laparoscopic surgery has become widespread in recent years. One of its complications is port site hernia (PHS). It can be difficult to close the fascia at the time of laparoscopy, especially in obese patients, and there is a risk of herniation through a fascial defect with incomplete closure. It is important to ascertain closure of the defect when repairing PHS to prevent recurrence. We report a 47-year-old woman who developed a PHS at the superior aspect of the umbilicus. We repaired the defect using the VersaOneTM Fascial Closure System with laparoscopic guidance. This system allows the port site to be reliably closed while observing the suture from the abdominal cavity. The incision is the same size as a port site. If the abdominal wall is thick and the PHS has a diameter of ~10 mm, this method is considered to be indicated, regardless of the site.

Recent high-throughput approaches have revealed a vast number of transcripts with unknown functions. Many of these transcripts are long noncoding RNAs (lncRNAs), and intergenic region-derived lncRNAs are classified as long intergenic noncoding RNAs (lincRNAs). Although Myosin heavy chain 6 (Myh6) encoding primary contractile protein is down-regulated in stressed hearts, the underlying mechanisms are not fully clarified especially in terms of lincRNAs. Here, we screen upregulated lincRNAs in pressure overloaded hearts and identify a muscle-abundant lincRNA termed Lionheart. Compared with controls, deletion of the Lionheart in mice leads to decreased systolic function and a reduction in MYH6 protein levels following pressure overload. We reveal decreased MYH6 results from an interaction between Lionheart and Purine-rich element-binding protein A after pressure overload. Furthermore, human LIONHEART levels in left ventricular biopsy specimens positively correlate with cardiac systolic function. Our results demonstrate Lionheart plays a pivotal role in cardiac remodeling via regulation of MYH6., Kuwabara et al. identify a novel long intergenic noncoding RNA (lincRNA), termed Lionheart, upregulated in pressure overloaded hearts in mice. Deleting this gene results in decreased systolic function and reduction in MYH6 protein levels following pressure overload. They demonstrate that Lionheart interacts with PURA, preventing its binding to the promoter region of Myh6 locus, leading to reduced MYH6 protein expression.

Recent reports, including ours, have indicated that microRNA (miR)-33 located within the intron of sterol regulatory element binding protein (SREBP) 2 controls cholesterol homeostasis and can be a potential therapeutic target for the treatment of atherosclerosis. Here, we show that SPAST, which encodes a microtubule-severing protein called SPASTIN, was a novel target gene of miR-33 in human. Actually, the miR-33 binding site in the SPAST 3′-UTR is conserved not in mice but in mid to large mammals, and it is impossible to clarify the role of miR-33 on SPAST in mice. We demonstrated that inhibition of miR-33a, a major form of miR-33 in human neurons, via locked nucleic acid (LNA)-anti-miR ameliorated the pathological phenotype in hereditary spastic paraplegia (HSP)-SPG4 patient induced pluripotent stem cell (iPSC)-derived cortical neurons. Thus, miR-33a can be a potential therapeutic target for the treatment of HSP-SPG4.

The vulnerability of the crotch on a side-to-side anastomosis to leak has been widely recognized. However, countermeasures to prevent leaks from the crotch have not proven to be sufficient. A side-to-side anastomosis was performed between two intestinal specimens using a linear stapler. We analyzed the burst pressures of anastomoses. Comparison was made in five groups, with different staple heights, presence of Neoveil® (Gunze, Japan), with or without crotch buttressed with nylon. Using an endoscope inserted into the intestinal lumen, we observed the burst process. We observed a significant difference in the resistance of the crotch to leak between the two types of reinforcement. In all experimental groups, the leak was observed not only on the serosal surface but also from within the lumen. Neoveil® significantly increased the burst pressure (41.4 ± 3.6 vs. 88.8 ± 14.6 mm Hg; p

Recent evidence suggests that the accumulation of macrophages as a result of obesity-induced adipose tissue hypoxia is crucial for the regulation of tissue fibrosis, but the molecular mechanisms underlying adipose tissue fibrosis are still unknown. In this study, we revealed that periostin (Postn) is produced at extraordinary levels by adipose tissue after feeding with a high-fat diet (HFD). Postn was secreted at least from macrophages in visceral adipose tissue during the development of obesity, possibly due to hypoxia. Postn−/− mice had lower levels of crown-like structure formation and fibrosis in adipose tissue and were protected from liver steatosis. These mice also showed amelioration in systemic insulin resistance compared with HFD-fed WT littermates. Mice deficient in Postn in their hematopoietic compartment also had lower levels of inflammation in adipose tissue, in parallel with a reduction in ectopic lipid accumulation compared with the controls. Our data indicated that the regulation of Postn in visceral fat could be beneficial for the maintenance of healthy adipose tissue in obesity.

Background Few studies have investigated the burst pressure of side-to-side anastomoses comparing different stapling devices that are commercially available. Objectives We conducted side-to-side anastomoses with a variety of staplers and compared burst pressure in the crotch of the anastomoses. Setting Nagoya City East Medical Center. Methods We conducted side-to-side anastomoses with 9 staplers with different shapes and forms. Fresh pig small intestines were used. A side-to-side anastomosis was performed between 2 intestine specimens using a linear stapler. The burst pressure of the anastomosis was recorded. Results In total, 45 staplers were used for this experiment. The site of leakage in all cases was the crotch. Regarding the influence of the number of staple rows, the burst pressure in 3-row staplers was significantly higher than in 2-row staplers. With regard to the relationship between staple height and burst pressure, staples with a height slightly shorter than the intestinal thickness showed the highest burst pressure. In a comparison of staplers with uniform staple heights and stamplers with staples of 3 different heights, the latter had significantly lower burst pressures. Neoveil significantly increased the burst pressure in the crotch and contributed to the highest burst pressure of all the staplers used in this experiment. Conclusions In this experiment, we defined the important factors that influence burst pressure at the crotch of a stapled, side-to-side anastomosis. These factors include the number of staple rows, the height of the staple compared with the thickness of the tissue, uniformity of staple height, and reinforcement of the staple line. In any surgical case requiring intestinal anastomosis, selection of a stapler is a critical step.

Objective— Abdominal aortic aneurysm (AAA) is an increasingly prevalent and ultimately fatal disease with no effective pharmacological treatment. Because matrix degradation induced by vascular inflammation is the major pathophysiology of AAA, attenuation of this inflammation may improve its outcome. Previous studies suggested that miR-33 (microRNA-33) inhibition and genetic ablation of miR-33 increased serum high-density lipoprotein cholesterol and attenuated atherosclerosis. Approach and Results— MiR-33a-5p expression in central zone of human AAA was higher than marginal zone. MiR-33 deletion attenuated AAA formation in both mouse models of angiotensin II– and calcium chloride–induced AAA. Reduced macrophage accumulation and monocyte chemotactic protein-1 expression were observed in calcium chloride–induced AAA walls in miR-33 −/− mice. In vitro experiments revealed that peritoneal macrophages from miR-33 −/− mice showed reduced matrix metalloproteinase 9 expression levels via c-Jun N-terminal kinase inactivation. Primary aortic vascular smooth muscle cells from miR-33 −/− mice showed reduced monocyte chemotactic protein-1 expression by p38 mitogen-activated protein kinase attenuation. Both of the inactivation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase were possibly because of the increase of ATP-binding cassette transporter A1 that is a well-known target of miR-33. Moreover, high-density lipoprotein cholesterol derived from miR-33 −/− mice reduced expression of matrix metalloproteinase 9 in macrophages and monocyte chemotactic protein-1 in vascular smooth muscle cells. Bone marrow transplantation experiments indicated that miR-33–deficient bone marrow cells ameliorated AAA formation in wild-type recipients. MiR-33 deficiency in recipient mice was also shown to contribute the inhibition of AAA formation. Conclusions— These data strongly suggest that inhibition of miR-33 will be effective as a novel strategy for treating AAA.

// Hideyuki Ishiguro 1, * , Tomotaka Okubo 1, * , Yoshiyuki Kuwabara 1 , Masahiro Kimura 1 , Akira Mitsui 1 , Nobuyoshi Sugito 1 , Ryo Ogawa 1 , Takeyasu Katada 1 , Tatsuya Tanaka 1 , Midori Shiozaki 1 , Koji Mizoguchi 1 , Yosuke Samoto 1 , Yoichi Matsuo 1 , Hiroki Takahashi 1 and Shuji Takiguchi 1 1 Nagoya City University Graduate School of Medicine, Department of Gastroenterological Surgery, Mizuho-ku, Nagoya 467-8601, Japan * These authors have contributed equally to this work Correspondence to: Hideyuki Ishiguro, email: h-ishi@med.nagoya-cu.ac.jp Keywords: colon cancer, β-catenin, NOTCH1, NICD1, prognosis Received: May 29, 2016 Accepted: June 27, 2017 Published: July 25, 2017 ABSTRACT Purpose and Methods: The translocation of β-catenin/CTNNB1 to the nucleus activates Wnt signaling and cell proliferation; however, the precise mechanism underlying this phenomenon remains unknown. Previous reports have provided evidence that NOTCH1 is involved in the Wnt signaling pathway. Therefore, we sought to determine the mechanism by which NOTCH1 influences the Wnt/β-catenin pathway. We constructed a vector expressing the NOTCH1 intracellular domain (NICD1) and transfected the vector into HCT116 which has low expression of NICD1. Furthermore, inhibition of NOTCH signal pathway in SW480 which has abundant NICD1 expression, was performed by transfection of siNICD1 or DAPT, gamma secretase inhibitor, treatment. In addition, we evaluated NICD1 and β-catenin localization in colon cancer cell lines and in 189 colon cancer tissue samples and analyzed the correlation between the nuclear localization of NICD1 and the clinicopathological features of colon cancer patients. Results: Immunohistochemical assays demonstrated that NICD1 and β-catenin exhibited a similar localization pattern in colon cancer tissues. In addition, we found that NICD1 induced the translocation of β-catenin to the nucleus and that NICD1 and β-catenin co-localized in the nucleus. Overexpression of NICD1 increased luciferase activity of Wnt signal pathway. On the other hand, reduction of NICD1 reduced luciferase activity of Wnt signaling pathway. In the 189 analyzed colon cancer cases, multivariate COX regression analysis demonstrated the independent prognostic impact of nuclear localization of NICD1(p=0.0376). Conclusion: NOTCH1 plays a key role in the Wnt pathway and activation of NOTCH1 is associated with the translocation of β-catenin to the nucleus.

Side-to-side anastomoses are more frequently performed. This method is relatively simple, timesaving, and can be applied in a variety of settings where anastomoses are necessary. Despite some advances, stapled anastomoses have inherent weak points. With any type of side-to-side anastomosis, the crotch is formed at the tip portion of the stapler; this crotch area is the weak point. We describe a novel surgical technique for side-to-side anastomosis using a reinforced crotch. After distal gastrectomy, a small incision was made on the greater curvature of the remnant stomach and the posterior side of the duodenum. We use a 60-mm linear stapler, namely, the Endo GIATM Reinforce Reload (Covidien Japan). Therefore, the stapler length inserted into the stomach and duodenum is 45 mm. The reinforce reloads have a preloaded reinforcement material on the both anvil and cartridge. One or two supporting sutures were added to the center of the common enterotomy. Pulling up on the two pieces of Neoveil® and the sutures, the common enterotomy was closed with a linear stapler. Delta-shaped anastomosis is then accomplished. We also use a reinforced reload in a side-to-side anastomosis between two segments of jejunum. Neoveil® is thin and soft; we found no problem using either a hand thrown suture or stapler to close the entry hole. In fact, we found that the excess Neoveil® is very useful. Neoveil® can be a substitute for the sutures. Only one or two hand thrown sutures were then necessary to close the common enterotomy. And we do not add the reinforce suture of the crotch at all. This novel method is a simple and useful method and can be used in side-to-side anastomoses in a variety of settings.

Rationale: Heart failure and atherosclerosis share the underlying mechanisms of chronic inflammation followed by fibrosis. A highly conserved microRNA (miR), miR-33, is considered as a potential therapeutic target for atherosclerosis because it regulates lipid metabolism and inflammation. However, the role of miR-33 in heart failure remains to be elucidated. Objective: To clarify the role of miR-33 involved in heart failure. Methods and Results: We first investigated the expression levels of miR-33a/b in human cardiac tissue samples with dilated cardiomyopathy. Increased expression of miR-33a was associated with improving hemodynamic parameters. To clarify the role of miR-33 in remodeling hearts, we investigated the responses to pressure overload by transverse aortic constriction in miR-33–deficient (knockout [KO]) mice. When mice were subjected to transverse aortic constriction, miR-33 expression levels were significantly upregulated in wild-type left ventricles. There was no difference in hypertrophic responses between wild-type and miR-33KO hearts, whereas cardiac fibrosis was ameliorated in miR-33KO hearts compared with wild-type hearts. Despite the ameliorated cardiac fibrosis, miR-33KO mice showed impaired systolic function after transverse aortic constriction. We also found that cardiac fibroblasts were mainly responsible for miR-33 expression in the heart. Deficiency of miR-33 impaired cardiac fibroblast proliferation, which was considered to be caused by altered lipid raft cholesterol content. Moreover, cardiac fibroblast–specific miR-33–deficient mice also showed decreased cardiac fibrosis induced by transverse aortic constriction as systemic miR-33KO mice. Conclusion: Our results demonstrate that miR-33 is involved in cardiac remodeling, and it preserves lipid raft cholesterol content in fibroblasts and maintains adaptive fibrotic responses in the remodeling heart.

Background Micro RNA (miR)‐33 targets cholesterol transporter ATP ‐binding cassette protein A1 and other antiatherogenic targets and contributes to atherogenic progression. Its inhibition or deletion is known to result in the amelioration of atherosclerosis in mice. However, mice lack the other member of the miR‐33 family, miR‐33b, which exists in humans and other large mammals. Thus, precise evaluation and comparison of the responsibilities of these 2 miRs during the progression of atherosclerosis has not been reported, although they are essential. Methods and Results In this study, we performed a comprehensive analysis of the difference between the function of miR‐33a and miR‐33b using genetically modified mice. We generated 4 strains with or without miR‐33a and miR‐33b. Comparison between mice with only miR‐33a (wild‐type mice) and mice with only miR‐33b (miR‐33a −/− /miR‐33b +/+ ) revealed the dominant expression of miR‐33b in the liver. To evaluate the whole body atherogenic potency of miR‐33a and miR‐33b, we developed apolipoprotein E–deficient/miR‐33a +/+ /miR‐33b −/− mice and apolipoprotein E–deficient/miR‐33a −/− /miR‐33b +/+ mice. With a high‐fat and high‐cholesterol diet, the apolipoprotein E–deficient/miR‐33a −/− /miR‐33b +/+ mice developed increased atherosclerotic plaque versus apolipoprotein E–deficient/miR‐33a +/+ /miR‐33b −/− mice, in line with the predominant expression of miR‐33b in the liver and worsened serum cholesterol profile. By contrast, a bone marrow transplantation study showed no significant difference, which was consistent with the relevant expression levels of miR‐33a and miR‐33b in bone marrow cells. Conclusions The miR‐33 family exhibits differences in distribution and regulation and particularly in the progression of atherosclerosis; miR‐33b would be more potent than miR‐33a.

With the widespread of the novel coronavirus (SARS-CoV-2), the inactivation of bacteria and viruses using ultraviolet (UV) light has been reevaluated. However, there are many applications where the safety to the human body itself and inactivation effect itself are questioned, and there is a movement to review the UV-C guidelines (Global Lighting Association, Position Statement on Germicidal UV-C Irradiation UV-C SAFETY GUIDELINES, 2020). Since the Minamata Convention on Mercurybans the production of mercury in principle, deep-ultraviolet light-emitting diodes (UVC-LEDs) are now being used in place of mercury lamps. In this paper, we will discuss effective irradiation methods for the inactivation of pathogens on solid surfaces, the inactivation of pathogens in water, and the inactivation of viruses in aerosols using UVC-LED.

Highlights • The indications for stripping of the esophagus have decreased due to the widespread of endoscopic mucosal resection and thoracoscopic surgery. • Even if indications for this procedure have decreased, this is an important option in the armamentarium of the esophageal surgeon., Introduction Patients with esophageal cancer frequently cannot tolerate thoracotomy due to their overall debilitated condition. Moreover, some patients have severe adhesions in the thoracic cavity. Eversion stripping of the esophagus is an option for resection in these patients. Presentation of case A 64-year-old man was admitted to our institution with the chief complaint of epigastric pain. Endoscopic examination showed a protruding lesion 22 cm from the incisors, with a superficial and circumferential mucosal irregularity on the distal side of the lesion. Biopsy revealed squamous cell carcinoma. Clinical stage was T1b(sm)N0M0, cStage I. In addition to the poor pulmonary status of the patient, adhesions in the intrathoracic cavity were predicted. The decision was made to perform esophageal resection without a thoracotomy. In order to ensure complete invagination of the esophagus, the esophagus was insufflated prior to stripping. The stripping process was observed with a gastroscope. During the stripping, the esophagus did not bunch up, and stripping was smooth and with minimal resistance. Discussion The stripping resection of the esophagus is an important option for the esophageal surgeon. In this case report, we describe a new eversion stripping method of the esophagus. This easy and reliable stripping method incorporates intraesophageal insufflation. Conclusion The indications for blunt esophageal dissection without thoracotomy have been decreasing. On the other hand, our method seems to be useful in optimal case of stripping of esophagus.

Acidic mammalian chitinase (AMCase) is implicated in asthma, allergic inflammation, and food processing. Little is known about genetic and evolutional regulation of chitinolytic activity of AMCase. Here, we relate human AMCase polymorphisms to the mouse AMCase, and show that the highly active variants encoded by nonsynonymous single-nucleotide polymorphisms (nsSNPs) are consistent with the mouse AMCase sequence. The chitinolytic activity of the recombinant human AMCase was significantly lower than that of the mouse counterpart. By creating mouse-human chimeric AMCase protein we found that the presence of the N-terminal region of human AMCase containing conserved active site residues reduced the enzymatic activity of the molecule. We were able to significantly increase the activity of human AMCase by amino acid substitutions encoded by nsSNPs (N45, D47, and R61) with those conserved in the mouse homologue (D45, N47, and M61). For abolition of the mouse AMCase activity, introduction of M61R mutation was sufficient. M61 is conserved in most of primates other than human and orangutan as well as in other mammals. Orangutan has I61 substitution, which also markedly reduced the activity of the mouse AMCase, indicating that the M61 is a crucial residue for the chitinolytic activity. Altogether, our data suggest that human AMCase has lost its chitinolytic activity by integration of nsSNPs during evolution and that the enzyme can be reactivated by introducing amino acids conserved in the mouse counterpart.

Recent studies have shown constitutive activation of the Notch signaling pathway in various types of malignancies. However, it remains unclear whether this signaling pathway is activated in gastric cancer. In the present study, the aim was to investigate the role of Notch signaling in gastric cancer by investigating the subcellular localization of Notch-associated proteins in tissue samples from gastric cancer patients. Samples were obtained from 115 gastric cancer patients who had undergone surgery at the Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Science without pre-operative chemotherapy or radiation. Subsequently the correlation between translocation of NOTCH1 intracellular cytoplasmic domain (NICD) into the nucleus (as measured by immunostaining) and survival in gastric cancer patients after surgery was investigated. The results were analyzed in reference to the patients' clinicopathological characteristics and the effects of these results on patient prognosis were determined. Significant correlations were observed between NICD nuclear localization and clinicopathological characteristics, such as tumor status (T factor), lymph node status (N factor), pathological stage and differentiation status. No significant correlations were observed between NICD nuclear localization and age, gender, tumor location, vein invasion or lymphatic invasion. Patients with >30% of cancer cell nuclei positively stained for NICD (as revealed by immunostaining) were associated with a significantly shorter survival following surgery than patients with

Patients with unresectable esophageal cancer suffer from dysphagia, causing severe malnutrition and reduced quality of life (QOL). We elect to perform bypass because patients can have greater long-term survival with chemoradiation following this operation. We sought to compare complications in cases of bypass without thoracotomy versus those with thoracotomy. Thirty-four locally advanced esophageal cancer patients between 2007 and 2014 were studied. Eighteen patients underwent thoracotomy, and 16 patients did not have a thoracotomy. CT was obtained to check the anastomosis and the oral stump of the esophagus and to measure the diameter of the intrathoracic esophagus. In the thoracotomy group, the rate of postoperative pulmonary complications was high. On the other hand, in the non-thoracotomy group, the rates of anastomotic leak and recurrent nerve paralysis were high. The stump of the esophagus was 2 cm lower in the T group than in the nT group. As the esophagus shortens after division, the final difference in esophageal height between the groups was only around 1 cm. We concluded that a viable gastric tube with a good blood supply as well as a careful cervical operation are the most important aspects of the esophageal bypass operation.

Connexin 43 (Cx43) is an important gap junction protein in vertebrates, which has been reported to function as a tumor suppressor in a number of organs. However, the mechanism underlying the effect of Cx43 on tumor progression remains unknown, with only a limited number of studies reporting on the role of Cx43 in esophageal cancer. In the present study, Cx43 expression was analyzed by immunohistochemical staining and the associations between Cx43 expression and clinicopathological characteristics or prognosis were evaluated. Cx43 was expressed at a high frequency in patients with esophageal squamous cell carcinoma (ESCC). Of the 98 ESCC cases investigated, positivity for Cx43 was observed in 62 cases (63.26%). In patients with high Cx43 expression, the survival rates were significantly reduced compared with those in patients with low Cx43 expression. Moreover, the overexpression of Cx43, as measured by immunohistochemistry, was an independent prognostic indicator of ESCC. Thus, our data indicated that Cx43 may be a candidate molecular prognostic marker and molecular target for the development of an effective therapeutic intervention for patients with esophageal cancer.

Background Few studies have been designed regarding optimal reinforcement of the crotch of a side-to-side anastomosis. The purpose of this study was to clarify the weak point of the side-to-side anastomosis and to evaluate the effect of bioabsorbable reinforcement material. Methods Fresh pig small bowel was used for all experiments. A side-to-side anastomosis was performed using a linear stapler, and the burst pressure of the anastomosis was measured. Three separate experiments were done. In experiment 1, the weak point and the burst pressure of that point were defined. In experiment 2, the burst pressure of the side of the anastomosis was measured. In experiment 3, we evaluated the effect of Neoveil® to strengthen the weak point of the anastomosis. Results The weak point of the side-to side anastomosis was the crotch and the burst pressure was 39.8 ± 5.7 mmHg. The burst pressure of the side of the anastomosis was 109.9 ± 7.9 mmHg. This was significantly higher than the burst pressure of the crotch (P = 0.008). The burst pressure of the crotch in the group with Neoveil® was 83.3 ± 14.9 mmHg. This pressure was significantly higher than the group with no Neoveil® reinforcement (P = 0.001). Conclusion These findings suggest that the use of Neoveil® as a buttressing material is associated with reinforced staple lines and increased crotch burst pressures compared to non-buttressed staple lines. Neoveil® was found to perform comparably to clinically available buttress materials in this ex vivo model. Reinforcement of the weak point of the side-to-side anastomosis with Neoveil®may lead to fewer anastomotic leaks., Highlights • The purpose of this study was to clarify the weak point of the side-to-side anastomosis and to evaluate the effect of Neoveil®. • The use of Neoveil® is associated with reinforced staple lines and increased crotch burst pressures compared to non-buttressed staple lines. • Neoveil® was found to perform comparably with clinically available buttress materials in this ex vivo model.

Introduction Various types of staplers are used for gastric tube formation after esophagectomy. Using a stapling device, a gastric tube can safely be created in a short amount of time. The problems with gastric tube creation using only linear type staplers include staple overlap as well as the problem of cost associated with using multiple staplers. To address this, both linear and radial type staplers have been introduced. We herein compare three methods of gastric tube creation. Methods From 2012 to 2014, 62 patients with esophageal cancer underwent esophagectomy with gastric tube reconstruction. We evaluated and compared the mean number of stapler loads and cost in each groups. Results The mean number of stapler loads was 6.24 in method A, 5.16 in method B, and 4.33 in method C. The mean cost accounting for total staple fires per case was 3116.07 dollars in the method A group, 2576.74 dollars in the method B group, and 2447.78 dollars in the method C group. Anastomotic leaks developed in 4 cases in the method A group and in 3 cases in the method B group. There were no anastomotic leaks in the method C group. Conclusion We hypothesize that by using radial type staplers, we can create a durable gastric tube and reduce the number of staplers and therefore reduce operative cost., Highlights • We herein compare three methods of gastric tube creation. • Using radial type staplers, we can create a durable gastric tube. • We also reduce the number of staplers and therefore reduce operative cost.

Micro light emitting diode (&mu, LED) displays have been in development since 2017, aimed for application in 2020. However, when using three-color, i.e., red, blue, and green LEDs, or blue LEDs that excite red and green phosphors, many challenges arise in mass production, cost, and quality. Our group has devised an ultraviolet (UV)-excited red, green, and blue (RGB) display that excites red, green, and blue phosphors using UV-LEDs. This paper studies how the composition and crystal defects of a light-emitting layer affect the luminous efficiency of a UV &mu, LED chip from the perspective of internal quantum efficiency (IQE). It was confirmed that the luminous efficiency improves by making the LED chips in the near ultraviolet range &mu, size. The UV &mu, LED chip emitting at 385 nm exhibited a more linear output than a 400-nm purple &mu, LED chip.

Here, we present a 76-year-old diabetic man who was diagnosed as having endogenous endophthalmitis caused by Streptococcus agalactiae that finally developed globe rupture, which is a rare endogenous endophthalmitis complication. This case highlight that endogenous endophthalmitis is an ophthalmological emergency with poor prognosis, thereby requiring prompt diagnosis and aggressive intervention. Keywords: Endogenous endophthalmitis, Globe rupture, Streptococcus agalactiae

Acute cardiac rupture and adverse left ventricular (LV) remodeling causing heart failure are serious complications of acute myocardial infarction (MI). While cardio-hepatic interactions have been recognized, their role in MI remains unknown. We treated cultured cardiomyocytes with conditioned media from various cell types and analyzed the media by mass spectrometry to identify α1-microglobulin (AM) as an Akt-activating hepatokine. In mouse MI model, AM protein transiently distributed in the infarct and border zones during the acute phase, reflecting infiltration of AM-bound macrophages. AM stimulation activated Akt, NFκB, and ERK signaling and enhanced inflammation as well as macrophage migration and polarization, while inhibited fibrogenesis-related mRNA expression in cultured macrophages and cardiac fibroblasts. Intramyocardial AM administration exacerbated macrophage infiltration, inflammation, and matrix metalloproteinase 9 mRNA expression in the infarct and border zones, whereas disturbed fibrotic repair, then provoked acute cardiac rupture in MI. Shotgun proteomics and lipid pull-down analysis found that AM partly binds to phosphatidic acid (PA) for its signaling and function. Furthermore, systemic delivery of a selective inhibitor of diacylglycerol kinase α-mediated PA synthesis notably reduced macrophage infiltration, inflammation, matrix metalloproteinase activity, and adverse LV remodeling in MI. Therefore, targeting AM signaling could be a novel pharmacological option to mitigate adverse LV remodeling in MI.

MicroRNA 33 (miR-33) targets ATP-binding cassette transporter A1 (ABCA1), and its deficiency increases serum high-density lipoprotein (HDL)-cholesterol (HDL-C) and ameliorates atherosclerosis. Although we previously reported that miR-33 deficiency increased peripheral Ly6Chigh monocytes on an ApoE-deficient background, the effect of miR-33 on the monocyte population has not been fully elucidated, especially in a wild-type (WT) background. We found that Ly6Chigh monocytes in miR-33−/− mice were decreased in peripheral blood and increased in bone marrow (BM). Expansion of myeloid progenitors and decreased apoptosis in Lin− Sca1+ c-Kit+ (LSK) cells were observed in miR-33−/− mice. A BM transplantation study and competitive repopulation assay revealed that hematopoietic miR-33 deficiency caused myeloid expansion and increased peripheral Ly6Chigh monocytes and that nonhematopoietic miR-33 deficiency caused reduced peripheral Ly6Chigh monocytes. Expression of high-mobility group AT-hook 2 (HMGA2) targeted by miR-33 increased in miR-33-deficient LSK cells, and its knockdown abolished the reduction of apoptosis. Transduction of human apolipoprotein A1 and ABCA1 in WT mouse liver increased HDL-C and reduced peripheral Ly6Chigh monocytes. These data indicate that miR-33 deficiency affects distribution of inflammatory monocytes through dual pathways. One pathway involves the enhancement of Hmga2 expression in hematopoietic stem cells to increase Ly6Chigh monocytes, and the other involves the elevation of HDL-C to decrease peripheral Ly6Chigh monocytes.

Background: In gastrointestinal surgery, the quality of anastomosis is one of the most important factors influencing the postoperative course. The purpose of this study was to verify the effectiveness and the mechanism of one type of reinforcement material. Methods: We analyzed the effect of Neoveil on the rate of staple line failure. Fresh pig small bowel was used. Neoveil sheets were placed on the anvil alone, cartridge alone or both sides of the stapler. Groups were: A, without Neoveil; B, the cartridge and anvil; C, the cartridge alone; D, the anvil alone. The burst pressures were measured. Results: In group A, a leak occurred at the intestinal stump in 5 of 10 cases (As). In the other 5 cases, the mesenteric side burst before failure of the staple line (Am). In groups B, C, and D, the mesenteric side burst before failure of the staple line. The median leak pressure was 100±46 mm Hg in group A (As; 57±6, Am; 143±12). In the other groups, the leak pressures were approximately Original Research Article 140 mm Hg. In group As, the middle staple only exists on the edge of stump. In group Am, however, both sides of the 3-row staple line exist on the edge of stump. Conclusion: The burst pressure of the stump became the result of the bipo of the stump staple line is affected by the arrangement of the staples. Neoveil obtaining a stronger staple line.