[Widely Applicable Strategies Against Cancer, Type II Diabetes, and Neurodegenerative Diseases by Means of Rationally Designed Anti-Amyloidogenic Molecules].

An increasing number of amyloidogenic proteins are being recognized for their contribution to the progression of various diseases, including cancer, type II diabetes, and neurodegenerative diseases. Detailed analyses of amyloids using cryo-electron microscopy have led to the development of rationally designed inhibitors of amyloid protein aggregation. In this review, we focused on widely applicable strategies against multiple amyloidogenic proteins based on the use of engineered molecules, namely peptidomimetic foldamers, steric zipper inhibitory peptides, di-phenyl-pyrazole derivatives, and chemicals involved in the disaggregation of amyloid fibrils. These strategies could facilitate efficient drug design across disease categories.

Isolation of High-Purity Betanin from Red Beet and Elucidation of Its Antioxidant Activity against Peroxynitrite: An in vitro Study.

Reactive oxygen species and reactive nitrogen species (RNS) are damaging for many biomolecules. Peroxynitrite (ONOO-) is the most toxic molecular species among RNS. Betalains are known to possess ONOO- scavenging ability. Betanin, a betalain isolated from red beet, possesses antioxidant, anti-inflammatory, and antitumor activities; however, detailed studies of this isolated pigment have not been conducted, owing to its instability under physiological conditions. This study aimed to isolate highly purified betanin from red beetroots using an improved purification method involving deproteinization and citric acid co-precipitation and evaluated its antioxidant activities. The purified betanin thus obtained had a significantly lower isobetanin content than the commercially available betanin dyes. The antioxidant activity of purified betanin examined in the 2,2-diphenyl-1-picrylhydrazyl assay, the direct ONOO- reaction, ONOO--dependent DNA damage, and lipid peroxidation reactions revealed that betanin possessed higher antioxidant capacity than general antioxidants such as ascorbic acid and quercetin. Furthermore, betanin showed indirect and direct cytoprotective effects against H2O2 and ONOO- cytotoxicity, respectively, in cultured mouse fibroblasts. To the best of our knowledge, this is the first study to demonstrate the cytoprotective effects of betanin against ONOO- toxicity. The highly purified betanin obtained in this study will aid in further exploring its physiological functions.

Accumulation of squalene in filamentous fungi Trichoderma virens PS1-7 in the presence of butenafine hydrochloride, squalene epoxidase inhibitor: biosynthesis of 13C-enriched squalene.

Squalene is a triterpenoid compound and widely used in various industries such as medicine and cosmetics due to its strong antioxidant and anticancer properties. The purpose of this study is to increase the accumulation of squalene in filamentous fungi using exogeneous butenafine hydrochloride, which is an inhibitor for squalene epoxidase. The detailed settings achieved that the filamentous fungi, Trichoderma virens PS1-7, produced squalene up to 429.93 ± 51.60 mg/L after culturing for 7 days in the medium consisting of potato infusion with glucose at pH 4.0, in the presence of 200 µm butenafine. On the other hand, no squalene accumulation was observed without butenafine. This result indicated that squalene was biosynthesized in the filamentous fungi PS1-7, which can be used as a novel source of squalene. In addition, we successfully obtained highly 13C-enriched squalene by using [U-13C6]-glucose as a carbon source replacing normal glucose.

Vertical Umbilical Incision Achieves Better Cosmesis Than Periumbilical Incision in Neonates and Infants.

PURPOSE:  The transumbilical approach is widely used for minimally invasive surgery in children. We compared herein the postoperative cosmesis between two types of transumbilical approach: a vertical incision versus periumbilical incision. METHODS:  Patients with a transumbilical laparotomy before age one year were prospectively enrolled between January 2018 and December 2020. A vertical incision or periumbilical incision was chosen at the surgeon's discretion. After excluding patients receiving a relaparotomy via another site, a questionnaire about the appearance of the umbilicus was completed by the patients' guardians at postoperative month 6 to assess satisfaction and determine the visual analog scale score. A photograph of the umbilicus was taken while the questionnaire was being administered for later assessment by surgeons blinded to the scar and umbilical shape. RESULTS:  Forty patients were enrolled; 24 patients received a vertical incision while 16 received a periumbilical incision. The incision length was significantly shorter in the vertical incision group (median: 2.0; range: 1.5-3.0 cm vs. median: 2.75; range: 1.5-3.6 cm) (p = 0.001). The patients' guardians reported significantly higher satisfaction (p = 0.002) and higher scores on the visual analog scale (p = 0.046) in the vertical incision group (n = 22) than in the periumbilical incision group (n = 15). The surgeons' evaluation was associated with significantly more patients with a vertical incision than with a periumbilical incision achieving a cosmetically preferable outcome, including an invisible or fine scar and a normal umbilical shape. CONCLUSION:  A vertical umbilical incision can provide better postoperative cosmesis than a periumbilical incision.

Factors predicting surgical difficulties in congenital biliary dilatation in pediatric patients.

BACKGROUND: The effects of disease classification and the patient's preoperative condition on the difficulty of performing a laparotomy for pediatric congenital biliary dilatation (CBD) have not been fully elucidated. METHODS: The present study retrospectively analyzed 46 pediatric CBD laparotomies performed at the study center between March 2010 and December 2021 and predictors of operative time. The patients were separated into a short operative time group (SOT) (≤ 360 min, n = 27) and a long operative time group (LOT) (> 360 min, n = 19). RESULTS: The preoperative AST and ALT values were higher, and the bile duct anastomosis diameter was larger, in the LOT. Correlation analysis demonstrated that the maximum cyst diameter, preoperative neutrophil-to-lymphocyte ratio, AST, ALT, AMY, and bile duct anastomosis diameter correlated positively with operative time. Multivariate analysis identified the maximal cyst diameter, preoperative AST, and bile duct anastomosis diameter as significant factors affecting surgical time. Postoperatively, intrapancreatic stones and paralytic ileus were observed in one patient each in the SOT, and mild bile leakage was observed in one patient in the LOT. CONCLUSIONS: The maximum cyst diameter, preoperative AST, and bile duct anastomosis diameter have the potential to predict the difficulty of performing a pediatric CBD laparotomy.

Successful laparoscopic-assisted partial splenectomy and splenopexy with umbilical approach to wandering spleen with an enlarged cyst in a pediatric patient.

A 10-year-old girl with a wandering spleen with an enlarged cyst was successfully treated by laparoscopic-assisted partial splenectomy and splenopexy. The patient visited our hospital with a complaint of a lower abdominal mass. Abdominal computed tomography showed malposition of the spleen and the presence of a 10 cm diameter splenic cyst (SC) in the lower pole. In surgery, the navel was opened with an inverted Y-shaped incision. The SC was punctured and aspirated the contents of the cyst, the migrating spleen was pulled out of navel and the partial splenectomy was done. The residual spleen was laparoscopically fixed by creating an extraperitoneal pocket. Pathologically, the cyst was covered with a vitrified fibrotic capsule and was diagnosed as a pseudocyst. We considered it a traumatic cyst. The postoperative course was uneventful. This minimally invasive laparoscopic procedure was feasible and effective for treating wandering spleen with a large SC in a pediatric patient.

Simulated slide tracheoplasty for congenital tracheal stenosis using three-dimensional printed models.

PURPOSE: The slide tracheoplasty (STP) is the standard treatment for severe congenital tracheal stenosis (CTS). Understanding the features of the tracheal stenosis in each case and choosing an appropriate incision design are very important for successfully executing the procedure. The present study aimed to evaluate the advantages of three-dimensional (3D) printed models of the trachea for improving CTS. METHODS: Three-D tracheal models were created using computed tomography (CT) data from ten patients undergoing STP for CTS. Simulated surgery was performed using the hollow models after reinforcing with them with a coating of gum spray. Clinical outcomes, including patient survival, postoperative surgical interventions, and time required for STP, were compared with the corresponding values in the last ten patients before the introduction of 3D model simulations. RESULTS: All ten patients for whom simulated surgery using a 3D tracheal model were conducted achieved good airway patency after their STP. The surgeons reported feeling that the 3D model simulations were highly effective although there was no significant difference in the clinical outcomes of the groups with or without simulated STP. The models were useful not only for surgical planning but also for sharing important information among the multidisciplinary team and the patients' family. CONCLUSION: Our experience using 3D tracheal models demonstrated several features enabling improvement in the surgical treatment of CTS.

[The Role of a Nurse Practitioner in Cardiovascular Surgery at a Japanese Private Hospital].

Since 2020, our hospital has introduced nurse practitioners( NP) into cardiovascular surgery with the aim to improve labor efficiency. A cardiovascular surgery NP has both pre- and postoperative roles. An NP is not only involved in a necessary intervention but also in an intervention as the first assistant regardless of regular or emergency surgery. By having an NP perform the work normally performed by doctors, a labor burden on doctors is reduced and care administered by the medical team is smoothened. This study reports the role of NPs in the field of cardiovascular surgery in private hospitals.

[Various Considerations on Robot-assisted Cardiac Surgery].

Robot-assisted cardiac surgery offers the most minimally-invasive approach to the surgical treatment of valvular heart disease and coronary artery disease. However, robot-assisted cardiac surgery is still far from being a standardized operation. We believe that with developing robotic technology, in the near future, robotic surgery will certainly play a key role in the field of cardiac surgery, thus tips and pitfalls for introducing robotic cardiac surgery and techniques of it should be described in more detail. After two years of our experience, we have performed about 200-cases of robot-assisted cardiac surgery, including robot-assisted mitral valve repair and minimally invasive coronary artery bypass grafting (CABG). The safety and reliability of those procedures have been well described from outside Japan. However, in Japan, we are still standing at the dawn of the robot-assisted cardiac surgery era, thus various experiences should be published from each institution where the robot-assisted cardiac surgery has already standarized. Here we present our experiences and recent technical consideration of robot-assisted cardiac surgery using the da Vinci Xi surgical system.

Reconsideration of Alzheimer's Disease Therapy from a Viewpoint of Amyloidogenic Evolvability.

 Presuming that Alzheimer's disease (AD) might represent an antagonistic pleiotropic phenomenon derived from the evolvability of multiple amyloidogenic proteins, targeting such proteins simultaneously could enhance therapeutic efficacy. Furthermore, considering that amyloid-ß (Aß) immunotherapies during reproductive life stage might adversely decrease Aß evolvability in an offspring's brain, the disease-modifying Aß immunotherapies should be limited to post-reproductive time in lifespan. Thus, current Aß immunotherapy strategies should be revised accordingly. Given that the "adiponectin paradox" might underlie both amyloidosis and cognitive dysfunction in aging brain, blocking activin signaling situated downstream of the adiponectin paradox might be an alternative strategy to prevent AD.

Outcomes of slide tracheoplasty for congenital tracheal stenosis in 80 children: A 22-year single-center experience.

PURPOSE: The application of slide tracheoplasty (STP) in the treatment of congenital tracheal stenosis (CTS) has improved patient outcomes over the past few decades. We reviewed our experiences with the procedure, elucidated risk factors, and discussed important aspects of perioperative management to improve outcomes. METHOD: Patients with CTS undergoing STP between July 1998 and December 2020 were enrolled. Patient characteristics, perioperative condition, management, operative details, and outcomes, including mortality and postoperative intervention, were collected from medical records. RESULTS: Eighty patients underwent STP. Sixty-five patients (81.3%) had an associated cardiovascular anomaly. Thirteen patients (16.3%) had unilateral lung agenesis or hypoplasia. Preoperative mechanical ventilation was necessary in 54 (67.5%) patients, and extracorporeal membrane oxygenation (ECMO) was required in eight patients (10.0%). An endotracheal tube was placed before the stenotic entrance to avoid granulation. During STP, the trachea was dissected as little as possible to maintain the blood supply. The one-year survival rate was 88.8% (nine patients died). One patient (1.3%) required postoperative balloon dilation, and none required stenting or granulation removal. Of the survivors, 62 (92.5%) achieved successful extubation without tracheostomy. Multivariable analysis revealed complex cardiovascular anomaly (P = 0.05) and preoperative ECMO (P = 0.019) to be adverse predictors of survival. CONCLUSION: Although STP can be performed successfully in CTS patients, surgeons and families should be aware of factors that may lead to a more difficult postoperative course or increase the mortality. Meticulous, perioperative positioning of the endotracheal tube and preserving the tracheal blood flow can minimize the need for postoperative intervention.

Robotic Total Endoscopic Coronary Bypass in 570 Patients: Impact of Anastomotic Technique in Two Eras.

BACKGROUND: In coronary artery bypass grafting, including robotic off-pump totally endoscopic coronary artery bypass (TECAB), the anastomotic technique is the most critical part of the procedure. We reviewed results in 570 patients over a 7-year period and compared outcomes between two eras based on predominant anastomotic technique: connectors vs running suture. METHODS: Between July 2013 and December 2020, 570 patients underwent off-pump TECAB: group 1 consisting of 378 patients, from July 2013 to August 2018, using predominantly the C-Port Flex A distal anastomotic stapler (Aesculap); and group 2 consisting of 192 patients, from September 2018 to December 2020, using predominantly a sutured technique (7-0 Pronova; Johnson & Johnson). Retrospective analysis of clinical outcomes was performed. RESULTS: Off-pump TECAB was completed in 98.8% (563 of 570 patients) with an observed/expected mortality of 0.6% (6 of 570 patients). The anastomotic device was used in 89% of 626 grafts in group 1 and only 11% of 305 grafts in group 2 (P = .001). There were no differences in multivessel TECAB (57% vs 53%; P = .331) or bilateral internal thoracic artery use (50% vs 43%; P = .127) in group 1 vs group 2, respectively. Operative time was shorter in group 1 (242 ± 84 vs 273 ± 88 minutes; P < .001). Early clinical outcomes were similar between groups, except for hospital stay, which was longer in group 1 (2.9 vs 2.3 days; P < .001). Graft patency was similar (98% vs 95%; P = .295) in group 1 vs group 2, respectively. CONCLUSIONS: Changing the predominant approach from stapled anastomosis to a sutured technique during robotic TECAB resulted in longer operative times. Both approaches led to excellent outcomes, including graft patency. The shorter operative times conferred by using staplers may flatten the learning curve and facilitate broader adoption of TECAB.

Efficacy of early endoscopic intervention in pediatric pancreatic duct injury management.

BACKGROUND: The optimal management method for pediatric pancreatic trauma is controversial. Moreover, the efficacy of stent placement via endoscopic retrograde pancreatography (ERP) remains poorly documented. METHODS: The present, retrospective review of pediatric patients with pancreatic trauma was conducted from 2010 to 2020 at a single institution. RESULTS: Ten, male children with the median age of 9.5 years (range 4-14 years) with a grade I (n = 2), II (n = 4) or III (n = 4) pancreatic injury were identified. Of six of these patients in whom ERP was performed, four had a pancreatic duct injury (PDI). Pancreatic stent placement was performed in all the patients with ERP at a site proximal to the injury in four patients and across the injury in two patients. A pseudocyst or pancreatic fluid collection was detected in five patients, of these, two with a grade II injury were managed successfully with conservative therapy while three with PDI required surgery. In the four patients with PDI, only one in whom the stent was placed across the PDI was able to avoid surgery. CONCLUSION: Therapeutic ERP might be effective even if a patient has a PDI, therefore, early ERP should be considered as a treatment option.

Inverse T-shaped sternotomy as novel thoracoplasty for severe chest deformation and tracheal stenosis.

BACKGROUND: Patients with severe motor and intellectual disabilities often suffer from tracheal stenosis due to chest deformation and brachiocephalic artery compression, which sometimes leads to serious complications, such as dying spell and tracheobrachiocephalic artery fistula. We herein described our experience of performing a novel and simple thoracoplastic procedure combined with brachiocephalic artery transection in two patients with severe chest deformation and tracheal stenosis. CASE PRESENTATION: The patients were a 12-year-old female with cerebral palsy due to periventricular leukomalacia and a 21-year-old male with subacute sclerosing panencephalitis stage IV in the Jabbour classification following a laryngotracheal separation. Both patients showed severe chest deformation and symptoms of airway stenosis resulting in dying spells. The sternum was laterally transected between the manubrium and the sternal body, and a manubriotomy was performed longitudinally, ending with an inverse T-shaped sternotomy. Since the clavicle and the first rib remained attached to the halves of the divided manubrium, the sternum was allowed to be left open, resulting in improvement of the mediastinal narrowing and tracheal stenosis. Postoperative computed tomography (CT) showed that the distance between the halves of the manubrium was maintained at 10-11 mm, and that the mediastinal narrowing in both patients improved; the sternocervical spine distance increased from 20 mm to 22  and 13 mm to 16 mm, respectively. The patients' tracheal stenosis below the sternal end of the clavicle and the manubrium and respiratory symptoms improved, and the patients are currently at home in a stable condition with no chest fragility and no upper limb movement disorder 1 year after surgery. CONCLUSIONS: Our observations suggested that the inverse T-shaped sternotomy combined with brachiocephalic artery transection may relieve symptoms of tracheal stenosis due to severe chest deformation in patients with severe motor and intellectual disabilities.

Possible Role of Activin in the Adiponectin Paradox-Induced Progress of Alzheimer's Disease.

Accumulating evidence suggests that the adiponectin (APN) paradox might be involved in promoting aging-associated chronic diseases such as Alzheimer's disease (AD). In human brain, APN regulation of the evolvability of amyloidogenic proteins (APs), including amyloid-ß (Aß) and tau, in developmental/reproductive stages, might be paradoxically manifest as APN stimulation of AD through antagonistic pleiotropy in aging. The unique mechanisms underlying APN activity remain unclear, a better understanding of which might provide clues for AD therapy. In this paper, we discuss the possible relevance of activin, a member of transforming growth factor ß (TGFß) superfamily of peptides, to antagonistic pleiotropy effects of APN. Notably, activin, a multiple regulator of cell proliferation and differentiation, as well as an endocrine modulator in reproduction and an organizer in early development, might promote aging-associated disorders, such as inflammation and cancer. Indeed, serum activin, but not serum TGFß increases during aging. Also, activin/TGFß signal through type II and type I receptors, both of which are transmembrane serine/threonine kinases, and the serine/threonine phosphorylation of APs, including Aß42 serine 8 and αS serine 129, may confer pathological significance in neurodegenerative diseases. Moreover, activin expression is induced by APN in monocytes and hepatocytes, suggesting that activin might be situated downstream of the APN paradox. Finally, a meta-analysis of genome-wide association studies demonstrated that two SNPs relevant to the activin/TGFß receptor signaling pathways conferred risk for major aging-associated disease. Collectively, activin might be involved in the APN paradox of AD and could be a significant therapeutic target.

Diabetes, inflammation, and the adiponectin paradox: Therapeutic targets in SARS-CoV-2.

Aging and pre-existing conditions in older patients increase severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) severity and its complications, although the causes remain unclear. Apart from acute pulmonary syndrome, Coronavirus 2019 (COVID-19) can increasingly induce chronic conditions. Importantly, SARS-CoV-2 triggers de novo type 2 diabetes mellitus (T2DM) linked to age-associated cardiovascular disease (CVD), cancers, and neurodegeneration. Mechanistically, SARS-CoV-2 induces inflammation, possibly through damage-associated molecular pattern (DAMP) signaling and 'cytokine storm,' causing insulin resistance and the adiponectin (APN) paradox, a phenomenon linking metabolic dysfunction to chronic disease. Accordingly, preventing the APN paradox by suppressing APN-related inflammatory signaling might prove beneficial. A better understanding could uncover novel therapies for SARS-CoV-2 and its chronic disorders.

Adiponectin paradox as a therapeutic target of the cancer evolvability in aging.

Recent study suggests that protofibril-formation of amyloidogenic proteins (APs) might be involved in evolvability, an epigenetic inheritance of multiple stresses, in various biological systems. In cancer, evolvability of multiple APs, such as p53, γ-synuclein and the members of the calcitonin family of peptides, might be involved in various features, including increased cell proliferation, metastasis and medical treatment resistance. In this context, the objective of this paper is to explore the potential therapeutic benefits of reduced APs evolvability against cancer. Notably, the same APs are involved in the pathogenesis of neurodegenerative disease and cancer. Given the unsatisfactory outcomes of recent clinical trial of Aß immunotherapy in Alzheimer's disease, it is possible that suppressing the aggregation of individual APs might also be not effective in cancer. As such, we highlight the adiponectin (APN) paradox that might be positioned upstream of AP aggregation in both neurodegenerative disease and cancer, as a common therapeutic target in both disease types. Provided that the APN paradox due to APN resistance under the diabetic conditions might promote AP aggregation, suppressing the APN paradox combined with antidiabetic treatments might be effective for the therapy of both neurodegenerative disease and cancer.

Connecting Alzheimer's Disease With Diabetes Mellitus Through Amyloidogenic Evolvability.

Type 2 diabetes mellitus (T2DM) has been clearlylinked to oxidative stress and amylin amyloidosis in pancreatic ß-cells. Yet despite extensive investigation, the biological significance of this is not fully understood. Recently, we proposed that Alzheimer's disease (AD)-relevant amyloidogenic proteins (APs), such as amyloid-ß (Aß) and tau, might be involved in evolvability against diverse stressors in the brain. Given the analogous cellular stress environments shared by both T2DM and AD, the objective of this study is to explore T2DM pathogenesis from the viewpoint of amyloidogenic evolvability. Similar to AD-related APs, protofibrillar amylin might confer resistance against the multiple stressors in ß-cells and be transmitted to offspring to deliver stress information, in the absence of which, type 1 DM (T1DM) in offspring might develop. On the contrary, T2DM may be manifested through an antagonistic pleiotropy mechanism during parental aging. Such evolvability-associated processes might be affected by parental diabetic conditions, including T1DM and T2DM. Furthermore, the T2DM-mediated increase in AD risk during aging might be attributed to an interaction of amylin with AD-related APs through evolvability, in which amylin protofibrillar formation presumably caused by adiponectin (APN) resistance could increase protofibril formation of AD-related APs in evolvability and subsequently lead to T2DM promotion of AD through antagonistic pleiotropy in aging. This suggests that targeting APN combined with an anti-T2DM agent might be therapeutic against neurodegeneration. Collectively, T1DM and T2DM might be linked through amylin evolvability, and a better understanding of amyloidogenic evolvability might also reveal clues to therapeutic interventions for AD comorbid with T2DM.

Surgical treatment of a giant right atrial myxoma.

BACKGROUND: Right atrial myxoma is a rare anomaly. When present, it can rarely cause blood flow obstruction in the right cardiac chamber depending on its size and location. We herein report a rare case of a giant right atrial myxoma, which caused right heart failure due to tricuspid valve obstruction, along with our treatment experience. CASE PRESENTATION: A 59-year-old woman was admitted to our hospital for palpitations and edema of the lower extremity. Computed tomography image and transthoracic echocardiography showed a 57 mm × 63 mm giant tumor obstructing the tricuspid valve inflow. The tumor was excised surgically and the residual septal defect was repaired with a Dacron patch. Tricuspid valve annuloplasty was performed additionally. The postoperative course was uneventful and the patient was discharged on postoperative day 5. CONCLUSION: Giant right atrial myxoma is a rare cause of tricuspid valve stenosis and right heart failure. Surgical resection is the most appropriate treatment option and should be performed as soon as possible after diagnosis.