Intraspecific divergence in a coastal plant, Euphorbia jolkinii, at a major biogeographic boundary in East Asia.

PREMISE: Quaternary climatic fluctuations and long-distance seed dispersal across the sea are critical factors affecting the distribution of coastal plants, but the spatiotemporal nature of population expansion and distribution change of East Asian coastal plants during this period are rarely examined. To explore this process, we investigated the genome-wide phylogenetic patterns of Euphorbia jolkinii Boiss. (Euphorbiaceae), which grows widely on littoral areas of Japan, Korea, and Taiwan. METHODS: We used plastome sequences and genome-wide single nucleotide polymorphisms in samples across the species range to reveal phylogeographic patterns and spatiotemporal distributional changes. We conducted ecological niche modeling for the present and the last glacial maximum (LGM). RESULTS: Genetic differentiation was observed between the northern and southern populations of E. jolkinii, separated by the major biogeographic boundary, the Tokara Gap. These two groups of populations differentiated during the glacial period and subsequently intermingled in the intermorainic areas of the central Ryukyu Islands after the LGM. Ecological niche models suggested that the potential range of E. jolkinii was restricted to southern Kyushu; however, it was widespread in the southern Ryukyu Islands and Taiwan during the LGM. CONCLUSIONS: This study provides evidence of genetic differentiation among coastal plant populations separated by the prominent biogeographical boundary. Although coastal plants are typically expected to maintain population connectivity through sea-drifted seed dispersal, our findings suggest that genetic differences may arise because of a combination of limited gene flow and changes in climate during the glacial period.

Task division by multiple console surgeons is beneficial for safe robotic pancreaticoduodenectomy implementation and education.

BACKGROUND: The optimal approach for the safe implementation and education of robotic pancreaticoduodenectomy (RPD) remains unclear. Prolonged operation time may cause surgeon fatigue and result in perioperative complications. To solve this issue, our department adopted task division by the console surgeon turnover between resection and reconstruction in 2022. METHODS: This study retrospectively investigated consecutive patients who underwent RPD from November 2009 (initial introduction of RPD) to December 2023. The analysis excluded patients who underwent concomitant resection of other organs. The cases performed by a single console surgeon (single approach) were compared with those performed by two or more console surgeons (multiple approach). RESULTS: This study analyzed 85 consecutive RPD cases, including 51 with the single approach and 34 with the multiple approach. The operation time was significantly shorter (832 vs. 618 min, p < 0.001), and the postoperative major complication was less frequent (45% vs. 12%, p = 0.003) in the multiple approach group, although less experienced surgeons performed the multiple approach (number of RPD experiences: 19 cases vs. 5 cases, p < 0.001). The console surgeon turnover between the resection and reconstruction resulted in a safe pancreatojejunostomy performed by the less experienced surgeon (number of pancreatic reconstruction experiences: 6.5 vs. 14 cases, p = 0.010). Surgeons who started RPD with a multiple approach observed a reduction in surgical time and a lower incidence of complications earlier than those who started with a single approach. CONCLUSION: Task division during the early introduction phase of RPD using the multiple approach demonstrated potential contributions to improved surgical outcomes and enhanced educational benefits.

Challenge in optimizing robotic pancreaticoduodenectomy including nerve plexus hanging maneuver: a Japanese single center experience of 76 cases.

BACKGROUND: Robotic pancreaticoduodenectomy (RPD) is technically demanding, and 20-50 cases are required to surpass the learning curve. This study aimed to show our experience of 76 cases from the introduction of RPD and report the changes in surgical results owing to the accumulation of cases and optimization of surgical techniques. METHODS: A total of 76 patients who underwent RPD between November 2009 and May 2023 at the Fujita Health University Hospital were divided into three groups: competency (n = 23, Nov 2009-Mar 2020), proficiency (n = 31, Apr 2020-Jun 2022), and mastery (n = 22, Jul 2022-May 2023) phases. In the mastery phase, for the education of new surgeons and maintenance of surgical quality, optimization of the procedure, including hanging maneuver with or without stapling transection of the retropancreatic tissue was implemented. The surgical outcomes were compared between the groups. RESULTS: The mean operation time decreased over time despite of the participation of newly started operators in mastery phase [competency: 921.5 min (IQR 775-996 min) vs. proficiency: 802.8 min (IQR 715-887 min) vs. mastery: 609.2 min (IQR 514-699 min), p < 0.001]. Additionally, Clavien-Dindo ≥ grade IIIa complications decreased from 52.2% in competency phase to 35.5% and 9.1% in proficiency and mastery phases, respectively (p = 0.005). CONCLUSION: Operation time and major complications decreased along the learning curve from the introduction of RPD. In addition, optimization of the procedure, including hanging maneuver of the retropancreatic tissue seemed to be effective in reducing operation time and educating new RPD surgeons.

Technical details of robotic pancreatojejunostomy using a modified Blumgart anastomosis: Thread manipulation using gauze and an assisted port.

BACKGROUNDS: Pancreatojejunostomy is a technically demanding procedure during robotic pancreaticoduodenectomy (RPD). Modified Blumgart anastomosis (mBA) is a common method for the pancreatojejunostomy; however, the technical details for robotic mBA are not well established. During RPD, we performed a mBA for the pancreatojejunostomy using thread manipulation with gauze and an additional assist port. METHODS: Patients who underwent robotic pancreatoduodenectomy at Fujita Health University from November 2009 to May 2023 were retrospectively investigated, and technical details for the robotic-modified Blumgart anastomosis were demonstrated. RESULTS: Among 78 patients who underwent RPD during the study period, 33 underwent robotic mBA. Postoperative pancreatic fistula (POPF) occurred in six patients (18%). None of the patients suffered POPF Grade C according to the international study group of pancreatic surgery definition. The anastomotic time for mBA was 80 min (54-125 min). CONCLUSION: Robotic mBA resulted in reasonable outcomes. We propose that mBA could be used as one of the standard methods for robotic pancreatojejunosotomy.

Preliminary comparative study of lower extremity pressure measurements under the conditions using former models and new lithotomy stirrups in rectal cancer surgery.

BACKGROUND: This study aimed to investigate the effect of the use of new lithotomy stirrups-2 on the pressure dispersal on lower limbs, which may lead to the prevention of well-leg compartment syndrome (WLCS) and deep venous thrombosis (DVT), which are the most commonly associated adverse events with laparoscopic and robot-assisted rectal surgery. METHODS: A total of 30 healthy participants were included in this study. The pressure (mmHg) applied on various lower limb muscles when using conventional lithotomy stirrups-1 and new type stirrups-2 was recorded in various lithotomy positions; 1) neutral position, 2) Trendelenburg position (15°) with a 0° right inferior tilt, and 3) Trendelenburg position (15°) with a 10° right inferior tilt. Using a special sensor pad named Palm Q®, and the average values were compared between two types of stirrups. RESULTS: The use of new lithotomy stirrups-2 significantly reduced the pressure applied on the lower limb muscles in various lithotomy positions compared with the use of lithotomy stirrups-1. The most pressured lower limb muscle when using both lithotomy stirrups was the central soleus muscle, which is the most common site for the development of WLCS and DVT. In addition, when using the conventional lithotomy stirrups-1, the pressure was predominantly applied to the proximal soleus muscle; however, when using lithotomy stirrups-2, the pressure was shifted to the more distal soleus muscle. CONCLUSION: These results suggest that the new lithotomy stirrups-2 is useful in reducing the pressure load on leg muscles, especially on the proximal to central soleus, and may reduce the incidence of WLCS and DVT after rectal surgery performed in the lithotomy position. Further clinical studies are needed to determine whether the use of lithotomy stirrups-2 prevents these complications in various clinical settings.

Multiple origins of two Ochrosia (Apocynaceae) species endemic to the Bonin (Ogasawara) Islands.

The genus, Ochrosia, is widely distributed from the West Indian Ocean throughout tropical Asia to the Middle Southern Pacific region. Ochrosia comprises many island-endemic species, suggesting that long-distance dispersal and isolation after migration are key factors for clarifying the diversification process. However, the phylogeny and biogeography of endemic Ochrosia species have not been evaluated well due to the difficulty of adequate sampling from the entire distribution range of the genus. In this study, we focused on two Ochrosia species endemic to the Bonin (Ogasawara) Islands in the northwest Pacific. The Bonin Islands are of volcanic origins and consist of two islands groups, the Ogasawara and Volcano Islands groups, approximately 300 km apart. Ochrosia nakaiana is endemic to the Ogasawara Islands group, whereas O. hexandra is endemic to the Volcano Islands group. To elucidate the phylogenetic positions of these two endemic Ochrosia species, we conducted molecular phylogenetic studies with dating and biogeographic analyses including other Ochrosia species. The phylogenetic trees showed that the two endemic species had distinct origins; O. nakaiana was closely related to O. oppositifolia and O. iwasakiana, whereas O. hexandra was related to O. mariannensis. Based on the chloroplast DNA phylogeny, the genus, Ochrosia, divided into two major lineages 36.6 million years ago. Further, the two endemic species of the Bonin Islands were independently derived approximately 1-2 million years ago. Ochrosia nakaiana originated from the Southeast Asia, New Caledonia, or other Pacific Islands, while O. hexandra derived from O. mariannensis in Micronesia. We demonstrated different origins of the two endemic Ochrosia species on the Bonin Islands. This study provided an excellent example of the complex origins and speciation of flora in the oceanic islands.

[A Case of Robotic Distal Pancreatectomy for Pancreatic Metastasis of Gastric Cancer].

A 78-year-old male who had received laparoscopic total gastrectomy for upper gastric cancer 30 months ago(pT3N0, pStage ⅡB)was referred for further treatment for a 30-mm in size mass at the splenic hilum. The mass was suspected of lymph node metastasis was suspected. Two courses of SOX therapy failed to achieve the tumor response. Since there was no other metastasis, surgical treatment was indicated. Robot distal pancreatectomy with splenectomy was performed. There was no finding of peritoneal metastasis during the operation. The operative time was 384 min, the blood loss 22 mL, respectively. The postoperative course was uneventful, and he was discharged on the 12th postoperative day. The histopathological examination found that the resected mass was pancreatic metastasis of gastric cancer. Despite 3 courses of SOX therapy after the operation, the tumor recurred at the liver and paraaortic lymph nodes 2 months later. The second-line ramucirumab plus paclitaxel was started and has continued for 11 months with partial response. Although oncological benefit of surgical resection for isolated metastasis of gastric cancer, including pancreatic metastasis, was unclear, the robotic approach for such an atypical case was safe and feasible, leading to smooth initiation of postoperative systemic therapy.

Relationship between obstructive sleep apnoea during rapid eye movement sleep and metabolic syndrome parameters in patients with type 2 diabetes mellitus.

PURPOSE: Sleep-disordered breathing (SDB) is associated with hypertension, poor glycemic control and dyslipidemia. Usually, apnoea events tend to be more prominent during rapid eye movement (REM) sleep than non-REM (NREM) sleep. We examined which SDB parameters are associated with blood pressure (BP), HbA1c and lipid profile in patients with type 2 diabetes (T2D). METHODS: A total of 185 patients with T2D who underwent polysomnography were analysed. Exclusion criteria were: the presence of pulmonary diseases, central sleep apnoea, treated SDB, or REM sleep < 30 min. To predict BP, HbA1c, and lipid profiles, we performed multiple linear regression analyses adjusted for known risk factors. Subsequently, we performed multivariable logistic regression analyses. RESULTS: Patient characteristics (mean ± standard deviation/median) were as follows: age 58.0 ± 11.8 years, body mass index 26.0 kg/m2 (24.1-28.9 kg/m2 ), systolic BP 134 ± 19 mmHg, mean BP 98 ± 14 mmHg, HbA1c 7.4% (6.8-8.4%), triglyceride 143 mg/dL (97-195 mg/dL), non-high density lipoprotein (non-HDL) cholesterol 143 mg/dL (120-163 mg/dL), REM-apnoea-hypopnea index (AHI) 35.1/h (21.1-53.1/h). The analyses revealed that REM-AHI was independently associated with systolic and mean BP, whereas NREM-AHI was not. A statistically significant association was not observed between REM-AHI and HbA1c or lipid profile. CONCLUSION: In patients with T2D, REM-AHI was associated with systolic and mean BP. The alteration of BP, associated with SDB during REM sleep, may be an important pathophysiological link between SDB and cardiovascular diseases.

[A Case of Rectal Cancer with Virchow Lymph Node Metastasis in Which Complete Response Was Achieved with Chemoradiation Therapy].

A 43-year-old man underwent a low anterior resection of the rectum due to upper rectal cancer. The pathological Stage was Ⅳ with para-aortic lymph node metastasis. Postoperative chemotherapy with CapeOX was initiated, but para-aortic lymph node metastasis was discovered 4months after the surgery. Chemoradiation therapy with Cape and Bev, and 70 Gy/28 Fr led to the disappearance of the metastasized lesions. At 13months after the surgery, FDG accumulation was observed in the Virchow's lymph node, and chemotherapy with IRIS and Bev was initially administered. Subsequently, chemoradiation therapy with S-1 and Bev, and 66 Gy/33Fr was administered, followed by chemotherapy with S-1 and Bev, S-1. These therapies led to complete response(CR). However, 35 months after the surgery, the Virchow's lymph node had enlarged again, and chemoradiation therapy with S-1 and 60 Gy/30Fr was administered. Although no FDG accumulation was detected in the lymph node at 40 months after the surgery, metastasis was found in the mediastinal lymph nodes. Panitumumab therapy achieved CR, and no metastasis had been identified at 60 months after the final therapy. Chemoradiation therapy is a treatment option to improve the prognosis of patients with metastasis only in the Virchow's lymph node.

Impact of sodium glucose cotransporter 2 inhibitor on histological features and glucose metabolism of non-alcoholic fatty liver disease complicated by diabetes mellitus.

AIM: The aim of this study was to investigate the therapeutic potential of sodium glucose cotransporter 2 inhibitor (SGLT2I) as an effective therapeutic option for non-alcoholic fatty liver disease (NAFLD). METHODS: In this prospective study, nine patients with NAFLD complicated by type 2 diabetes mellitus (DM), were introduced to the regimen of canagliflozin 100 mg once daily for 24 weeks and were evaluated by liver histology at pretreatment and at 24 weeks after the start of treatment. The primary outcome was histological improvement, defined as a decrease in NAFLD activity score of one point or more without worsening in fibrosis stage. Glucose metabolism was evaluated based on the meal tolerance test. The usefulness of extracellular and exosome microRNA-122 (miR-122) as early predictors of histological improvement was investigated. RESULTS: All of the nine patients achieved histological improvement. Scores of steatosis, lobular inflammation, ballooning, and fibrosis stage decreased by 78%, 33%, 22%, and 33% at 24 weeks compared to the pretreatment, respectively. Six patients showed improvement in insulin resistance, and the other three patients showed partial improvement of insulin secretion function. Six patients, who showed a decrease in both extracellular and exosome miR-122 ratios (the ratio of miR-122 levels at 1 day after treatment to that at baseline), showed histological improvement. Furthermore, one patient, who showed a decrease in exosome miR-122 ratios regardless of the increase in extracellular miR-122 ratios, also showed decreases in NAFLD activity score and fibrosis stage. CONCLUSION: A prospective study showed that SGLT2I for NAFLD complicated by DM improved histological features in connection with glucose metabolism. This trial was registered as clinical trial UMIN000018166.

UBIAD1 Plays an Essential Role in the Survival of Pancreatic Acinar Cells.

UbiA prenyltransferase domain-containing protein 1 (UBIAD1) is a vitamin K2 biosynthetic enzyme. We previously showed the lethality of this enzyme in UBIAD1 knockout mice during the embryonic stage. However, the biological effects of UBIAD1 deficiency after birth remain unclear. In the present study, we used a tamoxifen-inducible systemic UBIAD1 knockout mouse model to determine the role of UBIAD1 in adult mice. UBIAD1 knockout resulted in the death of the mice within about 60 days of administration of tamoxifen. The pancreas presented with the most prominent abnormality in the tamoxifen-induced UBIAD1 knockout mice. The pancreas was reduced remarkably in size; furthermore, the pancreatic acinar cells disappeared and were replaced by vacuoles. Further analysis revealed that the vacuoles were adipocytes. UBIAD1 deficiency in the pancreatic acinar cells caused an increase in oxidative stress and autophagy, leading to apoptotic cell death in the tamoxifen-induced UBIAD 1 knockout mice. These results indicate that UBIAD1 is essential for maintaining the survival of pancreatic acinar cells in the pancreas.

Efficacy and safety of repaglinide added to sitagliptin in Japanese patients with type 2 diabetes: A randomized 24-week open-label clinical trial.

Although sitagliptin and repaglinide monotherapies improve postprandial hyperglycemia, the long-term effects and safety of their combination has not been examined. In this randomized 24-week trial of Japanese patients with poor control (HbA1c 7.0-8.5%) by sitagliptin, we divided 40 patients randomly into two equal groups of the repaglinide add-on to sitagliptin (ADD-ON, n=20), or sitagliptin switched to repaglinide (SWITCH, n=20). The meal tolerance test was carried out at weeks 0 and 24. The primary outcomes were changes in HbA1c and area under the curves (AUC) of glucose from the baseline to week 24. The mean change in HbA1c from baseline to week 24 was larger in the ADD-ON (-0.87±0.63%, mean±SD), compared with the SWITCH (0.03±0.65%, p=0.000). Significant improvements were noted in the mean changes in fasting glucose and AUCs of glucose in the ADD-ON vs. SWITCH (p=0.007 and p=0.000). Insulin secretion relative to glucose elevation (ISG; defined as AUC insulin/AUC glucose) increased significantly in the ADD-ON, although the mean change in fasting insulin level was significantly decreased in the ADD-ON (p=0.015 and p=0.026). The AUC of glucagon was significantly lower at 24-week relative to baseline in the ADD-ON, but was not significant in the two groups (p=0.047 and p=0.056, respectively). The combination therapy produced significant reductions in HbA1c, AUC of glucose and fasting glucose compared with switching to repaglinide without weight gain or severe hypoglycemia. The improved glycemic control with this combination therapy may be at least in part due to augmentation of repaglinide-induced insulin secretion by sitagliptin.

Exponential increase of glutamic acid decarboxylase (GAD) antibody titer after initiating and stopping insulin in a patient with slowly progressive type 1 diabetes.

Few articles have described fluctuations in glutamic acid decarboxylase antibody (GADAb) levels after a diagnosis of slowly progressive type 1 diabetes (SPIDDM). Here, we present a case in which GADAb levels exponentially increased after initiating and stopping insulin. A 64-year-old female patient newly diagnosed with SPIDDM was admitted and started multiple daily insulin injections. The patient's GADAb titer was 6.9 U/mL (normal: <1.4 U/mL) and the patient had a type 1 diabetes susceptible HLA class II haplotype known in the Japanese population as: DRB1*04:05-DQB1*04:01. When the patient's "honeymoon period" set in, hypoglycemia was observed and the dose of insulin was reduced. Two months after the diagnosis, 1 unit of insulin glargine/day was being injected and the patient demonstrated good glycemic control. Subsequently, the patient's home doctor recommended that insulin injections be stopped. Three months after the diagnosis, the patient's GADAb titer suddenly increased to 1600 U/mL. The patient's GADAb titer decreased but was still positive (40 U/mL) 36 months after diagnosis. HbA1c levels were maintained below 7%, and oral glucose tolerance tests at 10, 26, and 36 months after diagnosis suggested that the patient had preserved insulin secretion. To the best of our knowledge, this is the first report that describes exponential increases in GADAb after initiating and stopping insulin in a patient with SPIDDM.

Robotic pancreatic tumor enucleation by the double bipolar technique using the da Vinci SP system: An initial case report with a technical detail.

Pancreatic tumor enucleation is a procedure that can preserve pancreatic function and is sometimes performed using a minimally invasive approach. Recently, a single-port robotic platform called da Vinci SP has been developed. However, the technical details of pancreatic tumor enucleation using da Vinci SP have not been reported to date. We report a male patient in his 70s who underwent robotic SP pancreatic tumor enucleation for a pancreatic neuroendocrine tumor. The dissection between the tumor and pancreatic parenchyma was performed using the double bipolar technique. The operative time was 139 min, and the estimated blood loss was 4 mL. The patient had an uneventful recovery and was discharged on the sixth day after the surgery. Robotic SP pancreatic tumor enucleation appears to be a feasible procedure with lower invasiveness and better cosmesis.

Robot-assisted approach using a laparoscopic articulating vessel-sealing device versus pure-robotic approach during distal pancreatectomy.

Robotic distal pancreatectomy (RDP) has emerged as a minimally invasive approach to left-sided pancreatic tumors. This study aimed to evaluate the efficacy of the robot-assisted approach (RAA) using a laparoscopic articulating vessel-sealing device (LAVSD) during RDP by comparing it with the pure-robotic approach (PRA). Among 62 patients who underwent RDP between April 2020 and December 2023 at Fujita Health University, 22 underwent RAA (the RAA group). In RAA, console surgeons mainly prepared the surgical fields, and assistant surgeons actively dissected the adipose and connective tissues using LAVSD. The surgical outcomes of these patients were compared with those of 40 consecutive patients who underwent RDP with PRA. In total, 28 males and 34 females with a median age of 71 years were analyzed. The console surgeon's prior experience of performing RDP was similar between the groups (RAA; median, 6 [range, 0-36], PRA; median, 5.5 [range, 0-34] cases). The operation time was significantly shorter in the TST group (median, 300.5 [range, 202-557] vs. 363.5 [range, 230-556] min, p = 0.015). Major complications (Clavien-Dindo ≥ grade 3a) occurred less frequently in the RAA group (4.6% vs. 25.0%, p = 0.028). Although the median postoperative hospital stay was slightly shorter in the RAA group (median, 12 [range, 8-38] vs. 14.5 [8-44] days, p = 0.095), no statistically significant difference was observed. Compared with PRA, RAA using LAVSD is found to be safe and feasible in introducing RDP for operators with little experience.

Advantageous properties of a new fungicide, isofetamid.

The fungicidal properties of a new fungicide, isofetamid, were examined to assess its antifungal spectrum, mode of action, and effects on the infection process of Botrytis cinerea. Additionally, we investigated its fungicidal activity against isolates of B. cinerea resistant to existing fungicides. In mycelial growth inhibition tests, isofetamid exhibited excellent fungicidal activity against ascomycetes but showed no activity against basidiomycetes and oomycetes. Respiratory enzyme assay using mitochondria revealed that isofetamid inhibited succinate dehydrogenase activity prepared from B. cinerea and other ascomycetes fungi used in the study. On the other hand, the activity of mitochondria prepared from Pythium, potato and rat were not inhibited. Isofetamid inhibited also many stages of the infection processes in B. cinerea. Furthermore, it exhibited high fungicidal activity against B. cinerea isolates that were resistant to existing fungicides.

Global cognition and executive functions of older adults with type 1 diabetes mellitus without dementia.

AIMS/INTRODUCTION: This study aimed to characterize the global cognition and executive functions of older adults with type 1 diabetes mellitus in comparison with type 2 diabetes mellitus. MATERIALS AND METHODS: This study included 37 patients with type 1 diabetes mellitus aged ≥65 years and 37 age- and sex-matched patients with type 2 diabetes mellitus. Patients with dementia scoring <24 on the Mini-Mental State Examination were excluded. General cognition, memory, classic, and practical executive function were investigated. RESULTS: Patients with type 1 diabetes mellitus demonstrated lower psychomotor speed scores on Trail Making Tests A and B (P < 0.001, P < 0.013) than those with type 2 diabetes mellitus. The dysexecutive syndrome behavioral assessment revealed similar results in patients with types 1 and 2 diabetes mellitus. The Wechsler Memory Scale-Revised verbal episodic memory and Montreal Cognitive Assessment Japanese version were similar in terms of general cognition, but worse delayed recall subset on the latter was associated with type 2 diabetes mellitus (P = 0.038). A worse Trail Making Test-A performance was associated with type 1 diabetes mellitus and age (P < 0.004, P < 0.029). CONCLUSIONS: Executive function of psychomotor speed was worse in older outpatient adults without dementia with type 1 diabetes mellitus than in those with type 2 diabetes mellitus but with no significant differences in the comprehensive and practical behavioral assessment of dysexecutive syndrome. Patients with type 1 diabetes had more severely impaired executive function, whereas those with type 2 had greater impaired memory than executive function.

Distinct Expression Profiles of Neuroblastoma-Associated mRNAs in Peripheral Blood and Bone Marrow of Non-High-Risk and High-Risk Neuroblastoma Patients.

Non-high-risk (non-HR) neuroblastoma (NB) patients have excellent outcomes, with more than a 90% survival rate, whereas HR NB patients expect less than a 50% survival rate. Metastatic disease is the principal cause of death among both non-HR and HR NB patients. Previous studies have reported the significant but limited prognostic value of quantitative PCR (qPCR)-based assays, measuring overlapping but different sets of neuroblastoma-associated mRNAs (NB-mRNAs), to detect metastatic disease in both non-HR and HR patient samples. A droplet digital PCR (ddPCR)-based assay measuring seven NB-mRNAs (CRMP1, DBH, DDC, GAP43, ISL1, PHOX2B, and TH mRNAs) was recently developed and exhibited a better prognostic value for HR patient samples than qPCR-based assays. However, it remained to be tested on non-HR patient samples. In the present study, we employed the ddPCR-based assay to study peripheral blood (PB) and bone marrow (BM) samples collected at diagnosis from eight non-HR and eleven HR cases and characterized the expression profiles of NB-mRNAs. The most highly expressed NB-mRNAs in PB and BM differed between non-HR and HR cases, with the CRMP1 mRNA being predominant in non-HR cases and the GAP43 mRNA in HR cases. The levels of NB-mRNAs in PB and BM were 5 to 1000 times lower in non-HR cases than in HR cases. The PB to BM ratio of NB-mRNAs was 10 to 100 times higher in non-HR cases compared to HR cases. The present case series suggests that non-HR and HR NB patients have the distinct expression profiles of NB-mRNAs in their PB and BM.

Evolution of sodium-glucose co-transporter 2 inhibitors from a glucose-lowering drug to a pivotal therapeutic agent for cardio-renal-metabolic syndrome.

Cardio-renal-metabolic (CRM) syndrome, which involves type 2 diabetes mellitus (T2DM), chronic kidney disease (CKD), and heart failure (HF), is a serious healthcare issue globally, with high morbidity and mortality. The disorders that comprise CRM syndrome are independent can mutually affect and accelerate the exacerbation of each other, thereby substantially increasing the risk of mortality and impairing quality of life. To manage CRM syndrome by preventing vicious interactions among individual disorders, a holistic treatment approach that can simultaneously address multiple disorders underpinning CRM syndrome is of great importance. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) lower blood glucose levels by inhibiting glucose reabsorption in the renal proximal tubule and were first indicated for the treatment of T2DM. Several cardiovascular outcome trials have demonstrated that SGLT2i not only lower blood glucose but also reduce the risk of hospitalization for HF and worsening renal function in patients with T2DM. Results have also suggested that the observed cardiorenal benefits of SGLT2i may be independent of their blood glucose-lowering effects. Several randomized controlled trials subsequently assessed the efficacy and safety of SGLT2i in patients without T2DM, and revealed considerable benefits of SGLT2i treatment against HF and CKD, regardless of the presence of T2DM. Thus, SGLT2i have become an essential therapeutic option to prevent the onset, slow the progression, and improve the prognosis of CRM syndrome. This review assesses the evolution of SGLT2i from a glucose-lowering drug to a therapeutic agent for CRM syndrome by evaluating epoch-making clinical studies, including randomized control trials and real-world studies.

Fungicidal spectrum and biological properties of a new fungicide, pyriofenone.

Pyriofenone is a new fungicide developed by Ishihara Sangyo Kaisha, Ltd. To determine the fungicidal spectrum of pyriofenone, in vivo pot tests and in vitro mycelial growth-inhibition tests were conducted. Pyriofenone showed excellent activity against wheat and cucumber powdery mildew and moderate efficacy against rice blast in the pot tests. In the mycelial growth-inhibition tests, most fungi were not affected by pyriofenone except for Botrytis cinerea, Helminthosporium sacchari, Pseudocercosporella herpotrichoides, Pyricularia oryzae, Rosellinia necatrix, and Verticillium dahliae. The fungicidal properties of pyriofenone on powdery mildew in cucumber and wheat were evaluated precisely. Pyriofenone exhibited excellent preventive and residual activities. It had high rainfastness in the cucumber leaves against powdery mildew. Pyriofenone also showed inhibitory activity on lesion development upon application until 2 days after inoculation, and the lesion expansion and sporulation of the cucumber powdery mildew fungus were effectively controlled. Furthermore, pyriofenone showed translaminar and vapor activities.