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Abstract Background Compartment syndrome commonly occurs in patients with forearm and lower leg fractures. Compartment syndromes of the gluteal and thigh muscles are less common. It is imperative that compartment syndrome be diagnosed and treated with fasciotomy as soon as possible. However, there are few reports on the diagnosis and treatment strategies for compartment syndromes that occur simultaneously in multiple anatomical regions or in the ipsilateral gluteal region and thigh. Case presentation We report on a 76-year-old man who was obliquely crushed under a tree extending from the right forearm to the left groin. He was brought to our emergency room, where he was diagnosed with compartment syndrome of the right forearm and left lower leg and crush syndrome. Emergency fasciotomy was performed. On the day after admission, swelling and tightness of the left gluteal thigh became apparent, and intracompartmental pressures were elevated, which led to an additional diagnosis of these compartment syndromes. A fasciotomy was performed, the gluteal skin incision was made according to the Kocher–Langenbeck approach (one of the posterior approaches for hip fractures), and the thigh was approached by extending the incision laterally. This surgical approach enabled the decompression of the compartments through a single incision and allowed for easier wound treatment and closure. Conclusion This case highlights the diagnosis and treatment of compartment syndrome in four anatomical regions. Extension of the Kocher–Langenbeck approach to the lateral thigh can be a useful surgical approach for ipsilateral gluteal and thigh compartment syndrome.

Solute carrier 12 (Slc12) is a family of electroneutral cation-coupled chloride (Cl−) cotransporters. Na+/K+/2Cl− (Nkcc) and Na+/Cl− cotransporters (Ncc) belong to the Nkcc/Ncc subfamily. Human and mouse possess one gene for the Na+/Cl− cotransporter (ncc gene: slc12a3), whereas teleost fishes possess multiple ncc genes, slc12a3 (ncc1) and slc12a10 (ncc2), in addition to their species-specific paralogs. Amphibians and squamates have two ncc genes: slc12a3 (ncc1) and ncc3. However, the evolutionary relationship between slc12a10 and ncc3 remains unresolved, and the presence of slc12a10 (ncc2) in mammals has not been clarified. Synteny and phylogenetic analyses of vertebrate genome databases showed that ncc3 is the ortholog of slc12a10, and slc12a10 is present in most ray-finned fishes, coelacanths, amphibians, reptiles, and a few mammals (e.g., platypus and horse) but pseudogenized or deleted in birds, most mammals, and some ray-finned fishes (pufferfishes). This shows that slc12a10 is widely present among bony vertebrates and pseudogenized or deleted independently in multiple lineages. Notably, as compared with some fish that show varied slc12a10 tissue expression profile, spotted gar, African clawed frog, red-eared slider turtle, and horse express slc12a10 in the ovaries or premature gonads. In horse tissues, an unexpectedly large number of splicing variants for Slc12a10 have been cloned, many of which encode truncated forms of Slc12a10, suggesting that the functional constraints of horse slc12a10 are weakened, which may be in the process of becoming a pseudogene. Our results elaborate on the evolution of Nkcc/Ncc subfamily of Slc12 in vertebrates. [ABSTRACT FROM AUTHOR]

Abstract Background Rhabdomyolysis is characterized by the destruction and necrosis of skeletal muscle tissue, resulting in acute kidney injury (AKI). Recombinant antithrombin (rAT) has DNA repair and vascular endothelial-protection properties. Herein, we investigated whether rAT therapy has beneficial effects against rhabdomyolysis-induced AKI. Ten-week-old male B6 mice were injected with 5 mL/kg of 50% glycerol intramuscularly in the left thigh after 24 h of fasting to create a rhabdomyolysis mouse model. Further, 750 IU/kg rAT was injected intraperitoneally at 24 and 72 h after the rhabdomyolysis model was established. The mice were euthanized after 96 h for histological analysis. Saline was administered to mice in the control group. Results Blood tests show elevated serum creatinine, urea nitrogen, and neutrophil gelatinase-associated lipocalin levels in rhabdomyolysis. Loss of tubular epithelial cell nuclei and destruction of the tubular luminal surface structure was observed in the untreated group, which improved with rAT treatment. Immunostaining for Ki-67 showed increased Ki-67-positive nuclei in the tubular epithelial cells in the rAT group, suggesting that rAT may promote tubular epithelial cell regeneration. The microvilli of the brush border of the renal tubules were shed during rhabdomyolysis, and rAT treatment reduced this injury. The vascular endothelial glycocalyx, which is usually impaired by rhabdomyolysis, became functional following rAT treatment. Conclusions Treatment with rAT suppressed rhabdomyolysis-induced AKI, suggesting that rAT therapy may be a novel therapeutic approach.

Abstract Recent advances in the analysis of intestinal bacteria have led to reports of variations in intestinal bacterial levels among hepatobiliary diseases. The mechanisms behind the changes in intestinal bacteria in various hepatobiliary diseases include the abnormal composition of intestinal bacteria, weakening of the intestinal barrier, and bacterial translocation outside the intestinal tract, along with their metabolites, but many aspects remain unresolved. Further research employing clinical studies and animal models is expected to clarify the direct relationship between intestinal bacteria and hepatobiliary diseases and to validate the utility of intestinal bacteria as a diagnostic biomarker and potential therapeutic target. This review summarizes the involvement of the microbiota in the pathogenesis of hepatobiliary diseases via the gut-liver axis.

Abstract Objectives Optimal stents for preoperative biliary drainage (PBD) for patients with possible resectable pancreatic cancer remain controversial, and risk factors for post‐endoscopic retrograde cholangiopancreatography pancreatitis (PEP), followed by PBD, are unknown. In this study, the efficacy and safety of fully covered self‐expandable metallic stents (FCSEMSs) and plastic stents (PSs) were compared, and the risk factors for PEP, followed by PBD, were investigated for patients with pancreatic cancer. Methods Consecutive patients with pancreatic cancer who underwent PBD between April 2005 and March 2022 were included. We retrospectively evaluated recurrent biliary obstruction, adverse events (AEs), and postoperative complications for FCSEMS and PS groups and investigated the risk factors for PEP. Results A total of 105 patients were included. There were 20 patients in the FCSEMS group and 85 patients in the PS group. For the FCSEMS group, the rate of recurrent biliary obstruction (0% vs. 25%, p = 0.03) was significantly lower. There was no difference in AE between the two groups. No significant differences were observed in the overall postoperative complications, but the volume of intraoperative bleeding was larger for the PS group than it was for the FCSEMS group (p < 0.001). From multivariate analysis, being female and lack of main pancreatic duct dilation were independent risk factors for pancreatitis (odds ratio, 5.68; p = 0.028; odds ratio, 4.91; p = 0.048). Conclusions FCSEMSs are thought to be preferable to PSs for PBD due to their longer time to recurrent biliary obstruction. Being female and the lack of main pancreatic duct dilation were risk factors for PEP.

Abstract Background The rate of residual liver recurrence after the resection of colorectal liver metastases is high, and most cases recur within 5 years of the initial hepatectomy. Here, we report two cases of residual liver recurrence after radical resection of colorectal liver metastases after a long recurrence-free survival period. Case presentation Case 1 involved a 62-year-old woman treated for ascending colon cancer in April 2011 who underwent right hepatectomy for synchronous colorectal liver metastasis in April 2012. However, in September 2021, computed tomography revealed residual recurrence in the lateral segment of the liver, and a lateral segmentectomy of the liver was performed. In Case 2, a 52-year-old man treated for cecal cancer in July 2002 underwent lateral segmentectomy of the liver for metachronous colorectal liver metastasis in October 2006. Subsequently, there was no recurrence; however, computed tomography showed residual liver recurrence in the right lobe of the liver in October 2021, and an expanded posterior hepatic segmentectomy was performed. Histopathological findings in both cases were consistent with colorectal liver metastases. Conclusions We encountered two cases in which residual liver recurrence was observed after a long period of recurrence-free survival. Although rare, there have been a few cases of late recurrence of liver metastases after radical resection of cancer liver metastases.

Tertiary lymphoid structures (TLSs) are complex lymphocyte clusters that arise in non-lymphoid tissues due to inflammation or cancer. A mature TLS with proliferating germinal centers is associated with a favorable prognosis in various cancers. However, the effect of TLS maturity on advanced colorectal cancer (CRC) remains unexplored. We analyzed the significance of TLS maturity and tumor Ki-67 expression in surgically resected tumors from 78 patients with pathological T4 CRC. Mature TLS was defined as the organized infiltration of T and B cells with Ki-67-positive proliferating germinal centers. We analyzed the relationship between TLS maturity and intratumoral immune cell infiltration. Mature TLS with germinal center Ki-67 expression was associated with microsatellite instability and improved survival; however, high tumor Ki-67 expression was associated with poor survival in the same cohort. Multivariate analysis identified the absence of mature TLS as an independent predictor of poor post-recurrence overall survival. Intratumoral infiltration of T lymphocytes and macrophages was significantly elevated in tumors with mature TLS compared to those lacking it. High Ki-67 levels and absent mature TLS were identified as poor prognostic factors in advanced CRC. Mature TLS could serve as a promising marker for patients at high-risk of CRC.

BackgroundPulmonary arterial hypertension (PAH) is a severe and rare disease in the cardiopulmonary system. Its pathogenesis involves vascular remodeling of the pulmonary artery, which results in progressive increases in pulmonary arterial pressure. Chronically increased pulmonary arterial pressure causes right ventricular hypertrophy and subsequent right heart failure. Pulmonary vascular remodeling is attributed to the excessive proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), which are induced by enhanced Ca2+ signaling following the up-/down-regulation of ion channel expression.ObjectivesIn the present study, the functional expression of two-pore domain potassium KCNK channels was investigated in PASMCs from idiopathic PAH (IPAH) patients and experimental pulmonary hypertensive (PH) animals.ResultsIn IPAH-PASMCs, the expression of KCNK1/TWIK1 and KCNK2/TREK1 channels was up-regulated, whereas that of KCNK3/TASK1 and KCNK6/TWIK2 channels was down-regulated. The similar up-regulated expression of KCNK1 and KCNK2 channels was observed in the pulmonary arterial smooth muscles of monocrotaline-induced PH rats, Sugen 5416/hypoxia-induced PH rats, and hypoxia-induced PH mice. The facilitated proliferation of IPAH-PASMCs was suppressed by the KCNK channel blockers, quinine and tetrapentylammonium. The migration of IPAH-PASMCs was also suppressed by these channel blockers. Furthermore, increases in the proliferation and migration were inhibited by the siRNA knockdown of KCNK1 or KCNK2 channels. The siRNA knockdown also caused membrane depolarization and subsequent decrease in cytosolic [Ca2+]. The phosphorylated level of c-Jun N-terminal kinase (JNK) was elevated in IPAH-PASMCs compared to normal-PASMCs. The increased phosphorylation was significantly reduced by the siRNA knockdown of KCNK1 or KCNK2 channels.ConclusionCollectively, these findings indicate that the up-regulated expression of KCNK1 and KCNK2 channels facilitates the proliferation and migration of PASMCs via enhanced Ca2+ signaling and JNK signaling pathway, which is associated with vascular remodeling in PAH.

Background/Aims We aimed to investigate (1) promising clinical findings for the recognition of focal type autoimmune pancreatitis (FAIP) and (2) the impact of endoscopic ultrasound (EUS)-guided tissue acquisition (EUS-TA) on the diagnosis of FAIP. Methods Twenty-three patients with FAIP were involved in this study, and 44 patients with resected pancreatic ductal adenocarcinoma (PDAC) were included in the control group. Results (1) Multivariate analysis revealed that homogeneous delayed enhancement on contrast-enhanced computed tomography was a significant factor indicative of FAIP compared to PDAC (90% vs. 7%, p=0.015). (2) For 13 of 17 FAIP patients (76.5%) who underwent EUS-TA, EUS-TA aided the diagnostic confirmation of AIPs, and only one patient (5.9%) was found to have AIP after surgery. On the other hand, of the six patients who did not undergo EUS-TA, three (50.0%) underwent surgery for pancreatic lesions. Conclusions Homogeneous delayed enhancement on contrast-enhanced computed tomography was the most useful clinical factor for discriminating FAIPs from PDACs. EUS-TA is mandatory for diagnostic confirmation of FAIP lesions and can contribute to a reduction in the rate of unnecessary surgery for patients with FAIP.

Advanced glycation end products (AGEs) accumulate in the plasma of pregnant women with hyperglycemia, potentially inducing oxidative stress and fetal developmental abnormalities. Although intrauterine hyperglycemia has been implicated in excessive fetal growth, the effects of maternal AGEs on fetal development remain unclear. We evaluated the differentiation regulators and cellular signaling in the skeletal muscles of infants born to control mothers (ICM), diabetic mothers (IDM), and diabetic mothers supplemented with either cis-palmitoleic acid (CPA) or trans-palmitoleic acid (TPA). Cell viability, reactive oxygen species levels, and myotube formation were assessed in AGE-exposed C2C12 cells to explore potential mitigation by CPA and TPA. Elevated receptors for AGE expression and decreased Akt and AMPK phosphorylation were evident in rat skeletal muscles in IDM. Maternal palmitoleic acid supplementation alleviated insulin resistance by downregulating RAGE expression and enhancing Akt phosphorylation. The exposure of the C2C12 cells to AGEs reduced cell viability and myotube formation and elevated reactive oxygen species levels, which were attenuated by CPA or TPA supplementation. This suggests that maternal hyperglycemia and plasma AGEs may contribute to skeletal muscle disorders in offspring, which are mitigated by palmitoleic acid supplementation. Hence, the maternal intake of palmitoleic acid during pregnancy may have implications for fetal health.

Background/Aims This study aimed to clarify the efficacy and safety of pancreatic duct lavage cytology combined with a cell-block method (PLC-CB) for possible pancreatic ductal adenocarcinomas (PDACs). Methods This study included 41 patients with suspected PDACs who underwent PLC-CB mainly because they were unfit for undergoing endoscopic ultrasonography-guided fine needle aspiration. A 6-Fr double lumen catheter was mainly used to perform PLC-CB. Final diagnoses were obtained from the findings of resected specimens or clinical outcomes during surveillance after PLC-CB. Results Histocytological evaluations using PLC-CB were performed in 87.8% (36/41) of the patients. For 31 of the 36 patients, final diagnoses (invasive PDAC, 12; pancreatic carcinoma in situ, 5; benignancy, 14) were made, and the remaining five patients were excluded due to lack of surveillance periods after PLC-CB. For 31 patients, the sensitivity, specificity, and accuracy of PLC-CB for detecting malignancy were 94.1%, 100%, and 96.8%, respectively. In addition, they were 87.5%, 100%, and 94.1%, respectively, in 17 patients without pancreatic masses detectable using endoscopic ultrasonography. Four patients developed postprocedural pancreatitis, which improved with conservative therapy. Conclusions PLC-CB has an excellent ability to detect malignancies in patients with possible PDACs, including pancreatic carcinoma in situ.

Objectives: The geriatric nutritional risk index (GNRI) is a nutrition-related risk index calculated easily from serum albumin and the ratio of body weight to ideal body weight. We investigated the prognostic values of the GNRI in elderly patients with obstructive colorectal cancer (OCRC) who had a self-expandable metallic stent inserted as a bridge to curative surgery. Methods: We retrospectively evaluated 61 patients aged 65 years with pathological stage I to III OCRC. Associations of preoperative GNRI and pre-stenting GNRI (ps-GNRI) with short- and long-term outcomes were examined. Results: Multivariate analyses revealed GNRI of

IntroductionCommon variants in the SLC30A8 gene, encoding the secretory granule zinc transporter ZnT8 (expressed largely in pancreatic islet alpha and beta cells), are associated with altered risk of type 2 diabetes. Unexpectedly, rare loss-of-function (LoF) variants in the gene, described in heterozygous individuals only, are protective against the disease, even though knockout of the homologous SLC30A8 gene in mice leads to unchanged or impaired glucose tolerance. Here, we aimed to determine how one or two copies of the mutant R138X allele in the mouse SLC30A8 gene impacts the homeostasis of zinc at a whole-body (using non-invasive 62Zn PET imaging to assess the acute dynamics of zinc handling) and tissue/cell level [using laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) to map the long-term distribution of zinc and manganese in the pancreas].MethodsFollowing intravenous administration of [62Zn]Zn-citrate (~7 MBq, 150 μl) in wild-type (WT), heterozygous (R138X+/−), and homozygous (R138X+/+) mutant mice (14–15 weeks old, n = 4 per genotype), zinc dynamics were measured over 60 min using PET. Histological, islet hormone immunohistochemistry, and elemental analysis with LA-ICP-MS (Zn, Mn, P) were performed on sequential pancreas sections. Bulk Zn and Mn concentration in the pancreas was determined by solution ICP-MS.ResultsOur findings reveal that whereas uptake into organs, assessed using PET imaging of 62Zn, is largely unaffected by the R138X variant, mice homozygous of the mutant allele show a substantial lowering (to 40% of WT) of total islet zinc, as anticipated. In contrast, mice heterozygous for this allele, thus mimicking human carriers of LoF alleles, show markedly increased endocrine and exocrine zinc content (1.6-fold increase for both compared to WT), as measured by LA-ICP-MS. Both endocrine and exocrine manganese contents were also sharply increased in R138X+/− mice, with smaller increases observed in R138X+/+ mice.DiscussionThese data challenge the view that zinc depletion from the beta cell is the likely underlying driver for protection from type 2 diabetes development in carriers of LoF alleles. Instead, they suggest that heterozygous LoF may paradoxically increase pancreatic β-cell zinc and manganese content and impact the levels of these metals in the exocrine pancreas to improve insulin secretion.

Abstract Objectives A difficult step in endoscopic ultrasound (EUS)‐guided drainage procedures is dilation of the puncture tract before stent deployment. The efficacy and safety of a novel spiral dilator, Tornus ES, for EUS‐guided drainage were investigated in this study. Methods This study was conducted as a prospective, single‐arm, observational study at Sendai City Medical center. Dilation of the puncture tract using a spiral dilator was attempted for all EUS‐guided drainage cases. The primary outcome was the technical success rate which was defined as successful stent placement in the puncture tract. Secondary outcomes were the success rate of dilation using a spiral dilator, procedure time, and adverse events related to the procedures. Results A total of 10 patients were enrolled between January and March 2022. Seven patients underwent EUS‐guided biliary drainage (hepaticogastrostomy for six and hepaticojejunostomy for one), and the remaining three patients underwent EUS‐guided gallbladder drainage. The technical success rate and the success rate of dilation using a spiral dilator were both 100%. The mean procedure time was 27 min. No adverse events related to the procedure occurred in all cases. Conclusions Dilation of the puncture tract using a spiral dilator was effective and safe and might make it easier to perform EUS‐guided drainage.

BackgroundHemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome occurs in pregnant and postpartum individuals. We observed serum syndecan-1 (SDC-1) levels, which is a component of the glycocalyx, in a patient with HELLP syndrome from admission to the postpartum period and examined their association as reflecting the pathophysiology related to endothelial injury.Case presentationA 31-year-old primiparous female patient without a previous medical history at a gestational age of 37 weeks and 6 days was transferred to our hospital the morning after a visit to a previous hospital with headache and nausea. Elevated transaminase, platelet count, and proteinuria were noted. Head magnetic resonance imaging revealed a caudate nucleus hemorrhage and posterior reversible encephalopathy syndrome. After she delivered her newborn through an emergency cesarean section, she was admitted to the intensive care unit. On day 4 post-delivery, the patient’s D-dimer concentration was elevated, and contrast-enhanced computed tomography was performed. The results indicated pulmonary embolism, and heparin administration was initiated. The serum SDC-1 level was highest on day 1 post-delivery and quickly decreased subsequently; however, it remained elevated during the postpartum period. Her condition gradually improved, and she was extubated on day 6 and discharged from the ICU on day 7 post-delivery.ConclusionWe measured SDC-1 concentration in a patient with HELLP syndrome and found that the clinical course correlated with SDC-1 levels, indicating that SDC-1 is elevated immediately before and after pregnancy termination in patients with HELLP syndrome. Therefore, SDC-1 fluctuations, combined with the elevation of the D-dimer level, may be a potential marker for the early detection of HELLP syndrome and estimation of the syndrome’s severity in the future.

Abstract Background Leriche syndrome is caused by atherosclerosis and is often characterized by symptoms such as intermittent claudication and numbness and coldness of the lower limbs. Its exact prevalence and incidence are unknown because it is a rare disease. We report a case of Leriche syndrome diagnosed incidentally on trauma pan-scan computed tomography (CT). Case presentation A 61-year-old Asian male was driving a passenger car and had a head-on collision with a dump truck that required an emergency call. The patient was transported to our hospital in a doctor’s helicopter. Physical examination revealed the following vital signs: respiratory rate, 23 breaths per min; SpO2, 98% under a 10-L administration mask; pulse rate, 133 beats per min; blood pressure, 142/128 mmHg; Focused Assessment with Sonography for Trauma, positive; Glasgow Coma Scale assessment, E3V5M6; and body temperature, 35.9 °C. Trauma pan-scan CT showed bilateral mandibular fractures, bilateral multiple rib fractures, bilateral pneumothorax, sternal fractures, hematoma around thoracic spine, small bowel perforation, mesenteric injury, right clavicle fracture, right ankle debridement injury, and thrombotic occlusion from just above the abdominal aortic bifurcation to the bilateral common iliac arteries. Although thrombotic occlusion needed to be differentiated from traumatic aortic injury, the presence of collateral blood vessels led to the diagnosis of Leriche syndrome, and conservative treatment was performed. Damage control surgery was required for the small bowel injuries. From the second day of admission, the patient was treated with continuous intravenous heparin and prostaglandin preparations. However, impaired blood flow and reperfusion injury in the right lower extremity progressed. On the fifth day of admission, right thigh amputation was performed. The patient required renal replacement therapy for 2 weeks starting from the third day of admission. Conclusions In this case, conservative therapy was initially chosen for Leriche syndrome. However, the complex factors in the acute phase of trauma led to development of hemorrhagic necrosis, requiring amputation of the lower extremity. Our findings indicate the need to carefully consider the unique factors affecting Leriche syndrome patients when considering treatment indications and choices for trauma.

Objectives: Understanding the relationship between sarcopenia and malignancy is increasingly important since they inevitably affect the aging population. We investigated the clinical significance of sarcopenia in nonmetastatic obstructive colorectal cancer (OCRC) patients who were inserted self-expandable metallic stent and underwent curative surgery. Methods: Plain cross-sectional CT images obtained before stenting were retrospectively analyzed in 92 patients. Muscle volume loss (myopenia) and decreased muscle quality (myosteatosis) were evaluated as skeletal muscle index (SMI) and intramuscular adipose tissue content (IMAC), respectively. Results: This study included 54 men and 38 women, with a median age of 70.5 years. The median interval between SEMS placement and the surgery was 17 days (range, 5-47). There were 35 postoperative complications. The median postoperative hospital stay was 15.5 days (range, 8-77). Twenty-eight patients (41.3%) were classified as SMI-low, and 31 (34.1%) patients were classified as IMAC-high. In multivariate analysis, IMAC-high [hazard ratio (HR) = 7.68, 95% confidence interval (CI) 2.22-26.5, P = 0.001] and right-sided tumor (HR = 5.79, 95% CI 1.36-24.7, P = 0.018) were independent predictors of postoperative complications. IMAC-high (HR = 23.2, 95% CI 4.11-131, P < 0.001) and elevated modified Glasgow prognostic score (mGPS) (HR = 5.85, 95% CI 1.22-28.1, P = 0.027) were independent predictors of infectious complications. Relapse-free survival and overall survival were not significantly different regardless of the SMI or IMAC status. Conclusions: IMAC was associated with postoperative complications and infectious complications. Myosteatosis might be a stronger predictor of postoperative complications than myopenia.

Background. Stathmin 1 (STMN1), a marker for immature neurons and tumors, controls microtubule dynamics by destabilizing tubulin. It plays an essential role in cancer progression and indicates poor prognosis in several cancers. This potential protein has not been clarified in clinical patients with neuroblastoma. Therefore, this study aimed to assess the clinical significance and STMN1 function in neuroblastoma with and without MYCN amplification. Methods. Using immunohistochemical staining, STMN1 expression was examined in 81 neuroblastoma samples. Functional analysis revealed the association among STMN1 suppression, cellular viability, and endogenous or exogenous MYCN expression in neuroblastoma cell lines. Result. High levels of STMN1 expression were associated with malignant potential, proliferation potency, and poor prognosis in neuroblastoma. STMN1 expression was an independent prognostic factor in patients with neuroblastoma. Furthermore, STMN1 knockdown inhibited neuroblastoma cell growth regardless of endogenous and exogenous MYCN overexpression. Conclusion. Our data suggest that assessing STMN1 expression in neuroblastoma could be a powerful indicator of prognosis and that STMN1 might be a promising therapeutic candidate against refractory neuroblastoma with and without MYCN amplification.

Human leukocyte antigen class I (HLA-I) is considered a genetic pathogen for ulcerative colitis (UC). This study aimed to investigate the significance of DNA damage and HLA-I expression in infiltrating immune cells and immune checkpoint protein PD-L1 expression in dysplasia/colitic cancer (CC) and sporadic colorectal cancer (SCRC). We performed immunohistochemical staining for HLA-I, PD-L1, γH2AX (DNA damage marker), and immune cell markers such as CD8, FOXP3, CD68, and CD163 (in surgically resected specimens from 17 SCRC patients with 12 adjacent normal mucosa (NM) and 9 UC patients with 18 dysplasia/CC tumors. The ratio of membrane HLA-I-positive epithelial cells in UC and dysplasia/CC tissues was significantly higher than that in NM and SCRC. High HLA-I expression in dysplasia/CC was associated with high positivity of γH2AX and PD-L1 expression compared to SCRC. The infiltration of CD8-positive T cells and CD68-positive macrophages in HLA-I-high dysplasia/CC was significantly higher than in UC and SCRC. Dysplasia/CC specimens with DNA damage exhibited high levels of HLA-I-positive epithelial cells with high CD8- and CD68-positive immune cell infiltration compared to UC and SCRC specimens. Targeting DNA damage in UC may regulate immune cell infiltration, immune checkpoint proteins, and carcinogenesis by modulating DNA damage-induced HLA-I antigen presentation.

We previously reported that glycation induces insulin resistance in the hearts of newborn pups from a gestational diabetes mellitus (GDM) rat model. Administration of n-3 unsaturated fatty acids suppressed glycation and improved signaling in GDM rat pups. In this study, we investigated their effects on cranial neurons using the GDM rat model and PC12 cells derived from rat adrenal pheochromocytomas. Additionally, we examined whether n-3 and n-7 unsaturated fatty acids (cis-palmitoleic acid [CPA] and trans-palmitoleic acid [TPA]) ameliorate the detrimental effects of high glucose exposure on rats. In the neonatal cerebrum of GDM rats, increased levels of advanced glycation end products (AGEs) inhibited Akt phosphorylation; however, CPA and TPA intake during pregnancy ameliorated these abnormalities. Furthermore, exposure to high-glucose-induced apoptosis in PC12 cells compared to the cells cultured in control glucose. PC12 cells exposed to high-glucose with fatty acids exhibited reduced AGE production and apoptosis induction compared to the high-glucose group. These findings suggest that a hyperglycemic environment during pregnancy promotes AGE formation in brain neuronal proteins and induces apoptosis. Both TPA and CPA mitigated these abnormalities; however, CPA is cytotoxic, highlighting its safety in pregnant women.

Objectives: It has been increasingly recognized that the progression of cancer is dependent not only on the tumor characteristics but also on the nutritious and inflammatory condition of the host. We investigated the relationship between the globulin-to-albumin ratio (GAR) and long-term outcomes in obstructive colorectal cancer (OCRC) patients who were inserted self-expandable metallic stent as a bridge to curative surgery. Methods: A total of 75 pathological stage II and III OCRC patients between 2013 and 2020 were retrospectively evaluated. The associations of the preoperative GAR with clinicopathological factors and patient survival were examined. Results: Receiver operating characteristic curve analysis demonstrated that the optimal cutoff value was 0.88. The GAR 0.88 status was significantly associated with the absence of lymph node metastasis (P = 0.011), longer postoperative hospital stay (17 days vs 15 days, P = 0.042), and not receiving adjuvant chemotherapy (P = 0.011). Relapse-free survival and cancer-specific survival were significantly shorter in the GAR 0.88 group (P = 0.007 and P = 0.023, respectively). Multivariate analyses revealed that the GAR 0.88 was independently associated with relapse-free survival [hazard ratio (HR) = 4.17, 95% confidence interval (CI) 1.32-13.14, P = 0.015)]. Moreover, CA19-9 37 (HR = 6.56, 95% CI 2.12-20.27, p = 0.001) and not receiving adjuvant chemotherapy (HR = 4.41, 95% CI 1.28-15.26, p = 0.019) were independent poor prognostic factors for relapse-free survival. Conclusions: The results demonstrated that the GAR was a significant prognostic factor for OCRC patients.

Abstract Background Anorectal malignant melanoma (ARMM) has an extremely poor prognosis, and there is no report of resection of liver metastases so far. We report herein a rare case of postoperative laparoscopic partial hepatic S7 resection for rectal malignant melanoma. Case presentation A 51-year-old female patient with a diagnosis of an ARMM underwent a laparoscopic rectal amputation. Eleven months later, computed tomography (CT) revealed a 14-mm nodule in liver segment 7 (S7), which was diagnosed as a hepatic recurrence of the ARMM. Because no other recurrences were found, a laparoscopic partial resection of S7 was performed. Pathological analysis found intracellular melanin deposition, and immunostaining was S-100 (+), HMB-45 (+), and SOX-10 (+). Based on these findings, a liver metastasis of malignant melanoma was diagnosed. The patient is alive 7 months after the second surgery and has so far experienced no recurrences. Conclusion We reported an extremely rare case of a laparoscopic resection of a liver metastasis following surgery for ARMM.

Background: Atlantoaxial rotatory fixation (AARF) causes the atlantoaxial joint to be fixed in a rotated position, resulting in painful torticollis. We report a case of pediatric AARF associated with severe head trauma requiring emergency craniotomy and was treated with conservative treatment. Case presentation: A 10-year-old boy was struck by a van while walking across the street. Upon admission to our trauma care center, his Glasgow Coma Scale score was 11 points (E3V3M5), pupils were 4 mm bilateral regular circles, and other vital signs were stable. Plain computed tomography (CT) revealed left acute epidural hematoma, traumatic subarachnoid hemorrhage, cerebral contusion, pneumoencephalopathy, and rightward deviation of the axial vertebra. We performed an emergency craniotomy due to an enlarged hematoma on a repeat head CT scan and decreased level of consciousness. Based on imaging studies, rightward deviation of the axial vertebra was diagnosed as AARF; however, since the patient was already on ventilatory management and no physical findings were obtained, conservative treatment with cervical collar fixation was started. His condition improved, and he was extubated on day 3, released from the cervical collar on day 10, discharged from the hospital on day 17, and followed-up until day 32. Conclusions: AARF is often caused by minor trauma or inflammation in children; however, we experienced a case complicated by severe head trauma, which was treated conservatively and showed a good clinical progress. Since AARF treatment depends on the length of time from onset, early diagnosis, in trauma care, carefully assessing factors other than major trauma, will lead to improved prognosis.

Introduction: Myocardial dysfunction occurs in patients with sepsis due to vascular endothelial injury. Recombinant human thrombomodulin (rhTM) attenuates vascular endothelial injuries through endothelial glycocalyx (eGC) protection. Hypothesis: We hypothesized that rhTM attenuates myocardial dysfunction via the inhibition of vascular endothelial injury during sepsis. Methods: Ten-week-old male C57BL6 mice were injected intraperitoneally with 20 mg/kg of lipopolysaccharide (LPS). In rhTM-treated mice, rhTM was injected intraperitoneally at 3 and 24 h after LPS injection. Saline was injected intraperitoneally as control. To assess for eGC injury, intensity score was measured 48 h after the LPS injection. To confirm vascular endothelial injuries, ultrastructural analysis was performed using scanning (SEM) and transmission electron microscopy (TEM). Results: The survival rate of the rhTM group at 48 h after LPS injection was significantly higher than that of the control group (68% vs. 17%, p < 0.05). The serum level of troponin I in the rhTM group was lower than that in the control (2.2 ± 0.4 ng/dL vs 9.4 ± 1.1 ng/dL, p < 0.05). The expression of interleukin-6 (IL-6) was attenuated in the rhTM-treated group than in the control (65.3 ± 15.3 ng/mL vs 226.3 ± 19.4 ng/mL, p < 0.05). The serum concentration of syndecan-1, a marker of glycocalyx damage, was significantly decreased 48 h post-administration of LPS in the rhTM-treated group than in the control group. In ultrastructural analysis using SEM and TEM, eGC peeled off from the surface of the capillary lumen in the control. Conversely, the eGC injury was attenuated in the rhTM group. Gene set enrichment analysis revealed that osteomodulin, osteoglycin proline/arginine-rich end leucine-rich repeat protein, and glypican-1, which are proteoglycans, were preserved by rhTM treatment. Their protein expression was retained in endothelial cells. Conclusion: rhTM attenuates sepsis-induced myocardial dysfunction via eGC protection.

Abstract To evaluate the effect of cryoprecipitate (CRYO) transfusion in women referred for postpartum hemorrhage (PPH). This retrospective cohort study included patients with primary PPH referred to Gifu University Hospital between April 2013 and March 2020. We analyzed the effect of CRYO transfusion on fluid balance 24 h after the initial examination using a multivariable linear regression model adjusted for several confounding variables. To evaluate whether outcomes were modified by active bleeding, an interaction term of CRYO*active bleeding was incorporated into the multivariable model. We identified 157 women: 38 in the CRYO group (cases) and 119 in the control group. Fluid balance in the aforementioned period tended to decrease in the CRYO group compared with that in the control group (coefficient − 398.91; 95% CI − 1298.08 to + 500.26; p = 0.382). Active bleeding on contrast-enhanced computed tomography affected the relationship between CRYO transfusion and fluid balance (p = 0.016). Other outcomes, except for the overall transfusion requirement, were not significantly different; however, the interaction effect of active bleeding was significant (p = 0.016). CRYO transfusion may decrease the fluid balance in the first 24 h in PPH patients, especially in those without active bleeding.

Background/Aims The aim of this study was to evaluate the safety of sedation with propofol as an alternative to benzodiazepine drugs in outpatient endoscopy. Methods In this prospective study, examinees who underwent outpatient endoscopy under propofol sedation and submitted a nextday questionnaire with providing informed consent were evaluated. Periprocedural acute responses, late adverse events within 24 hours, and examinee satisfaction were evaluated. Results Among the 4,122 patients who received propofol in the 17,978 outpatient-based endoscopic examinations performed between November 2016 and March 2018, 2,305 eligible examinees (esophagogastroduodenoscopy for 1,340, endoscopic ultrasonography for 945, and total colonoscopy for 20) were enrolled, and their responses to a questionnaire were analyzed. The mean propofol dose was 69.6±24.4 mg (range, 20–200 mg). Diazepam, midazolam, and/or pentazocine in combination with propofol was administered to 146 examinees. Mild oxygen desaturation was observed in 59 examinees (2.6%); and mild bradycardia, in 2 (0.09%). Other severe reactions or late events did not occur. After eliminating 181 invalid responses, 97.7% (2,065/2,124) of the patients desired propofol sedation in future examinations. Conclusions Propofol sedation was found to be safe-without severe adverse events or accidents-for outpatient endoscopy on the basis of the patients’ next-day self-evaluation. Given the high satisfaction level, propofol sedation might be an ideal tool for painless endoscopic screening.

Abstract Syndecan-1 (SDC-1) is found in the endothelial glycocalyx and shed into the blood during systemic inflammatory conditions. We investigated organ dysfunction associated with changing serum SDC-1 levels for early detection of organ dysfunction in critically ill patients. To evaluate the effect of SDC-1 on laboratory parameters measured the day after SDC-1 measurement with consideration for repeated measures, linear mixed effects models were constructed with each parameter as an outcome variable. A total of 94 patients were enrolled, and 831 samples were obtained. Analysis using mixed effects models for repeated measures with adjustment for age and sex showed that serum SDC-1 levels measured the day before significantly affected several outcomes, including aspartate aminotransferase (AST), alanine transaminase (ALT), creatinine (CRE), blood urea nitrogen (BUN), antithrombin III, fibrin degradation products, and D-dimer. Moreover, serum SDC-1 levels of the prior day significantly modified the effect between time and several outcomes, including AST, ALT, CRE, and BUN. Additionally, increasing serum SDC-1 level was a significant risk factor for mortality. Serum SDC-1 may be a useful biomarker for daily monitoring to detect early signs of kidney, liver and coagulation system dysfunction, and may be an important risk factor for mortality in critically ill patients.

Stent-graft placement is an important treatment for traumatic renal artery dissection, but it may occasionally be technically difficult to advance a catheter through the lesion of the dissection due to severe stenosis of the true rumen. A triple-coaxial (triaxial) system, which consists of a small microcatheter, a large microcatheter, and a 4-Fr. catheter, has recently become available, and it contributes to super-selective catheterization. We thought this system may be useful for passing catheters through the dissection. We herein report a 30-year-old male patient with traumatic renal artery dissection, who was successfully treated by stent-graft placement using the triaxial system.

Abstract Background Heat-related illnesses include symptoms such as heat syncope/cramps, heat exhaustion, and life-threatening heat stroke. Usually, a heat stroke causes cerebellar ataxia, cognitive impairment, dysphagia, and aphasia. We report a very rare case of a patient who developed severe heat stroke complicated by multiple cerebral infarctions. Case presentation An 80-year-old Asian woman was found lying unconscious at her house, with no air conditioner and closed windows; the highest outside temperature was 36.1 °C. She was brought to our hospital unconscious with a high bladder temperature (42.5 °C) and disseminated intravascular coagulation (DIC score 4). She was diagnosed with severe heat stroke and managed with rapid cooling, intravenous fluids therapy, antibiotic therapy, and anti-coagulation therapy for DIC. Anti-coagulation therapy consisted of treatment with recombinant thrombomodulin for 4 days (days 1–4) and recombinant antithrombin for 1 day (day 1). A head computed tomography (CT) and magnetic resonance imaging (MRI) examination were performed on day 3, because she was still unconscious. Diffuse-weighted imaging showed high-signal intensities, indicating multiple lesions. An intracranial magnetic resonance angiography showed normal results. Imaging indicated new multiple cerebellar infarctions complicated with DIC. A tracheotomy was performed on day 9 because her conscious condition had not improved. She was transferred to another hospital for subacute care on day 23. Conclusions Early management of heat stroke using anti-DIC, anti-bacterial, and fluid resuscitation therapy can help prevent complications such as intracranial hemorrhaging.

Background: Eosinophilic chronic rhinosinusitis (ECRS) is a subtype of chronic rhinosinusitis associated with asthma. CD69 is an important marker of activation for eosinophils. But, whether a correlation exist between the CD69 expression on eosinophils and clinical findings is unclear. Methods: We performed quantitative PCR and/or flow cytometry using tissue and purified eosinophils from the blood and nasal polyps of 12 patients with ECRS and from 8 patients without ECRS (controls). We assessed clinical findings including nasal polyp (NP) scores, sinus CT findings, and pulmonary function test results, and examined their possible association with the CD69 expression. We also performed CD69 cross-linking experiments in mouse eosinophils to investigate the functional role of CD69. Results: Levels of cytokine mRNAs (IL-4, -5, -10, and -13) were significantly higher in purified NP eosinophils and tissues from patients with ECRS than the levels of those in controls. The expressions of major basic protein (MBP), eosinophilic cationic protein (ECP), eosinophilic-derived neurotoxin (EDN), eosinophil peroxidase (EPX) in cytotoxic granules, and CD69 mRNA were significantly higher in purified eosinophils from NPs than in those from blood. We also found a correlation between expression of CD69 and clinical findings. Moreover, we found EPX release from mouse eosinophils following CD69 cross-linking. Conclusions: These data suggest that increased CD69 expression by eosinophils is not only a biomarker for nasal obstruction and pulmonary dysfunction, but also a potential therapeutic target for patients with ECRS and asthma. Keywords: Asthma, CD69, Chronic rhinosinusitis, Eosinophil, Nasal polyp

Abstract Background Pelvic fracture with high energy trauma has a high mortality rate, especially in men. In addition, severe multiple trauma, major hemorrhage, and administration of red blood cells predict mortality in elderly patients with pelvic fracture. We herein report a rare case in which multiple arterial embolization occurred after pelvic fracture. Case presentation An 83-year-old male cyclist was transported to our hospital after being struck by a car. On arrival, he was diagnosed with multiple trauma, including rib fractures with hemothorax, lumbar fractures of the transverse process, and injuries in the right acetabulum, left adrenal gland, and liver. He underwent massive transfusion and transcatheter arterial embolization due to extravasation from the right superior gluteal artery and left adrenal gland. On the second day, owing to right lower leg ischemia, serum creatinine kinase and myoglobin levels were markedly elevated from the reference value; hence, a right above-knee amputation was performed 12 h after the accident. However, both protein levels remained high after amputation, resulting in acute renal injury, which was treated via hemodiafiltration on hospital day 3. In addition, sustained low efficiency hemodialysis and plasma exchange were performed on hospital day 4. Despite these treatments, the patient’s hemodynamics did not improve, and he died on hospital day 8. The autopsy revealed necropsy of the iliopsoas muscles and the digestive tract. Conclusions The causes of the patient’s death were considered to be persistent rhabdomyolysis and severe hypotension due to iliopsoas necrosis and peritonitis due to digestive tract necrosis. Multiple arterial embolization caused by consumption coagulopathy associated with multiple trauma may account for severe outcomes in this case.

Glycocalyx is present on the surface of healthy endothelium, and the concentration of serum syndecan-1 can serve as an injury marker. This study aimed to assess endothelial injury using serum syndecan-1 as a marker of endothelial glycocalyx injury in patients who underwent hemodialysis. In this single-center, retrospective, observational study, 145 patients who underwent hemodialysis at the Gifu University Hospital between March 2017 and December 2019 were enrolled. The median dialysis period and time were 63 months and 3.7 h, respectively. The serum syndecan-1 concentration significantly increased from 124.6 ± 107.8 ng/ml before hemodialysis to 229.0 ± 138.1 ng/ml after hemodialysis (P < 0.001). Treatment with anticoagulant nafamostat mesylate inhibited hemodialysis-induced increase in the levels of serum syndecan-1 in comparison to unfractionated heparin. Dialysis time and the change in the syndecan-1 concentration were positively correlated. Conversely, the amount of body fluid removed and the changes in the syndecan-1 concentration were not significantly correlated. The reduction in the amount of body fluid removed and dialysis time inhibited the change in the syndecan-1 levels before and after hemodialysis. In conclusion, quantitative assessment of the endothelial glycocalyx injury during hemodialysis can be performed by measuring the serum syndecan-1 concentration, which may aid in the selection of appropriate anticoagulants, reduction of hemodialysis time, and the amount of body fluid removed.

Abstract Background Critical illness myopathy (CIM) is associated with severe skeletal muscle wasting and impaired function in intensive care unit (ICU) patients. The mechanisms underlying CIM remain incompletely understood. To elucidate the biological activities occurring at the transcriptional level in the skeletal muscle of ICU patients with CIM, the gene expression profiles, potential upstream regulators, and enrichment pathways were characterized using RNA sequencing (RNA-seq). We also compared the skeletal muscle gene signatures in ICU patients with CIM and genes perturbed by mechanical loading in one leg of the ICU patients, with an aim of reducing the loss of muscle function. Methods RNA-seq was used to assess gene expression changes in tibialis anterior skeletal muscle samples from seven critically ill, immobilized, and mechanically ventilated ICU patients with CIM and matched control subjects. We also examined skeletal muscle gene expression for both legs of six ICU patients with CIM, where one leg was mechanically loaded for 10 h/day for an average of 9 days. Results In total, 6257 of 17,221 detected genes were differentially expressed (84% upregulated; p

Radiation therapy against cancer cells often causes radiation resistance via accumulation of hypoxia-inducible factor 1 subunit alpha (HIF-1α) under hypoxic conditions and severe side effects. Radiation sensitizers without side effects are required to overcome hypoxia-induced radiation resistance and decrease radiation-related side effects in patients with refractory cancer. We previously developed oxygen nanobubble water (NBO2 water) and demonstrated that it suppresses hypoxia-induced radiation resistance in cancer cell lines within the single-nanometer range. This study aimed to elucidate whether NBO2 water could act as a radiosensitizer via regulation of HIF-1α in a tumor-bearing mouse model. Six-week-old female BALB/c mice subcutaneously injected with tumor cells received control water or NBO2 water for 28 days, after which biochemical examinations and radiation treatment were performed. Hypoxic tumor regions were detected immunohistochemically. We found that NBO2 water sensitized radiation reactivity in the xenografted tumors. Notably, NBO2 water administration downregulated the accumulation of HIF-1α in xenografted tumors and did not affect the vital organs of healthy mice. The combination of radiation and single-nanometer NBO2 water without severe side effects may be a promising therapeutic option to improve radiation sensitivity in cancer patients without tolerance to invasive treatments.

Collecting duct carcinoma (CDC) is a rare, extremely aggressive form of renal cancer. Recently, immune checkpoint inhibitors (ICI), anti-programmed death-1 (PD-1) antibody, and anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibody were approved for use against metastatic renal cell carcinoma. We herein described two cases of metastatic renal collecting duct carcinoma treated with a combination immunotherapy consisting of nivolumab and ipilimumab. In the first case, which included a bone metastasis, the best response achieved was stable disease (SD) for one year. In the second case, which was accompanied by a lung metastasis, the best response achieved was a partial response. The outcome of these cases suggested that the combination of nivolumab and ipilimumab is effective against renal collecting duct carcinoma.

Abstract Background Metformin-associated lactic acidosis is a well-known life-threatening complication of metformin. We here report the case of a patient who developed metformin-associated lactic acidosis without organ manifestations, due to the simultaneous ingestion of an overdose of metformin and alcohol, and who recovered with high-flow high-volume intermittent hemodiafiltration. Case presentation A 44-year-old Asian woman with type 2 diabetes attempted suicide by ingesting 10 tablets of metformin 500 mg and drinking approximately 600 mL of Japanese sake containing 15% alcohol. She was transferred to our emergency department because of disturbed consciousness. Continuous intravenous administration of noradrenalin (0.13 μg/kg per minute) was given because she was in shock. Laboratory findings included a lactate level of 119 mg/dL (13.2 mmol/L), bicarbonate of 14.5 mmol/L, and serum metformin concentration of 1138 ng/mL. She was diagnosed as having metformin-associated lactic acidosis worsened by alcohol. After 4560 mL of bicarbonate ringer (Na+ 135 mEq/L, K+ 4 mEq/L, Cl− 113 mEq/L, HCO3 − 25 mEq/L) was administered, high-flow high-volume intermittent hemodiafiltration. (dialysate flow rate: 500 mL/min, substitution flow rate: 3.6 L/h) was carried out for 6 h to treat metabolic acidosis and remove lactic acid and metformin. Consequently, serum metformin concentration decreased to 136 ng/mL and noradrenalin administration became unnecessary to maintain normal vital signs. On hospital day 12, she was moved to the psychiatry ward. Conclusions HFHV-iHDF may be able to remove metformin and lactic acid efficiently and may improve the condition of hemodynamically unstable patients with metformin-associated lactic acidosis.

Abstract Background Thyrotoxic crisis and pheochromocytoma multisystem crisis are rare, life-threatening, emergency endocrine diseases with various clinical manifestations. Here we report a case of a patient who simultaneously developed thyrotoxic crisis and pheochromocytoma multisystem crisis and required intensive cardiovascular management. Case presentation A 60-year-old Asian man experienced nausea and vomiting, and subsequently developed dyspnea and cold sweats while farming. His serum free thyroxine, free triiodothyronine, and thyrotropin receptor antibody levels were elevated at 2.9 ng/dL, 7.2 pg/dL, and 4.7 IU/L, respectively. Serum thyrotropin levels were suppressed at less than 0.01 μIU/mL. Thyroid echography demonstrated no thyroid swelling (23 × 43 mm). A whole body computed tomography was performed for systemic evaluation. This revealed exophthalmos and a mass of size 57 × 64 mm in the anterior pararenal space. Based on these findings, we made an initial diagnosis of thyrotoxic crisis secondary to exacerbation of Grave’s hyperthyroidism. Treatment was begun with an iodine agent at a dose of 36 mg/day, thiamazole at a dose of 30 mg/day, and hydrocortisone at a dose of 300 mg daily for 3 consecutive days. To control tachycardia, continuous intravenously administered propranolol and diltiazem infusions were given. At the same time, small doses of doxazosin and carvedilol were used for both alpha and beta adrenergic blockade. On hospital day 5, his blood pressure and serum catecholamine concentrations (adrenalin 42,365 pg/mL, dopamine 6409 pg/mL, noradrenalin 72,212 pg/mL) were still high despite higher beta blocker and calcium channel blocker doses. These findings contributed to the diagnosis of pheochromocytoma multisystem crisis with simultaneous thyrotoxic crisis. We increased the doses of doxazosin and carvedilol, which stabilized his hemodynamic status. On hospital day 16, metaiodobenzylguanidine scintigraphy showed high accumulation in the right adrenal gland tumor. After retroperitoneal laparoscopic adrenalectomy on hospital day 33, his condition stabilized. He was discharged on hospital day 58. Conclusions Since he required more intensive cardiovascular management for thyrotoxic crisis, beta blockade was increased under intensive care unit monitoring even though initial alpha blockade is recommended in pheochromocytoma. When these crises occur simultaneously, cardiovascular management can be very challenging.

Inhibition of GDF8 increases muscle mass in mice, but is less effective in monkeys and humans. Here the authors show that activin A also inhibits muscle hypertrophy and that concomitant inhibition of activin A and GDF8 synergistically increases muscle mass in mice and non-human primates.

Abstract The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) system is a useful tool for creation of mutant mice with mutations mirroring those in human patients. Various methods have been developed for this purpose, including deletions, inversions, and translocations. So far, mutant mice with deletions of up to 1.2 megabases (Mb) have been generated by microinjection of the CRISPR/Cas9 system into fertilized eggs; however, a method for generation of mutant mice with a deletion of more than several Mb size is necessary because such deletions have often been identified as possible causes of human diseases. With an aim to enable the generation of disease models carrying large deletions with a breakpoint in custom-designed sequences, we developed a method for induction of an Mb-sized deletion by microinjection of a pair of sgRNAs, Cas9, and a donor plasmid into fertilized eggs. Using this method, we efficiently and rapidly generated mutant mice carrying deletions up to 5 Mb.

Patients with advanced hepatocellular carcinoma (HCC) undergoing molecular targeted therapy often experience non-negligible adverse events (AEs). Paradoxically, certain AEs are reportedly associated with a good prognosis. We aimed to identify factors predictive of treatment duration and overall survival (OS) in patients with HCC undergoing lenvatinib therapy. Forty-six consecutive patients with advanced HCC who received lenvatinib therapy from April 2018 to November 2019 were prospectively followed until November 2019. Treatment efficacy was assessed according to the modified Response Evaluation Criteria in Solid Tumors for 2–3 months after therapy initiation. The disease control rate (DCR) was defined as the percentage of patients with a complete response, partial response, or stable disease. The DCR was 65.2%, with a median survival of 10.2 months. Grade 2/3 hypoalbuminemia resulted in shorter treatment duration. Factors predictive of longer OS were a Child-Pugh score of 5 at baseline and the occurrence of Grade 2/3 hypothyroidism. Conversely, Grade 2/3 hypoalbuminemia was associated with a poorer prognosis. An AE of Grade 2/3 hypothyroidism was associated with a better prognosis in patients receiving lenvatinib treatment for advanced HCC. Continuing anticancer therapy with appropriate thyroid hormone replacement may contribute to longer OS.

Grain filling ability is mainly affected by the translocation of carbohydrates generated from temporarily stored stem starch in most field crops including rice (Oryza sativa L.). The partitioning of non-structural stem carbohydrates has been recognized as an important trait for raising the yield ceiling, yet we still do not fully understand how carbohydrate partitioning occurs in the stems. In this study, two rice subspecies that exhibit different patterns of non-structural stem carbohydrates partitioning, a japonica-dominant cultivar, Momiroman, and an indica-dominant cultivar, Hokuriku 193, were used as the model system to study the relationship between turgor pressure and metabolic regulation of non-structural stem carbohydrates, by combining the water status measurement with gene expression analysis and a dynamic prefixed 13C tracer analysis using a mass spectrometer. Here, we report a clear varietal difference in turgor-associated starch phosphorylation occurred at the initiation of non-structural carbohydrate partitioning. The data indicated that starch degradation in Hokuriku 193 stems occurred at full-heading, 5 days earlier than in Momiroman, contributing to greater sink filling. Gene expression analysis revealed that expression pattern of the gene encoding α-glucan, water dikinase (GWD1) was similar between two varieties, and the maximum expression level in Hokuriku 193, reached at full heading (4 DAH), was greater than in Momiroman, leading to an earlier increase in a series of amylase-related gene expression in Hokuriku 193. In both varieties, peaks in turgor pressure preceded the increases in GWD1 expression, and changes in GWD1 expression was correlated with turgor pressure. Additionally, a threshold is likely to exist for GWD1 expression to facilitate starch degradation. Taken together, these results raise the possibility that turgor-associated starch phosphorylation in cells is responsible for the metabolism that leads to starch degradation. Because the two cultivars exhibited remarkable varietal differences in the pattern of non-structural carbohydrate partitioning, our findings propose that the observed difference in grain-filling ability originated from turgor-associated regulation of starch phosphorylation in stem parenchyma cells. Further understanding of the molecular mechanism of turgor-regulation may provide a new selection criterion for breaking the yield barriers in crop production.