Intralobular distribution of ovarian-like stroma in pancreatic mucinous cystic neoplasms: a discussion on its tumorigenesis.

Pancreatic mucinous cystic neoplasm (MCN) has two histological components: tumor epithelia and ovarian-like stroma (OLS). To examine the progression and changes in pancreatic MCNs, we analyzed the distribution, amount, immunohistochemical phenotype, presence of theca cells of OLS, and tumor epithelium in 45 surgically resected MCN cases, comparing them with tumor sizes. The OLS data of female MCN cases were also compared between those who were ≤ 51 years old and those > 51 years old to see the effect of menopause on MCN histology. Non-mucinous type epithelium was present in all low-grade MCNs, but its ratio decreased with tumor size (p < 0.001), suggesting that epithelial mucinous changes are a progression phenomenon. The intralobular distribution of OLS was observed in 28.8% of MCN cases and was related to smaller tumor size (p < 0.0001), suggesting intralobular involvement of early MCNs. The nuclear expression of ß-catenin and the cytoplasmic expression of α-smooth muscle actin (SMA) was observed in almost all OLS. OLS tended to be lesser among female cases aged > 51 years than those ≤ 51 years old, however it did not reach statistical significance. This is the first study to show the intralobular distribution of OLS.

Effect of Roxadustat on the Pharmacokinetics of Simvastatin, Rosuvastatin, and Atorvastatin in Healthy Subjects: Results From 3 Phase 1, Open-Label, 1-Sequence, Crossover Studies.

Roxadustat inhibits breast cancer resistance protein and organic anion transporting polypeptide 1B1, which can affect coadministered statin concentrations. Three open-label, 1-sequence crossover phase 1 studies in healthy subjects were conducted to assess effects from steady-state 200-mg roxadustat on pharmacokinetics and tolerability of 40-mg simvastatin (CL-0537 and CL-0541), 40-mg atorvastatin (CL-0538), or 10-mg rosuvastatin (CL-0537). Statins were dosed concomitantly with roxadustat in 28 (CL-0537) and 24 (CL-0538) healthy subjects, resulting in increases of maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve from the time of dosing extrapolated to infinity (AUCinf ) 1.87- and 1.75-fold for simvastatin, 2.76- and 1.85-fold for simvastatin acid, 4.47- and 2.93-fold for rosuvastatin, and 1.34- and 1.96-fold for atorvastatin, respectively. Additionally, simvastatin dosed 2 hours before, and 4 and 10 hours after roxadustat in 28 (CL-0541) healthy subjects, resulted in increases of Cmax and AUCinf 2.32- to 3.10-fold and 1.56- to 1.74-fold for simvastatin and 2.34- to 5.98-fold and 1.89- to 3.42-fold for simvastatin acid, respectively. These increases were not attenuated by time-separated statin dosing. No clinically relevant differences were observed for terminal elimination half-life. Concomitant 200-mg roxadustat and a statin was generally well tolerated during the study period. Roxadustat effects on statin Cmax and AUCinf were statin and administration time dependent. When coadministered with roxadustat, statin-associated adverse reactions and the need for statin dose reduction should be evaluated.

Pancreaticoduodenectomy with reconstructing blood flow of the gastric conduit after esophagectomy with concomitant celiac axis stenosis: a case report.

BACKGROUND: Pancreaticoduodenectomy after esophageal resection is technically difficult, because blood flow of the gastric conduit should be preserved. Celiac axis stenosis (CAS) is also a problem for pancreaticoduodenectomy, because arterial blood supply for the liver comes mainly through the collateral route from the superior mesenteric artery (SMA) via the gastroduodenal artery (GDA). Herein, we report the case of a patient with pancreatic head cancer who underwent a pancreaticoduodenectomy after esophagectomy with concomitant CAS. CASE PRESENTATION: A 76-year-old man with pancreatic head cancer was referred to our department. He had a history of esophagectomy with retrosternal gastric conduit reconstruction for esophageal cancer. Computed tomography showed severe CAS and a dilated collateral route between the SMA and the splenic artery (SPA). We prepared several surgical options depending on the intraoperative findings, and performed radical pancreaticoduodenectomy with concomitant resection of the distal gastric conduit. The right gastroepiploic artery (RGEA) of the remnant gastric conduit was fed from the left middle colic artery (MCA) with microvascular anastomosis. Despite CAS, when the GDA was dissected and clamped, good blood flow was confirmed, and the proper hepatic artery did not require reconstruction. The patient was discharged on postoperative day 90. CONCLUSIONS: We successfully performed radical pancreaticoduodenectomy after esophagectomy with concomitant CAS, having prepared multiple surgical options depending upon the intraoperative findings.

Manipulation of phase slips in carbon-nanotube-templated niobium-nitride superconducting nanowires under microwave radiation.

We study the manipulation of thermal/quantum phase slips (tPSs/qPSs) in ultra-thin niobium-nitride superconducting nanowires (scNW) grown on carbon-nanotube templates. These NWs exhibit resistive steps in current-voltage (I-V) characteristics, and the number of phase slip centers (PSCs) in an NW can be tuned by the NW length. Under microwave (MW) radiation, emergence of each single PSC can be precisely controlled by varying the MW power. For thin and short scNW, a dip structure between the qPS-dominated low-temperature region and the tPS-dominated high-temperature region were observed owing to anti-proximity effect by electrodes.

Relationship between the Induced Iron Overload Model and Hepatic Erythropoiesis in Xenopus laevis.

Iron is an essential element for hemoglobin synthesis during erythropoiesis. Iron overload, in contrast, adversely affects erythropoiesis and causes organ dysfunction. Research using various animal models may help to elucidate pathophysiological mechanisms induced by excess iron. In the present study, we evaluated the relationship between iron metabolism and erythropoietic activity in the African clawed frog, Xenopus laevis. In X. laevis, both erythropoiesis and iron metabolism occur in the liver. First, we developed a method to quantify iron levels in the liver and plasma using 2-nitroso-5-[N-n-propyl-N-(3-sulfopropyl) amino] phenol (Nitroso-PSAP). We then measured iron levels and analyzed hematopoietic parameters in frogs that were orally administered sodium ferrous citrate (SFC). The hepatic iron level increased in the SFC group, but the number of erythrocytes, hematocrit, and hemoglobin concentration did not change, suggesting that the regulation of the production and release of mature erythrocytes in the liver was not directly affected by dietary iron. At four days after administration of 2 mg/kg SFC, the number of immature erythrocytes decreased in the liver. Interestingly, atypical blood cells with hyper-segmented nuclei were observed, identified by acridine orange cell staining; these atypical blood cells were hardly detectable under the steady state. Compared with previously reported results in mice, the increase in the hepatic iron levels was small, but our results indicate that SFC affects hematopoietic activity. These results establish a novel model for iron metabolism and provide new insights into the relationship between iron metabolism and erythropoiesis in vertebrates.

Anatomic characterization of the femoral nutrient artery: Application to fracture and surgery of the femur.

The localization of nutrient foramina and direction of nutrient canals have been studied. However, information about the origin and extraosseous course of nutrient arteries is lacking in some types of long tubular and irregular bones. Thus, we aimed to reexamine the origin and course of the femoral nutrient artery (FNA) through cadaveric dissection to clarify its anatomic characteristics. Sixty thighs were collected from 57 cadavers. To fix the cadavers and visualize the small arterial branches, 10% formalin was injected from the femoral artery, followed by an injection of acrylic ink. The arterial tree in the posterior part of the thigh was recorded by line drawings. The femur received single or double FNAs via the femoral nutrient foramina, which were on and along the linea aspera. In cases with single FNA (41 of the 60 thighs), it typically arose from the four parts of the profunda femoris system: profunda femoris artery between the origins of the third and fourth perforating arteries; second perforating artery; third perforating artery; and terminal branch. In cases with double FNAs (remaining 19 thighs), the superior FNA typically arose from the second perforating artery, and the inferior FNA arose from the terminal branch of the profunda femoris artery and popliteal system. FNAs are described as branches of the perforating arteries in Terminologia Anatomica and anatomy textbooks. However, we found that FNAs also frequently arose from the profunda femoris artery and popliteal system, in addition to the perforating arteries. Clin. Anat. 33:479-487, 2020. © 2019 Wiley Periodicals, Inc.

A phase I, open-label, single-dose micro tracer mass balance study of 14C-labeled ASP7991 in healthy Japanese male subjects using accelerator mass spectrometry.

ASP7991 is a calcimimetic that acts on the calcium-sensing receptor on parathyroid cell membranes and suppresses parathyroid hormone (PTH) secretion in the treatment of secondary hyperparathyroidism. The mass balance and metabolite profile of [14C]ASP7991 were investigated in six healthy male subjects after a single oral dose of [14C]ASP7991 [1 mg, 18.5 kBq (500 nCi)] in solution. [14C] radioactivity in plasma, urine and feces was analyzed using Accelerator mass spectrometry. ASP7991 was rapidly absorbed, metabolized and excreted. Mean recovery of [14C] radioactivity in urine and feces was 30.08% and 49.31%, respectively, and mean total recovery of [14C] radioactivity was 79.39%. The majority of [14C] radioactivity in urine and feces was excreted within the first 72 h following administration. Seven metabolites were detected in plasma, urine and feces samples, and their structures were determined by mass spectrometry. The main metabolic pathways of ASP7991 in humans were predicted to be N-dealkylation, followed by N-acetylation and taurine conjugation to a carboxylic acid moiety. Our findings show that a mass balance study using micro radioactivity doses is suitable for elucidating the pharmacokinetics of the absorption, metabolism and excretion of administered drugs.

Anatomic characterization of the humeral nutrient artery: Application to fracture and surgery of the humerus.

Anatomic characterization of the humeral nutrient artery varies among the several textbooks on human anatomy. To clarify the anatomic characteristics of the humeral nutrient artery, we reexamined its origin and course by cadaveric dissection. In typical cases, one prominent nutrient foramen was situated on the anteromedial surface of the humeral shaft, and the nutrient canal distally penetrated the cortical bone layer. The humeral nutrient artery originated from the brachial artery below the level of the nutrient foramen as a short ascending branch. On reaching near the nutrient foramen, the humeral nutrient artery formed a hairpin loop on the periosteum to enter into the nutrient foramen. In some cases, an accessory nutrient foramen was also found near the groove for the radial nerve on the posterior surface of the humerus. This accessory nutrient foramen received an accessory humeral nutrient artery that originated from the radial collateral artery. The present findings corresponded well with the descriptions in the anatomy textbooks published in English-speaking countries. However, textbooks published in German-speaking countries describe only one type of humeral nutrient artery, the branch of the profunda brachii artery. Terminologia Anatomica, the international standard in human anatomic terminology, most likely adopted the description in the German anatomy textbooks, and thus, it is necessary to correct the position of the humeral nutrient artery in the hierarchy of Terminologia Anatomica for accurate morphological description. Clin. Anat. 30:978-987, 2017. © 2017 Wiley Periodicals, Inc.

Morphological and immunohistochemical comparison of intrapancreatic nerves between chronic pancreatitis and type 1 autoimmune pancreatitis.

OBJECTIVES: The abdominal pain associated with chronic pancreatitis (CP) may be related to the increased number and size of intrapancreatic nerves. On the other hand, patients with type 1 autoimmune pancreatitis (AIP) rarely suffer from the pain syndrome, and there are no previous studies concerning the histopathological findings of intrapancreatic nerves in patients with type 1 AIP. The current study is aimed at investigating the differences in the histopathological and immunohistochemical findings of intrapancreatic nerves in patients with CP and type 1 AIP. METHODS: Neuroanatomical differences between CP and type 1 AIP were assessed by immunostaining with a pan-neuronal marker, protein gene product 9.5 (PGP9.5). The number (neural density) and area (neural hypertrophy) of PGP9.5-immunopositive nerves were quantitatively analyzed. Furthermore, the expression of nerve growth factor (NGF), and a high affinity receptor for NGF, tyrosine kinase receptor A (TrkA), was assessed by immunohistochemistry. RESULTS: Both neural density and hypertrophy were significantly greater in pancreatic tissue samples from patients with CP than those with normal pancreas or type 1 AIP. NGF expression was stronger in type 1 AIP than in CP, whereas TrkA expression in type 1 AIP was poorer than in CP. CONCLUSIONS: Although CP and type 1 AIP are both characterized by the presence of sustained pancreatic inflammation, they are different in terms of the density and hypertrophy of intrapancreatic nerve fibers. It is possible that this may be related to the difference in the activity of the NGF/TrkA-pathway between the two types of pancreatitis.

Fluorescence cytology with 5-aminolevulinic acid in EUS-guided FNA as a method for differentiating between malignant and benign lesions (with video).

BACKGROUND: EUS-guided FNA (EUS-FNA) has been increasingly performed to obtain specimens for the pathological evaluation of patients with GI and pancreaticobiliary masses as well as lymphadenopathies of unknown origin. Photodynamic diagnosis by using 5-aminolebulinic acid (ALA) has been reported to be useful for enabling the visual differentiation between malignant and normal tissue in various cancers. OBJECTIVE: To evaluate the diagnostic accuracy of fluorescence cytology with ALA in EUS-FNA. DESIGN: A prospective study. SETTING: A single center. PATIENTS: A total of 28 consecutive patients who underwent EUS-FNA for the pathological diagnosis of a pancreaticobiliary mass lesion or intra-abdominal lymphadenopathy of unknown origin. INTERVENTIONS: Patients were orally administered ALA 3 to 6 hours before EUS-FNA. The sample was obtained via EUS-FNA for fluorescence cytology and conventional cytology. A single gastroenterologist performed the fluorescence cytology by using fluorescence microscopy after the procedure, independently of the conventional cytology by pathologists. MAIN OUTCOME MEASUREMENTS: The accuracy of fluorescence cytology with ALA in the differentiation between benign and malignant lesions by comparing the results of fluorescence cytology with the final diagnosis. RESULTS: Of the 28 patients included in the study, 22 were considered as having malignant lesions and 6 patients as having benign lesions. Fluorescence cytology could correctly discriminate between benign and malignant lesions in all patients. Therefore, both the sensitivity and specificity of fluorescence cytology were 100% in our study. LIMITATIONS: Fluorescence cytology was performed by only 1 gastroenterologist with a small number of patients. CONCLUSION: Fluorescence cytology with ALA in EUS-FNA may be an effective and simple method for differentiating between benign and malignant lesions.

Severe obstructive sleep apnea increases cystatin C in clinically latent renal dysfunction.

BACKGROUND: Obstructive sleep apnea (OSA) increases the risk of cardiovascular disease (CVD) and has been reported to be associated with chronic kidney disease (CKD). Recent studies have demonstrated that cystatin C is a prognostic biomarker of the risk of death and CVD even in patients without established CKD. METHODS: In a cross-sectional study, we enrolled 267 consecutive OSA patients without CKD who had an apnea-hypopnea index (AHI) ≥ 5 events per hour in overnight polysomnography. CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m(2) according to the modification of diet in renal disease (MDRD) equation (modified for Japanese). Serum cystatin C levels were measured in all patients. RESULTS: Cystatin C was significantly correlated with age (r = 0.37), body mass index (BMI) (r = 0.12), AHI (r = 0.17), C-reactive protein (CRP) (r = 0.12), and Brachial-ankle pulse wave velocity (r = 0.18). Logistic regression analysis demonstrated that severe OSA defined by an AHI ≥ 30 events per hour was an independent variable for the highest quartiles of serum cystatin C levels (≥0.88 mg/L) (OR: 2.04, 95% CI: 1.04-4.01, P = 0.04) even after adjustment for age, BMI ≥ 25, hypertension, and diabetes mellitus. CONCLUSIONS: This study indicates that severe OSA independently increases serum cystatin C levels in patients without CKD. Cystatin C is considered to be a biomarker that reflects both clinically latent renal dysfunction and cardiovascular risk that are influenced by OSA.