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Background Autoantibodies (AAbs) against immunoglobulin E (IgE) antibodies (Abs) and their high-affinity receptor alpha subunits (FceRIα) are key factors in the elicitation of type IIb autoimmune chronic spontaneous urticaria (type IIb aiCSU). In this study, we aimed to develop a new method to detect functional anti-FceRIα and anti-IgE AAbs, which can crosslink the plural FceRІα molecules and IgE Abs on the surface of mast cells and basophils, in sera from aiCSU patients using the amplified luminescence proximity homogeneous assay (Alpha). Methods Sera were obtained from 14 aiCSU patients, as diagnosed by recurrent chronic spontaneous urticaria episodes and positive results for the autologous serum skin test and/or histamine release test (HRT). The AAbs to FceRIα and IgE Abs were determined in sera from aiCSU patients using enzyme-linked immunosorbent assay (ELISA) and Alpha by cross-linking (AlphaCL) of IgE Abs and/or FceRІα. Results Serum anti-FceRIα and anti-IgE AAb levels were not significantly different between aiCSU patients and healthy subjects in ELISA. Anti-FceRIα AAbs were detected in 10 of 14 aiCSU patients who displayed positive (5/5) and negative (5/9) results in the HRT for anti-FceRIα AAbs by AlphaCL, whereas no signals were observed in healthy subjects. Additionally, anti-IgE AAbs were detected in two of four aiCSU patients who displayed positive results in the HRT for anti-IgE AAbs. Conclusions A new assay method using AlphaCL can detect anti-FceRIα and anti-IgE AAbs with FceRIα- and IgE-crosslinking abilities in sera from aiCSU patients. This simple and practical assay method may be available as a diagnostic tool for urticaria patients.

Cytotoxic agents are classified according to the severity of skin injury after extravasation. However, injuries caused by extravasation of noncytotoxic agents have not been sufficiently investigated, although the risk of extravasation is mentioned in medical safety information published by the Japan Council for Quality Health Care. Therefore, in this study, we focused on noncytotoxic electrolyte solutions and infusions and evaluated skin injuries during leakage using extravasation model rats. Rats were anesthetized and intradermally injected with 100 µL of an electrolyte solution or infusion. Injection lesions were macroscopically and histopathologically evaluated for extravasation injuries. Each electrolyte solution and infusion were classified into three categories (vesicants, irritants, and non-tissue-damaging agents) depending on the degree of skin injury. Similar to saline, 0.3% potassium chloride and 0.6% magnesium sulfate showed almost no injury, and 3% sodium chloride and BFLUID

Background Some patients with wheat-dependent exercise-induced anaphylaxis (WDEIA) or wheat allergy showed negative ω-5 gliadin-specific IgE test and high level of grass pollen-specific IgE. It was presumed that these patients developed allergic reaction upon cross-reaction of their IgE antibodies raised against grass pollen allergens to wheat allergens. This study aimed to clarify clinical characteristics and wheat allergens of this phenotype of WDEIA/wheat allergy, which were tentatively diagnosed as grass pollen-related wheat allergy (GPWA). Methods A total of six patients with GPWA were enrolled, and controls were 17 patients with grass pollen allergy but no episode of wheat allergy, and 29 patients with other wheat allergies: 18 with conventional WDEIA and 11 with hydrolyzed wheat protein allergy. Sensitization to wheat proteins was determined by basophil activation test (BAT). IgE-binding proteins in wheat flour were identified by immunoblotting followed by mass spectrometry. Wheat allergen-specific IgE tests were established by CAP-FEIA system. Results All the six patients with GPWA were sensitized to water-soluble wheat proteins in BAT and IgE-immunoblotting, and peroxidase-1 (35 kDa) and beta-glucosidase (60 kDa) were identified as specific IgE-binding wheat proteins. The binding of patient IgE to these proteins was inhibited by pre-incubation of patient sera with grass pollen. The peroxidase-1- and beta-glucosidase-specific IgE tests identified three and four of six patients with GPWA, respectively, but only two of 29 controls, indicating high specificity of these tests. Conclusions Peroxidase-1 and beta-glucosidase are specific wheat allergens for GPWA among grass pollen allergy and other types of wheat-induced food allergies.

Background Instillation of sterile graded talc in the pleural space is performed to prevent reaccumulation of malignant pleural effusion after drainage. Talc is thought to encourage pleural adhesions as part of the repair process by provoking inflammation, suggesting that adhesions are less likely to form in patients taking corticosteroids or other drugs with anti-inflammatory effects. However, the relationship between steroid therapy and pleurodesis efficacy remains unclear. Case presentation We report the outcomes of six patients who underwent pleurodesis at Hiroshima University Hospital while being treated with systemic steroid therapy for non-cancer-related illnesses. Talc pleurodesis was successful at the first attempt in five of the six patients. The five successful cases were receiving low-dose oral prednisolone or methyl prednisolone (range, 1–20 mg/day) at the time of pleurodesis and had serum albumin levels ranging from 2.2 to 3.0 g/dL. In contrast, the patient in whom pleurodesis was unsuccessful was receiving a higher dose of prednisolone (40 mg/day) intravenously and had a relatively low serum album level (1.7 g/dL). Conclusions The outcome of pleurodesis may be affected by the dose and/or route of systemic steroid therapy. Further analysis with more patients will be necessary to clarify the relationship between steroid dosage and talc pleurodesis success rate.

Optimization of medication therapy for the elderly is a matter of rapidly growing importance, which is addressed by pharmacists through comprehensive reviews. In this study, the impact of medication review by pharmacists on medication optimization and avoidance of adverse drug events (ADE) was investigated, as well as differences in the triggers for pharmaceutical intervention to allow for optimization of medication by patient age. Data for this study were collected from reports recorded between April 2013 and March 2019 for patients admitted to the Hiroshima University Hospital. In response to pharmacists' proposals, prescriptions were modified in 18932 cases, comprising 17% of the total 111479 patients during hospitalization. The frequency of such intervention was higher in elderly patients aged ≥65 years than in those

Background Pancreaticobiliary maljunction and intrahepatic gallstones are at a high risk for biliary malignancy. Lysophosphatidylcholine (LPC) is increased in the bile of these patients, and we have previously reported that LPC-induced cytotoxicity causes senescence-associated secretory phenotype (SASP) in cholangiocytes. We aimed to determine the protective effect of phosphatidylcholine (PC) on LPC-induced cholangiocyte cytotoxicity. Methods MMNK-1, a human immortalized cholangiocyte cell line was treated with LPC with or without PC. To assess the biological effects of SASP components on cholangiocarcinoma, HuH28 and HuCCT1 (human cholangiocarcinoma cell lines) were cultured in the conditioned media where MMNK-1 cells treated with LPC. Results The presence of PC reduced reactive oxygen species generation and oxidative DNA damage in MMNK-1 treated with LPC. Moreover, SA-β-gal activity was markedly downregulated by PC. The secretion of SASP components, including interleukin (IL)-8, IL-6, and C-C motif chemokine ligand 2 was also substantially reduced in the presence of PC. Cellular proliferation and migration were enhanced in HuCCT1 and HuH28 cells when cultured in the conditioned media, and these observations were suppressed by simultaneous addition of PC. Conclusion PC protects cholangiocytes against LPC-induced cytotoxicity and cellular senescence, suggesting its potential as a target for inhibiting LPC-related carcinogenesis and its promotion.

Clinical use of olanzapine frequently causes severe hyperglycemia as an adverse effect. In this study, we elucidated mechanisms by which olanzapine reduced insulin secretion using the hamster pancreatic β-cell line HIT-T15. Reverse transcriptional-PCR analysis revealed expression of dopamine (D2, D3 and D4), serotonin (5-HT2A, 5-HT2B, 5-HT2C, and 5-HT6), and histamine (H1 and H2) receptors in HIT-T15 cells. Olanzapine decreased insulin secretion from HIT-T15 cells at clinically relevant concentrations (64–160 nM). A dopamine D2 agonist, D3 antagonist, and D4 antagonist suppressed insulin secretion, whereas a D2 antagonist and D3 agonist increased it. A serotonin 5-HT2B agonist slightly increased insulin secretion, while a 5-HT2C antagonist slightly decreased it. Other agonists and antagonists for serotonin receptors did not affect insulin secretion. A histamine H1 agonist increased insulin secretion, whereas an H1 antagonist and H2 agonist suppressed it. Our results suggest that dopamine (D2, D3 and D4), serotonin (5-HT2B and 5-HT2C), and histamine (H1 and H2) receptors, which are expressed on pancreatic β-cells, directly modulate insulin secretion from pancreatic β-cells. Thus, olanzapine may induce hyperglycemia in clinical settings by suppressing insulin secretion from pancreatic β-cells through inhibition of dopamine D3, serotonin 5-HT2B and 5-HT2C, and histamine H1 receptors.

The combination of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin with rituximab (DA-EPOCH-R) is used for non-Hodgkin lymphoma patients. Febrile neutropenia (FN) is a common complication of treatment with myelo-suppressive chemotherapy, so preventing FN is important for maintaining chemotherapy dosage. Recently, pegfilgrastim has been used as the primary prophylaxis of FN in Japan, but there have been few cases reported using pegfilgrastim for the primary prophylaxis in DA-EPOCH-R. In this study, we retrospectively compared the efficacy of pegfilgrastim with that of filgrastim in patients receiving DA-EPOCH-R in Hiroshima University Hospital. Efficacy assessment was based on incidence of FN and serious neutropenia (neutrophil count

Background: Aspirin enhances food allergy symptoms by increasing absorption of ingested allergens. The objective of this study is to elucidate the role of aspirin in facilitating intestinal absorption of the wheat allergen, gliadin, in rats. Methods: Plasma concentrations of gliadin were determined after oral administration by gavage or administration into a closed intestinal loop in rats. We used an in situ intestinal re-circulating perfusion experiment to examine the effect of pepsin on aspirin-facilitated gliadin absorption. Fluorescein isothiocyanate (FITC)-labeled dextran-40 (FD-40) was used as a marker of non-specific absorption. The molecular size of gliadin and its allergenicity in plasma were examined using immunoblot analysis and intradermal reaction tests with Evans blue dye (EBD) extravasation, respectively. Results: Aspirin increased plasma concentrations of gliadin after oral administration but had no effect in the closed intestinal loop study. An in situ intestinal re-circulating perfusion study showed that FITC-labeled gliadin was absorbed similarly to FD-40. Aspirin increased absorption of both intact and pepsin-digested gliadin, with a more significant effect on absorption of pepsin-treated gliadin. Immunoblotting showed that most gliadin was absorbed in intact form. When the gliadin fraction was extracted from rat plasma after gavage and injected intradermally into gliadin-sensitized rats, EBD extravasation was observed at injection sites in a gliadin dose-dependent manner. Conclusions: Aspirin increased the absorption of intact and pepsin-digested gliadin via the paracellular pathway, maintaining their allergenicity. Moreover, the effect of aspirin on gliadin absorption was enhanced by modification and digestion of gliadin in the stomach., This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (No. 16K08371).

Aim Rho-kinase (ROCK) inhibitor could ameliorate liver fibrosis by suppressing hepatic stellate cell (HSC) activation. However, because systemic administration of ROCK inhibitor causes serious adverse effects, we developed a drug delivery system selectively delivering ROCK inhibitor to HSCs. Here, we examined whether our developed vitamin A (VA)-coupled liposomal ROCK inhibitor reduced liver fibrosis in rats without causing systemic adverse effects. Methods LX-2 HSCs were analyzed for morphological changes and the expression of profibrotic proteins. The inhibitory effects of VA-coupled liposomal ROCK inhibitor on liver fibrosis were confirmed in a rat model of liver fibrosis induced by i.p. injection of carbon tetrachloride. The degree of liver fibrosis, biochemical changes, and survival rates were also investigated. Results Vitamin A-coupled liposomal ROCK inhibitor had an effect at approximately 1/100 the amount of the free ROCK inhibitor for inhibiting the activation of LX-2 cells and caused significant decreases in the expression levels of α-smooth muscle actin (SMA) and transforming growth factor (TGF)-β1. The degree of liver fibrosis was suppressed by treatment with VA-coupled liposomal ROCK inhibitor, and the expression of α-SMA and TGF-β1 in liver tissues was also significantly suppressed. In addition, serum levels of alanine aminotransferase and hyaluronic acid were significantly reduced, and there was no decline in kidney function, which has been noted as a systemic adverse effect of ROCK inhibitor. Furthermore, VA-coupled liposomal ROCK inhibitor improved survival rates in rats with liver fibrosis. Conclusion Vitamin A-coupled liposomal ROCK inhibitor efficiently suppressed liver fibrosis without causing systemic adverse effects.

When undergoing 90Y-ibritumomab tiuxetan (90Y-IT) treatment, patients are discharged from hospital soon after initiation of treatment and followed up as outpatients. Thus it is important to apprise patients of the safety information regarding 90Y-IT treatment. However, studies investigating the safety of 90Y-IT in real-world clinical practice are lacking. We sought to investigate the adverse events arising from 90Y-IT administration to patients in our hospital. Patients who received 90Y-IT treatment at Hiroshima University Hospital from April 2010 to December 2014 were eligible for this study. The medical records of the patients were reviewed retrospectively. Eleven patients (median age, 65 years) were enrolled. Patients were classified into 3 groups according to the number of prior regimens: 1, 2-3, or >3, consisting of 5, 4, and 2 patients, respectively. The number of patients with induced grade 3 and 4 hematotoxicity, respectively, was 5 and 0 for leukocytopenia, 3 and 2 for neutropenia, and 3 and 2 for thrombocytopenia. The median nadir time was 37 d for leukocytopenia, 37 d for neutropenia, 36 d for thrombocytopenia, and 43 d for anemia. Patients with 2 or more prior regimens tended to experience grade 3 or 4 hematotoxicity more frequently than those with 1 prior regimen. In conclusion, we showed that hematotoxicity is a major adverse event of 90Y-IT treatment and that the nadir time is later than that with conventional anticancer agents. Medical staff, including pharmacists, should direct attention to the initial symptoms of hematotoxicity, especially in those patients who have received several prior regimens.

Background In high-dose methotrexate (HD-MTX) therapy, delayed elimination of MTX from plasma leads to severe adverse effects. However, the risk factors for the delayed elimination of plasma MTX are still unclear. Objective The purpose of this study was to investigate the factors related to the delayed MTX elimination in HD-MTX monotherapy. Methods This retrospective study was performed on patients who received HD-MTX monotherapy between April 2009 and March 2019 at the Hiroshima University Hospital. Patients were divided into a “Normal” and a “Delayed” group according to their MTX plasma concentration at 48 or 72 hours after administration. Patient characteristics, dose of HD-MTX, MTX plasma concentration, and adverse effects were analyzed and compared between the 2 groups. Results A total of 74 patients were included in this study. Logistic analysis of patient baseline characteristics was performed to identify risk factors for delayed MTX elimination. Serum albumin (ALB) was detected as a risk factor. Univariate and multivariate analysis revealed that low ALB level (Conclusions and Relevance Our study showed that low ALB is a risk factor for delayed MTX elimination in HD-MTX monotherapy. Pharmacokinetic analysis is needed to establish the dose of HD-MTX in patients with a low ALB level.

Shrimp is a causative food that elicits food-dependent exercise-induced anaphylaxis (FDEIA). In this study, we sought to identify IgE-binding allergens in patients with shrimp-FDEIA. Sera were obtained from eight patients with shrimp-FDEIA and two healthy control subjects. Proteins were extracted from four shrimp species by homogenization in Tris buffer. Immunoblot analysis revealed that IgE from patient sera bound strongly to a 70-kDa and a 43-kDa protein in a preparation of Tris-soluble extracts from Litopenaeus vannamei. Mass spectrometry identified the 70-kDa and 43-kDa proteins as a P75 homologue and fructose 1,6-bisphosphate aldolase (FBPA), respectively. To confirm that the putative shrimp allergens were specifically recognized by serum IgE from shrimp-FDEIA patients, the two proteins were purified by ammonium sulfate precipitation followed by reversed-phase HPLC and/or anion-exchange hydrophobic interaction chromatography and then subjected to immunoblot analysis. Purified P75 homologue and FBPA were positively bound by serum IgE from one and three, respectively, of the eight patients with shrimp-FDEIA, but not by sera from control subjects. Thus, P75 homologue and FBPA are identified as IgE-binding allergens for shrimp-FDEIA. These findings could be useful for the development of diagnostic tools and desensitization therapy for shrimp-FDEIA patients.

Introduction In humans, intracortical bone remodeling is performed by a basic multicellular unit (BMU) composed of osteoclasts and osteoblasts penetrating through cortical bones. As a result, secondary osteons and their boundaries, cement lines, can be observed on the transverse section. There have been few reports mention whether there is diversity within a single individual and on the relevance to bone remodeling. The purpose of this study is to investigate the morphological diversity of secondary osteons in human femoral bone and to examine the relationship with bone remodeling. Material and methods First of all, we developed an original method to get the cross-sectional images of the cortical bones around the whole circumference for the purpose of evaluating the morphology of the secondary osteon exhaustively. Then, a total of ten cross-sectional slices from one right human femoral bone of male were prepared and stained with this method. The osteon population density and complexity of cement lines in osteons were evaluated in detail. Results Within this femoral bone, the osteon population density was significantly higher in the periosteal side and in the posterior area. Conversely, the cement line density and the osteon complexity were higher in the endosteal side; the proportion of complexed osteon significantly increased from the periosteal side toward the endosteal side. Discussion The results suggested that there were diversities in osteon population densities and osteon morphological pattern within one human femoral bone. It seemed that the BMUs ran to avoid the existing regions of osteon in the periosteal sides and to overlap the existing osteon in the endosteal sides. This seemed to be one of the novel viewpoints in the morphological analysis of secondary osteons. It might be better for the orthopedic surgeons to be aware that the osteon distribution in the cortical bone is not uniform.

We previously developed Hokushin wheat line as a hypoallergenic wheat lacking ω5-gliadin (1BS-18), a major allergen for wheat-dependent exercise-induced anaphylaxis. However, the allergenicity of 1BS-18 has not been understood completely. In this study, we evaluated the allergenicity of 1BS-18 such as anaphylactic elicitation ability and sensitization ability using rats sensitized with ω5-gliadin or glutens prepared from Hokushin (Hokushin gluten) or 1BS-18 (1BS-18 gluten). Rats were sensitized by intraperitoneal administration of ω5-gliadin, Hokushin gluten or 1BS-18 gluten. Immunoglobulin E-mediated systemic anaphylaxis was evaluated by measuring changes in rectal temperature for 30 min after intravenous challenge with ω5-gliadin or the test glutens in unsensitized rats or rats sensitized with ω5-gliadin or the test glutens. In ω5-gliadin-sensitized rats, intravenous challenge with ω5-gliadin or Hokushin gluten significantly decreased the rectal temperature at 30 min after challenge while challenge with 1BS-18 gluten did not reduce the rectal temperature. Furthermore, intravenous challenge with ω5-gliadin significantly decreased the rectal temperature in rats sensitized with Hokushin gluten or 1BS-18 gluten. However, the reduced degree observed in 1BS-18 gluten-sensitized rats was smaller than that in Hokushin gluten-sensitized rats. In conclusion, 1BS-18 elicited no allergic reaction in ω5-gliadin-sensitized rats and had less sensitization ability for ω5-gliadin than that of Hokushin wheat., Graphical abstract Image 1, Highlights • ω5-Gliadin is a major allergen for wheat allergy-dependent exercise-induced anaphylaxis. • 1BS-18 is developed as a hypoallergenic wheat lacking ω5-gliadin. • 1BS-18 elicited no allergic reaction in ω5-gliadin-sensitized rats. • 1BS-18 had less sensitization ability for ω5-gliadin than that of regular wheat.

Background The effect of oral immunotherapy (OIT) on wheat allergy is promising in terms of the potential to obtain desensitization; however, the frequency of exercise-induced allergic reactions on desensitization (EIARDs) and the associated risk factors remain to be determined. Methods Twenty-five patients underwent rush OIT for wheat allergy, and 21 achieved the full-dose intake of wheat products (5 g of wheat protein). Exercise-provocation tests were repeatedly performed after the ingestion of a full-dose wheat product. The time-course of the levels of the specific IgEs (sIgE) to wheat extract, total gliadin, deamidated gliadin, recombinant gliadin components (α/β-, γ- and ω-5-), and glutenin (high and low molecular weight) components was analyzed using ImmunoCAP® , ELISA, or IgE immunoblotting. Results Fourteen patients (66.7%) were diagnosed as EIARD+, which remained 5 years after rush OIT in 11 patients (52.4%). There were no differences in the clinical backgrounds of the EIARD+ and EIARD- patients. However, EIARD+ patients showed significantly higher sIgE levels to all gliadin and glutenin components than EIARD- patients before OIT. The sIgE levels to each component decreased equally after 1 and 2 years of OIT. On IgE immunoblotting, sera from all patients reacted to the multiple gluten bands, and some reacted to the water-soluble bands. The intensity of all IgE-reactive bands also became equally lighter after OIT. Conclusions EIARDs were frequently observed and remained for a long period after successful OIT for wheat allergy. None of the specific wheat components were found to contribute to EIARDs.

A 16-year-old male high-school student experienced generalized itchy wheal and dyspnea during physical exercise after lunch. Each food material of his lunch was examined using a prick-prick test, allergen-specific IgE test (ImmunoCAP

When undergoing

Intraocular irrigating solution containing 1 µg/mL adrenaline is widely used during cataract surgery to maintain pupil dilation. Prepared intraocular irrigating solutions are recommended for use within 6 h. After the irrigating solution is admistered for dilution, the adrenaline may become oxidized, and this may result in a decrease in its biological activity. However, the stability of adrenaline in intraocular irrigating solution is not fully understood. The aim of this study was to evaluate the stability of adrenaline in clinically used irrigating solutions of varying pH. Six hours after mixing, the adrenaline percentages remaining were 90.6%±3.7 (pH 7.2), 91.1%±2.2 (pH 7.5), and 65.2%±2.8 (pH 8.0) of the initial concentration. One hour after mixing, the percentages remaining were 97.6%±2.0 (pH 7.2), 97.4%±2.7 (pH 7.5), and 95.6%±3.3 (pH 8.0). The degradation was especially remarkable and time dependent in the solution at pH 8.0. These results indicate that the concentration of adrenaline is decreased after preparation. Moreover, we investigated the influence of sodium bisulfite on adrenaline stability in irrigating solution. The percentage adrenaline remaining at 6 h after mixing in irrigating solution (pH 8.0) containing sodium bisulfite at 0.5 µg/mL (concentration in irrigating solution) or at 500 µg/mL (concentration in the undiluted adrenaline preparation) were 57.5 and 97.3%, respectively. Therefore, the low concentration of sodium bisulfite in the irrigating solution may be a cause of the adrenaline loss. In conclusion, intraocular irrigation solution with adrenaline should be prepared just prior to its use in surgery.

Enhancement of oral absorption of food allergens by non-steroidal anti-inflammatory drugs (NSAIDs), especially aspirin, is considered an exacerbating factor in the development of food allergies. In this study, we examined the effect of aspirin on oral sensitization to and absorption of the egg-white allergen ovalbumin (OVA) in rats. The absorption of OVA was evaluated by measuring the plasma concentration of OVA after oral administration by gavage. To evaluate oral sensitization to OVA, plasma levels of immunoglobulin (Ig) E and IgG1 antibodies (Abs) specific to OVA were determined by enzyme-linked immunosorbent assay after initiation of sensitization. High-dose aspirin (30 mg/kg) increased oral OVA absorption and plasma levels of OVA-specific IgE and IgG1 Abs compared with those observed in vehicle-treated rats. In contrast, low-dose aspirin (3 mg/kg) exerted no changes in either absorption or sensitization. Spermine, an absorption enhancer, increased the oral absorption of OVA to nearly the same extent as high-dose aspirin, whereas the plasma levels of OVA-specific IgE and IgG1 Abs exhibited no significant differences between spermine- and vehicle-treated rats. Among the NSAIDs, diclofenac and indomethacin increased sensitization to OVA, similar to high-dose aspirin, but meloxicam exerted no effects on Ab levels. In conclusion, we showed that high-dose aspirin enhanced oral sensitization to OVA. Our study suggests that enhanced oral sensitization to OVA cannot be ascribed to increased absorption of OVA from the intestinal tract. Although the mechanisms underlying this enhancement of sensitization are still controversial, our study suggests that modification of cytokine production due to impairment of the intestinal barrier function and inhibition of cyclooxygenase-1 activity by aspirin may be involved.

Inadvertent leakage of noncytotoxic agents causes severe tissue injury. In this study, we macroscopically and histopathologically evaluated the extent of skin injury caused by extravasation of hyperosmolar or vasopressor agents in rats. Rats were intradermally administered saline (100 µL), the hyperosmolar agents mannitol (5-20 mg/100 µL) and glucose (5-50 mg/100 µL), or the vasopressors dopamine (2 mg/100 µL), adrenaline (0.1 mg/100 µL), and noradrenaline (0.1 mg/100 µL). Lesion size (erythema, induration, ulceration, and necrosis) was monitored after agent injection. Skin tissue biopsies were evaluated at 24 h after agent injection. Mannitol and glucose induced severe lesions in a concentration (and osmolarity)-dependent manner. Mannitol and glucose at 10-20% (w/v) induced inflammation, and lesions healed within 3-6 d. In contrast, ≥25% (w/v) glucose elicited severe skin lesions with ulceration and necrosis within 24 h, which healed gradually 16-22 d after injection. The severity of extravasation injury caused by vasopressors varied. Adrenaline and noradrenaline induced severe injury with ulceration and necrosis, which healed over 23.3 and 18.3 d, respectively. In contrast, dopamine induced erythema and induration, and damage duration was only 5.7 d. In conclusion, mannitol and glucose at osmolarities of 549-1098 and 833-1110 mOsm/L, respectively, can be classified as "irritants," while ≥1388 mOsm/L glucose can be classified as a "vesicant." As for vasopressors, adrenaline and noradrenaline can be classified as "vesicants" whereas dopamine can be classified as an "irritant."

Osteons are the primary sites of cortical bone lesions. However, many aspects of osteon microstructure remain poorly understood. This study aimed to explores interindividual differences in the osteon morphotype distributions in the human femoral diaphysis by evaluating the secondary osteon distributions in samples from human femurs. Two anonymized bone fragments from two modern Japanese femurs were examined. Twelve continuous transverse femoral diaphysis specimens were prepared from each fragment. Imaging examinations were conducted using a circularly polarized light microscope, and cross-sectional images were rendered using graphical synthesis software. Osteons in the images were identified as either bright-type osteons, dark-type osteons, or an others type. The two femurs were compared, and the secondary osteon morphotype distributions in different regions of their cross-sections were analyzed. When the two femurs were compared, significant differences in osteon density were observed in some regions and cross-sections. The dark-type osteon presence was strongest in the anterior and posterior regions of the femurs. The analytical method used in this study was found to be able to evaluate osteon microstructure. The results suggest that examining additional specimens and analyzing the biomechanical underpinnings of interindividual differences in osteon distribution patterns may help to improve our understanding of osteon microstructure.

This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (No. 16K08371)., Supplementary data related to this article can be found at https://doi.org/10.1016/j.alit.2018.04.012.