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Machiko Matsumoto-Sasaki,1 Kaoruko Simizu,1 Masanobu Suzuki,2 Masaru Suzuki,1 Hirokazu Kimura,1 Yuji Nakamaru,2 Yoichi M Ito,3 Akihiro Honma,2 Satoshi Konno1 1Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan; 2Department of Otolaryngology-Head and Neck Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan; 3Data Science Center, Promotion Unit, Institute of Health Science Innovation for Medical Care, Hokkaido University Hospital, Sapporo, JapanCorrespondence: Kaoruko Simizu, Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, Japan, Tel +81-11-706-5911, Fax +81-11-706-7899, Email okaoru@med.hokudai.ac.jpPurpose: Biologics have been used increasingly for the treatment of severe asthma. However, established guidelines for the selection, switching, or discontinuation of biologics do not exist. We aimed to identify the clinical characteristics of patients with asthma who required switching biologics and the factors associated with switching biologics.Patients and Methods: This was a retrospective study of 42 patients with severe asthma treated with biologics at the Hokkaido University Hospital between 23rd June 2016 and 30th April 2021, when two biologics were available in Japan. We compared the characteristics of subjects who continued and switched biologics. The time to switch the biologics was assessed by type 2 inflammatory biomarkers, pulmonary function indices, and the presence of comorbidities, including the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC) score and aspirin exacerbated respiratory diseases (AERD), using the Kaplan–Meier method and a multivariate Cox proportional hazards model.Results: Eight and five patients were treated by mepolizumab and benralizumab at baseline, respectively among the 31% (13/42) who switched the biologics. Subjects who required switching biologics were characterized by high blood eosinophil counts, younger age, JESREC scores of 11 points or higher, and AERD. The time taken to switch biologics was significantly shorter in the subgroups with high JESREC scores (≥ 11) or AERD, compared with their counterparts with low JESREC scores or without AERD (both, P < 0.05). JESREC scores of ≥ 11, but not the presence of AERD, were associated with time to switch biologics.Conclusion: The presence of eosinophilic chronic rhinosinusitis based on JESREC scores of ≥ 11 and younger age were factors associated with switching biologics in asthma.Keywords: aspirin-exacerbated respiratory disease, asthma, biologics, comorbidities, eosinophilic chronic rhinosinusitis

Background Kimura's disease (KD) is known to be dominant among young Asian men, but it can also occur in middle- and advanced-aged people. The clinical characteristics of KD, especially by age, are not well known. Aim This study was performed to investigate the effects of age on the clinical characteristics of KD. Design We conducted a case series study. Methods All case studies of patients diagnosed with KD were collected via a PubMed search of studies published until August 2018. The data were analyzed by age group. Results In total, 215 studies were reviewed (238 patients; mean age of 36 years). The male:female ratio was 4:1 overall, 17:1 in patients aged <20 years, 4:1 in patients aged 20–39 years and 2:1 in patients aged ≥40 years (P = 0.01). The percentage of patients with pruritus was 15.4% overall, 3.8% in patients aged <20 years, 15.5% in patients aged 20–39 years and 21.7% in patients aged ≥40 years (P = 0.02). The time to diagnosis was 5.3 years overall, 3.2 years in patients aged <20 years, 4.7 years in patients aged 20–39 years and 7.1 years in patients aged ≥40 years (P < 0.01). Conclusions The proportion of female patients affected the incidence of pruritus, and the time to diagnosis increased as the patients' age increased. There were no significant age-related differences in region/race, complications, multiplicity, laterality, anatomical distribution, maximum size, eosinophil count, immunoglobulin E level, initial treatment, recurrence or outcomes. This may be useful information for the diagnosis of KD. [ABSTRACT FROM AUTHOR]

Background: Kimura's disease (KD) is known to be dominant among young Asian men, but it can also occur in middle- and advanced-aged people. The clinical characteristics of KD, especially by age, are not well known., Aim: This study was performed to investigate the effects of age on the clinical characteristics of KD., Design: We conducted a case series study., Methods: All case studies of patients diagnosed with KD were collected via a PubMed search of studies published until August 2018. The data were analyzed by age group., Results: In total, 215 studies were reviewed (238 patients; mean age of 36 years). The male:female ratio was 4:1 overall, 17:1 in patients aged <20 years, 4:1 in patients aged 20-39 years and 2:1 in patients aged ≥40 years (P = 0.01). The percentage of patients with pruritus was 15.4% overall, 3.8% in patients aged <20 years, 15.5% in patients aged 20-39 years and 21.7% in patients aged ≥40 years (P = 0.02). The time to diagnosis was 5.3 years overall, 3.2 years in patients aged <20 years, 4.7 years in patients aged 20-39 years and 7.1 years in patients aged ≥40 years (P < 0.01)., Conclusions: The proportion of female patients affected the incidence of pruritus, and the time to diagnosis increased as the patients' age increased. There were no significant age-related differences in region/race, complications, multiplicity, laterality, anatomical distribution, maximum size, eosinophil count, immunoglobulin E level, initial treatment, recurrence or outcomes. This may be useful information for the diagnosis of KD., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Perforation due to colon cancer maycause peritonitis and septic shock. In these cases, we maynot be able to rescue the patients in spite of emergencysurgical intervention; in these conditions, owing to limitations of operation time, it is difficult for us to assess the state or extent of the disease and to perform an ideal oncological surgerywith dissection of lymph nodes. To overcome these limitations, we introduce the concept of "damage control surgery" developed in the trauma region to treat perforations of colon cancer. There are 3 steps: first, the perforated intestine is resected and the peritoneal cavityis lavaged to control contamination. Open abdominal management is used as a temporaryabdominal closure; second, sepsis is treated in the ICU; and third, based on the treatment strategydecided upon after consulting a colorectal surgeon and the patient's family, a colostomy, anastomosis, and extra dissection of lymph node are performed before abdominal closure. We report the fatal case of a 92-year-old woman who had developed severe shock to indicate the significance of this strategy.

A 58-year-old woman suffered spontaneous recurrent hemarthrosis of the knee. In the clinical course, pigmented villonodular synovitis was mostly suspected, but in arthroscopic surgery the lateral meniscus appeared to be upturned and stuck into the lateral pouch with the meniscal ganglion cyst. It was suggested that meniscal tear with meniscal ganglion cyst was related with recurrent hemarthrosis. Generally, both the meniscal ganglion cysts and spontaneous recurrent hemarthrosis are highly rare conditions. In this case, we speculated that a negligible power could induce the meniscal tear with recurrent hemarthrosis in the particular situation in which the meniscal ganglion cyst existed. In other words, the meniscal ganglion cyst might basically and physically relate with hemorrhagic condition. Arthroscopically, the meniscal ganglion cyst was removed together with the anterior segment of the lateral meniscus. Recurrent hemarthrosis was treated successfully by resection of the meniscus.

After transection of the inferior alveolar nerve (IAN), the whisker pad area, which is innervated by the infraorbital nerve (ION) that was not injured, showed hypersensitivity to mechanical stimulation. Two days after IAN transection, threshold intensity for escape behavior to mechanical stimulation of the ipsilateral whisker pad area was less than 4.0 g, indicating mechanical allodynia. A total of 68 single fiber discharges were recorded from ION fibers at 3 days after IAN transection. The responses of C- and A-fibers were classified according to their conduction velocity. The C-fiber activities were not affected by IAN transection, whereas A-fiber activities were significantly enhanced by IAN transection as indicated by an increase in background activity and mechanically evoked response. Since the A-fiber responses were significantly affected by IAN transection, patch clamp recording was performed from middle to large diameter retrogradely labeled and acutely dissociated trigeminal ganglion (TRG) neurons. The I(K) (sustained) and I(A) (transient) currents were significantly smaller and hyperpolarization-activated current (I(h)) was significantly larger in TRG neurons of rats with IAN transection as compared to those of naive rats. Furthermore, current injection into TRG neurons induced high frequency spike discharges in rats with IAN transection. These data suggest that changes in K(+) current and I(h) observed in the uninjured TRG neurons reflect an increase in excitability of TRG neurons innervated by the ION after IAN transection, resulting in the development of mechano-allodynia in the area adjacent to the injured IAN innervated region.

While acute lindane treatment and chronic ethanol feeding to rats have been associated with hepatic oxidative stress, the possible roles of these stresses in the pathogenesis of hepatic lesions reported in acute lindane intoxication and in those observed in some models of chronic alcoholism have not been established. Our previous studies in rats chronically fed ethanol regimens and then treated with a single intraperitoneal (i.p.) dose of lindane (20 mg/kg) showed that while lindane per se was invariably associated with hepatic oxidative stress, chronic ethanol feeding only produced this stress when the dietary level of vitamin E was relatively low. Chronic ethanol pretreatment did not significantly affect the lindane-associated oxidative stress, and neither chronic ethanol feeding nor acute lindane, single or in combination, produced any histologic and biochemical evidence of liver damage. In the present experiment, the acute dose of lindane was increased to 40 mg/kg, and we have studied a larger number of prooxidant and antioxidant hepatic factors. Male Wistar rats (115.5 +/- 5.4 g) were fed ad lib for 11 weeks a calorically well-balanced and nutritionally adequate basal diet, or the same basal diet plus a 32% ethanol/25% sucrose solution, also ad lib, and were then injected i.p. with a single dose of lindane or with equivalent amounts of corn oil. The results indicated that acute lindane treatment to naive rats increased practically all the prooxidant hepatic factors examined (cytochromes P450 and b5, NADPH cytochrome c reductase, NADPH oxidase), as well as the generation of microsomal superoxide radical and thiobarbituric acid reactive substances of liver homogenates, but did not modify any of the antioxidant hepatic factors studied. Conversely, the chronic administration of ethanol alone did not significantly affect the prooxidant hepatic factors but reduced some of the antioxidants (i.e., the activities of GSH-Px and the contents of alpha-tocopherol and ubiquinols 9 and 10). Although chronic ethanol pretreatment further increased the superoxide generation induced by lindane per se, it did not increase but generally reduced the effects of lindane per se on the other prooxidant factors studied. Furthermore, although acute lindane administration to ethanol-pretreated rats was associated with decreases in GSH and catalase (not affected by ethanol or lindane treatment alone), it did not substantially modify the reducing effects of ethanol feeding per se on GSH-Px, alpha-tocopherol, and ubiquinols. Once again, neither chronic ethanol feeding nor lindane treatment, single or in combination, was associated with any evidence of liver damage.

A 69-year-old woman was hospitalized several times because of asthma attacks. Laboratory data revealed an increase in eosinophils and elevation of serum IgE. Both chest radiographs and computed tomography showed fine nodular shadows in both lung fields. Tissue samples obtained by trans-bronchial lung biopsy (TBLB) revealed extra-vascular granuloma. The patient complained of numbness of the extremities and neuron conduction velocity was low. Based on these findings, Churg-Strauss syndrome was diagnosed. Prednisolone improved the patient's symptoms. Patients with this syndrome reportedly respond well if it is diagnosed and treated with corticosteroids early. Chest roentgenography reveals various abnormal shadows in patients with this syndrome. For early diagnosis, TBLB is helpful and comparatively safe. This case was unusual because extra-vascular granuloma was found by TBLB.

From 2 years of age, children enjoy trying to button and unbutton their jacket. The clothing of the children at this stage should have the form which fits their motor skills so as to develop their interest in buttons and to help their study in manipulating buttons. We observed processes of dressing and actions of buttoning and unbuttoning at the nursery school, for children in the 3.3-5.9 year range. Also, we experimented about dressing mainly for children in 2 year range to observe the process of manipulating buttons. As factors of experiment, we took two buttonhole directions (vertical and across) and three sizes of buttons (1, 2, 3 cm). The direction of buttonholes was significant at the 5% level. We recognized that buttonholes in the vertical direction were easier for children to button. We came to the following conclusion: for an open front of children's clothing, buttons having a 2 cm diameter and buttonholes in the vertical direction were the best.

The effect of hyperthyroidism on liver glutathione (GSH) metabolism was studied in fed rats after the administration of 0.1 mg T3/kg body wt, for 1-3 consecutive days. T3-calorigenesis resulted in elevated rates of O2 consumption by the liver, together with higher lipid peroxidative processes and GSH depletion, compared to the euthyroid state. The study of the enzymes related to GSH metabolism revealed no significant changes in the activity of glutathione peroxidase and glutathione reductase, with decreases (27-41%) in the activity of glutathione-S-transferases and marked elevation (133%) in that of gamma-glutamyl transferase, 3 days after T3 treatment. At this experimental time, the activity of the NADPH generating enzyme glucose-6-phosphate dehydrogenase was enhanced by 84% in the liver of T3-treated rats, compared to that in the controls. In these conditions, the canalicular efflux of GSH was not altered by T3, whereas net and fractional rates of sinusoidal GSH efflux were enhanced by 86% and 288%, respectively. The latter effect of hyperthyroidism was found in parallel with an enhancement in sinusoidal lactate dehydrogenase and protein release, suggesting that loss of GSH might be related to a permeabilization of the hepatocyte plasma membrane. Liver GSH turnover assessed after a pulse of [35S]cysteine resulted in a 209% increase in the fractional turnover rate in hyperthyroid rats over controls, under steady state conditions for both hepatic GSH pools, leading to a 62% enhancement in the respective turnover flux. Data suggest that the elevation in the sinusoidal GSH efflux from the liver and in the hepatic capacity to degrade the tripeptide are major mechanisms leading to GSH depletion in the liver of T3-treated rats. As the increased GSH use is not balanced by the elevation in GSH synthesis, a lower steady state level of GSH is attained in the liver.

Rats treated with diets containing 20 ppm of alpha- or gamma-hexachlorocyclohexane (HCH) for 15 or 30 days showed increased levels of liver cytochrome P-450 followed by increased production of both thiobarbituric acid reactants by liver homogenates and microsomes and superoxide anion production by liver microsomes. In these animals superoxide dismutase (SOD) activity was also increased. In consequence, the ratio between SOD activity and microsomal superoxide radical (O2-.) production showed a slight increase after 15 days of treatment. However, after 30 days, there was a tendency for this ratio to decrease. Other parameters studied were liver glucose-6-phosphate dehydrogenase, glutathione peroxidase, glutathione reductase and catalase (CAT) activities. Among them, only CAT activity showed a 26% and 38% increase after 15 or 30 days of treatment with the alpha-isomer. It is suggested that when lipid peroxidation is involved in the mechanism of toxicity of a xenobiotic, this parameter can be used to determine the no-observed-effect level.

We experienced 5 cases of acute renal failure due to rhabdomyolysis during the last two years and investigated those etiologies. Diagnosis of rhabdomyolysis was established by the detection of elevated serum creatine phosphokinase, myoglobin, aldolase, myoglobinuria as well as by the clinical course. The respective underlying illness of the 5 cases were grand mal seizures, infection (high fever), heat stroke, diabetes mellitus with hyperosmolar nonketotic coma and cerebral infarction treated by barbiturate. In this investigation, however, any single cause was not enough as the etiologies of rhabdomyolysis. There were multiple factors responsible to rhabdomyolysis in each case, such as hypokalemia, hypophosphatemia, shock, arteriosclerosis, etc. Some cases could not be classified as traumatic or non-traumatic rhabdomyolysis. Thus, in one case, acute renal failure due to rhabdomyolysis induced by the combination of grand mal seizures and serum potassium/phosphate depletion. 2 cases recovered without hemodialysis. 3 cases died in multiple organ failure, included a case treated by hemodialysis. We conclude that acute renal failure due to rhabdomyolysis induced easily by numerous diseases and early diagnosis is recommended.

The DNAs of six human stomach cancer cell lines were analysed, and specific gene amplification was observed; namely, an 8-fold amplified c-Ki-ras-2 gene (1 case) and a 20-fold amplified c-myc gene (1 case). In addition, it was found that a single 11-kbp-Eco-R1 fragment, having weak homology to the Ki-ras gene, was amplified 5-10 fold in three out of the six cell lines. The DNAs of two of these three cell lines gave rise to foci upon transfection into NIH3T3 cells and the primary and secondary transformants seemed to carry a similar 11-kbp-Eco-R1 fragment. It was also found that one of the DNAs from human stomach cancers gave rise to NIH3T3 cell foci upon DNA transfection. DNAs of secondary transformants commonly retained six Eco-R1 fragments that contained human Alu repeats. The size of this gene was estimated to be about 50 kbp. The Southern blot hybridization profile of this gene revealed it to be clearly different from known active human oncogenes. Furthermore, about 70% of this gene has been isolated and portions of it used as probes to test for homologies to known viral oncogenes. The gene appears to be unrelated to 14 viral oncogenes so far tested.

1. Four hours after treatment of rats with lindane (60 mg/kg), hepatic GSH content was decreased (22%) and GSSG was increased (20%), while biliary concentration and excretion of both GSH and GSSG and bile flow were diminished. These changes coincide with the onset of hepatic lipid peroxidation. 2. The changes induced by lindane at 4 h disappeared at 6 h after treatment, but liver GSSG content (91%), biliary GSSG excretion (133%) and bile flow (42%) were enhanced at 24 h. 3. The data indicate that lindane treatment elicits marked changes in hepatocyte glutathione status, with a decrease in the GSH/GSSG ratio at early (2-4 h) and late (24 h) periods of poisoning.