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Objectives: Although some patients with postviral olfactory dysfunction (PVOD) recover spontaneously, many others are left with the degree of smell loss and there are no established drugs for the treatment of patients with PVOD. Valproic acid (VPA) has been widely used for the treatment of epilepsy. Its potential neuroregenerative effects have been shown via animal studies. This is the first study to treat PVOD patients with VPA. This open-label, single-arm, phase II study was conducted to investigate the effects of VPA in patients with PVOD., Methods: The patients received oral tablets of VPA 200 mg twice a day for 24 weeks. In total, 11 patients with PVOD were recruited. Oder scores of recognition and detection threshold (measured with a T&T olfactometer), and visual analog scale were examined during the treatment., Results: All odor scores significantly improved over time. Although the mean duration of olfactory dysfunction in this study was 11.5 months, both odor recognition threshold and odor detection threshold scores significantly improved 4 weeks after treatment initiation compared to the pre-treatment threshold scores. The olfactory recovery rates in patients treated with VPA were clearly better than those we previously reported in PVOD patients who received Toki-shakuyaku-san, the traditional treatment in Japan. The olfactory recovery rates of patients with PVOD at 12 weeks and 24 weeks of VPA treatment were both 77.8%, and the olfactory cure rates at 12 weeks and 24 weeks of VPA treatment were 33.3% and 44.4%, respectively. No serious adverse events were observed., Conclusions: VPA seems to be a safe treatment option in patients with PVOD. The effects of VPA treatment for PVOD patients should be studied with a controlled study design in the future.

Sublingual immunotherapy (SLIT) with Japanese cedar (JCe) pollinosis was expected to be effective for Japanese cypress (JCy) pollinosis. However, only a half of JCy pollinosis patients clinically improved. Therefore, we examined the immunological effect of SLIT for JCy pollinosis. Peripheral blood mononuclear cells (PBMCs) from patients with JCe and JCy pollinosis who did and did not receive SLIT were incubated with Cry j 1, Cha o 1 and Cha o 3 antigens. Basophil activation test (BAT) were performed. Production of IL-5 and IL-17 induced by antigens was inhibited in the SLIT group. Cry j 1-specific production of IL-10 was increased, and serum Cry j 1-specific IgE and -IgG4 were elevated. However, Cha o 1- or Cha o 3-specific production of IL-10 and specific IgG4 was not increased. Antigens-specific BAT did not decrease after SLIT. New SLIT with JCe and JCy is needed for patients with combined JCe and JCy pollinosis., Competing Interests: Declaration of Competing Interest TO is employees of Taiho Pharmaceutical Co., LTD. AY has received fee for speaking from Torii Co., LTD in this work. TS receives scholarship donations from Shionogi & Co., LTD. But, none of the authors has any potential financial conflict of interest related to this manuscript., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Group 2 innate lymphoid cells (ILC2s) play important roles in allergic inflammation. However, their roles in the pathophysiology of allergic rhinitis (AR) are poorly understood., Objective: Prevalence of ILC2s in the inferior nasal turbinate (INT) tissues and the activating mechanisms of ILC2s were examined in patients with house dust mite (HDM)-induced AR., Methods: Eighteen patients with HDM-induced AR and 13 control subjects were recruited. Fresh INT tissues and peripheral blood mononuclear cells (PBMCs) were analysed using flow cytometry. Nasal lavage fluids (NLF) were collected at 10 minutes after the nasal provocation test (NPT) with HDM disc, and released mediators were measured by ELISA. Sorted ILC2s were cultured and stimulated with mediators associated with AR., Results: The prevalence of ILC2s was significantly increased in nasal mucosa of patients with HDM-induced AR, and it was positively correlated with the number of infiltrating eosinophils. ILC2s in the INT tissues expressed a prostaglandin D 2 (PGD 2 ) receptor, chemoattractant receptor-homologous molecule-expressed TH2 cells (CRTH2) and a cysteinyl leukotriene (cysLTs) receptor, CysLT1. After NPT, the number of eosinophils and concentrations of PGD 2 and cysLTs were significantly increased in the NLF from AR patients. PGD 2 and cysLTs significantly induced IL-5 production from cultured PBMC-derived ILC2s dose-dependently. PGD 2 -induced and cysLTs-induced productions of IL-5 and IL-13 from ILC2s were completely inhibited by ramatroban, a dual CRTH2 and thromboxane receptor antagonist, and montelukast, a CysLT1 antagonist, respectively., Conclusions: PGD 2 -CRTH2 and cysLTs-CysLT1 axes may activate tissue-resident ILC2s to produce Th2 cytokines, IL-5 and IL-13, leading to the development of allergic inflammation in AR., (© 2019 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Tableting failure due to binding is often caused by powder adhesion to the die wall. The present study was undertaken to develop a novel approach for analyzing the binding characteristics of various formulations and manufacturing methods, named "Binding Identification for Net Detriment" (BIND). Binding characteristics with raloxifene hydrochloride as a model preparation were evaluated by visual observation, ejection force and BIND. The surface replication method was initially employed to monitor powder adhesion to the die wall. Microscopic images with replicates were analyzed qualitatively and quantitatively. For the validation, BIND and measurement of the friction between a tablet and the die wall were performed. The qualitative data on BIND agreed with visual observations; however, there were some data discrepancies between the ejection force and visual observations. For the formulation without lubricant, BIND showed a 30.2% powder adhesion rate, while the formulation containing 1% lubricant exhibited a powder adhesion rate of 4.1%. Thus, BIND demonstrated that the use of the wet tableting method reduced powder adhesion compared with the direct tableting method. BIND allowed qualitative and quantitative analysis of powder adhesion for both powder compression and tablet ejection. BIND is a promising tool for analyzing powder adhesion to the die wall., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Epithelial cell-derived IL-33 has an important role in the initiation and activation of innate allergic inflammation. IL-33 acts as a cytokine through the ST2 receptor (ST2L) and it stimulates the production of Th2 cytokines. Soluble ST2 (sST2) may regulate Th2 responses by neutralizing the activity of IL-33. Basophils express ST2L and produce IL-5 in response to IL-33. However, the role of the epithelial cell-basophil interaction and sST2 in IL-5 production remains unclear., Methods: Cultured human bronchial epithelial (hBE33) cells, that contained the human IL-33 gene (i.e., hBE33 cells) and a human basophilic cell line, KU812 cells, were used to study the epithelial cell-basophil interaction in the production of IL-5 induced by HDM., Results: At 15 min after incubation, HDM stimulated the rapid release of IL-33 from cultured hBE33 cells. IL-33 and the supernatant of HDM-treated hBE33 cells stimulated IL-5 production from KU812 cells. Anti-IL-33 antibody and anti-ST2 antibody treatment of KU812 cells suppressed IL-5 production, which had been induced by the supernatant of HDM-treated hBE33 cells. The hBE33 cells secreted sST2 in a time-dependent manner. The production of sST2 by KU812 cells co-cultured with hBE33 cells was significantly increased, compared with KU812 cells cultured with the supernatant of hBE33 cells. Soluble ST2 suppressed IL-5 production by KU812 cells, which was induced by the supernatant of HDM-treated hBE33 cells., Conclusions: Epithelial cell-derived IL-33 promoted IL-5 production by KU812 cells. The subsequently produced sST2 has important roles in regulating Th2 responses., (Copyright © 2018 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

IL-25 likely has vital roles in initiating and activating type-2 immune responses in AR. We hypothesized that the molecules produced IL-25 by allergen-producing organisms such as JC is involved in the pathogenesis of AR. Participants included 13 patients with Japanese cedar pollinosis and 10 HCs. We measured the IL-25 protein concentration in nasal secretions and in culture supernatants of PNECs. NHBE cells were stimulated with pharmacological and immunological agents and JC. The IL-25 concentration in nasal secretions was significantly higher in patients with Japanese cedar pollinosis than in HCs. JC stimulated IL-25 production from PNECs. TNF-α, IL-4, and IL-13 significantly enhanced JC-induced IL-25 production; their activation by serine proteases was sufficient to enhance IL-25 production. Furthermore, the NADPH oxidase activity, including JC enhanced IL-25 production. A better understanding of JC-induced IL-25 production by epithelial cells may allow the development of novel therapeutic and preventive strategies for Japanese cedar pollinosis., (Copyright © 2018 Elsevier Inc. All rights reserved.)

We herein present three cases of abnormally expanded frontal sinuses (pneumoceles) with severe infection in patients with mental retardation and brain atrophy. Two patients previously underwent laryngotracheal separation surgery, and bacteriological examinations of purulent nasal discharge revealed infections caused by drug-resistant bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii. As conservative medical treatments were ineffective, all three patients were treated by computed tomography-guided endoscopic sinus surgery. This navigation system is useful for safer surgery in the area of anatomic deformity. The clinical findings, possible etiologies and surgical treatment of these cases are discussed., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Rationale: Cystatin A and SPINK5 are endogenous protease inhibitors (EPIs) that may play key roles in epithelial barrier function., Objectives: To investigate the roles of EPIs in the pathogenesis of chronic rhinosinusitis (CRS)., Methods: We examined the expression of cystatin A and SPINK5 in the nasal epithelial cells of patients with CRS. Additionally, the in vitro effects of recombinant EPIs on the secretion of the epithelial-derived cytokines IL-25, IL-33, and thymic stromal lymphopoietin in airway epithelial cells, and the in vivo effects of recombinant EPIs in the nasal epithelium of mice exposed to multiple airborne allergens (MAA) were examined., Measurements and Main Results: Compared with control subjects and patients with noneosinophilic CRS, patients with eosinophilic CRS showed significantly lower protein and mRNA expression of cystatin A and SPINK5 in the nasal epithelium. Allergen-induced production of IL-25, IL-33, and thymic stromal lymphopoietin in normal human bronchial epithelial cells was inhibited by treatment with recombinant cystatin A or SPINK5. Conversely, the production of these cytokines was increased when cystatin A or SPINK5 were knocked down with small interfering RNA. Chronic MAA exposure induced goblet cell metaplasia and epithelial disruption in mouse nasal epithelium and decreased the tissue expression and nasal lavage levels of cystatin A and SPINK5. Intranasal instillations of recombinant EPIs attenuated this MAA-induced pathology., Conclusions: Cystatin A and SPINK5 play an important role in protecting the airway epithelium from exogenous proteases. The preservation of EPIs may have a therapeutic benefit in intractable airway inflammation, such as eosinophilic CRS.

Aim: We reevaluated waist circumference as a diagnostic criterion of metabolic syndrome (MetS) in Japanese., Methods: We enrolled 5,571 subjects (3,148 men and 2,423 women) who had health check-ups in our center. The criterion was reevaluated using the positive predictive value of a receiver-operating characteristics (ROC) curve at 10 different hypothesized lengths of waist circumference with or without a cluster of risk factors. We also drew ROC curves based on the atherosclerotic findings of clinical examinations., Results: Based on the ROC curves, the optimal waist circumference cut-off was 85 cm in men and 80 cm in women. Using this 80 cm cut-off point in women, misdiagnosis rates of MetS were lowered (-19.1--56.6%) compared to the cut-off point currently in use. Integrating the influence of height, namely by using a waist-to-height(2) ratio, misdiagnosis rates in shorter populations were decreased in both men and women., Conclusion: These data suggested an optimal waist circumference cut-off to improve the diagnostic probability of MetS in Japanese women of 80 cm, as well as the utility of an easily detected anthropometric index such as a waist-to-height (cm x 100/cm) or waist-to-height(2) (cm x 10,000/cm(2)) ratio, determined as 51 in men and 52 in women, or 30 in men and 33 in women, respectively.

We developed a sandwich enzyme immunoassay for intact type IV collagen (IV-C) using two monoclonal antibodies as a marker of basement membrane metabolism, and examined the relationship between serum IV-C and diabetic complications. Serum IV-C was measured in 186 diabetics with or without clinical signs of retinopathy, neuropathy, and/or nephropathy, and 328 healthy subjects. Serum IV-C was significantly (P less than .01) higher in diabetics (mean +/- SE: 124.83 +/- 2.94 ng/ml) than in healthy subjects (73.32 +/- 1.42 ng/ml). In diabetics with microangiopathy, serum IV-C became higher as clinical signs worsened. Especially in diabetics with nephropathy, serum IV-C became higher with the elevation of blood urea nitrogen (BUN), serum creatinine, and beta 2-microglobulin. Serum IV-C level seems to be a useful marker for assessment of the activity or progression of diabetic microangiopathy, and for evaluation of therapeutic effects.

A procedure for effective application of ultrafiltration is described for preparation of serum catecholamine samples suitable for a sensitive radioreceptor assay. Each of the fresh serum samples unsuitable for the direct receptor assay was dialyzed by applying centrifugal force into a capsule-shaped porous core whose surface was tightly covered with a molecular filtration membrane. Interfering macromolecular serum components were left outside the capsule during the centrifugation or forced dialysis. The ultrafiltrate in the capsule was readily recovered by another centrifugation, and was found satisfactory as an assay specimen. In the radioreceptor assay system adapted to detect 30 pg per assay tube, epinephrine added to fresh serum to make the final concentration approximately 1 X 10(-8) mol/L was recovered semiquantitatively. Serum catecholamine level determined was equivalent to beta-adrenergic receptor reactivity that could be expressed in terms of (-)-epinephrine concentration.

Patients with cirrhosis of the liver (LC group, n = 12) frequently have glucose intolerance secondary to hepatic dysfunction. We compared HbA1 levels and other measures of blood sugar control in the LC group with those in healthy controls (N group, n = 43), patients with diabetes mellitus (DM group, n = 36), or patients with chronic hepatitis without evidence of cirrhosis (CH group, n = 12). HbA1 levels and the mean values of fasting plasma glucose for the past month (FPG) were as follows: LC group 6.40 +/- 0.36 (mean +/- SEM)% and 130 +/- 20 mg/dl, DM group 10.29 +/- 0.45% and 172 +/- 11 mg/dl, CH group 10.70 +/- 0.86% and 176 +/- 21 mg/dl, N group 6.52 +/- 0.11% and 83 +/- 1 mg/dl, respectively. HbA1 in the LC group was similar to that in the N group, although FPG in the former was higher (p less than 0.05). All groups showed statistically significant positive correlations between HbA1 levels and (a) FPG, (b) the daily profile of plasma glucose values, (c) the total or peak plasma glucose values during a 50 g-OGTT. The regression line in the LC group, however, was statistically different from that in DM or CH group. Thus, HbA1 in the LC group is lower than that in DM or CH in spite of equivalent glucose intolerance. Therefore, we suggest caution in the interpretation of HbA1 levels in hepatic cirrhosis.

A case of tertiary hyperparathyroidism with a parathyroid adenoma and hyperplasia was described as the first report in Japan. A 24-year-old man manifesting hypercalcemia had been treated with hemodialysis for 9 years. On admission, clubbed fingers richitic rosaries and a palpable node in the neck were the major physical findings. Laboratory examinations revealed hypercalcemia had elevated levels of plasma parathyroid hormone (PTH) in a c-terminal assay. Nevertheless the levels of PTH found by a n-terminal assay disclosed an only small increase. The PTH levels were scarcely decreased after a bolus injection of calcium gluconate. A large tumor corresponding to the palpable node was resected. Histologically, the tumor was an adenoma with thick fibrous capsule and interparenchymal bands. Other parathyroid glands showed secondary clear cell hyperplasia without signs of cellular hyperactivity.

We quantitatively assessed peripheral and autonomic nerve function in diabetic patients and compared them with various parameters of their diabetic status. Motor and sensory nerve conduction velocity (MCV, SCV), vibratory perception threshold (VPT) and the coefficient of variation of the ECG R-R interval (CV R-R) were measured in 85 diabetic patients aged 20-59 years. These values were compared with those of age-matched healthy subjects. Moreover, in 53 patients, MCV, SCV, VPT and CV R-R were investigated by multivariate analysis in relation to clinical parameters. In diabetics, MCV, SCV and CV R-R were significantly lower and VPT was higher than in age-matched healthy controls. The prevalence of impaired values in diabetics was 70% for VPT in the toe, 60% for SCV, and 55% for MCV, CV R-R and VPT in the finger. Impairments of MCV, SCV, CV R-R and VPT were closely correlated with diabetic retinopathy, proteinuria and duration of disease. Categorical regression analysis (multivariate analysis) revealed that the impairment of conduction velocity was closely related to diabetic retinopathy and to hypo- or areflexia, that the impairment of the vibratory perception threshold was related to ischemic changes in ECG and to hypo- or areflexia, and that the reduction of CV R-R was related to orthostatic hypotension and to proteinuria. These findings suggest that diabetic neuropathy progresses in parallel with other complications, and that it is a heterogeneous syndrome rather than a single entity.

To evaluate the function of the central nervous system of patients with occupational vibration disease, electroencephalograms and auditory brainstem responses (ABR) were recorded in 20 male subjects with occupational vibration disease whose age ranged from 46 to 67 years (mean 57.4 yr). All the subjects had operated chain saws from 10 to 25 yr (mean 15.2 yr) and had frequently complained of many subjective symptoms induced by central nervous system disturbances such as headache, head heaviness, tinnitus, vertigo, and insomnia, which corresponded to stage 3 in the diagnostic criteria of Andreeva-Galanina. Twenty-six healthy men whose age ranged from 40 to 67 yr (mean 53.0 yr) were selected as controls. Electroencephalograms were recorded with a 12-channel electroencephalograph, using unipolar and bipolar leads. Auditory brainstem responses were recorded by signal averaging technique using 100 microseconds alternating clicks. The stimuli were presented at 70 dB above threshold (SL) with a rate of 10 per second. The following results were obtained. 1. By electroencephalography, the incidence of diffuse alpha pattern, slow alpha wave and drowsy pattern was 32%, 32%, and 42%, respectively. 2. Click thresholds in the patients were obviously higher than those in the healthy controls. 3. The occurrence rate of wave II of ABR in the patients (61.8%) was significantly lower than that in the healthy controls (85.0%) (p less than 0.05). 4. The interpeak latencies I-V and III-V of ABR in the patients were significantly longer than those in the healthy controls.(ABSTRACT TRUNCATED AT 250 WORDS)

In order to evaluate the functions of the peripheral somatic nerve and autonomic nerve in patients with occupational vibration disease objectively and quantitatively, four examinations were performed on twenty 44-63 yr old patients with occupational vibration disease and their total operating time ranged from 5,000 to 43,750 h. 1) Motor nerve conduction velocities (MCV) and sensory nerve conduction velocities (SCV) of the ulnar and median nerves were measured using conventional methods. 2) Electrogustatory thresholds under the controlled area of the chorda tympani nerve were measured by Tomita's method using an electrogustometer (610-M, M.E.C.). 3) Dopamine-beta-hydroxylase (DBH) activity in blood was assayed by the photometric assay of Nagatsu and Udenfriend. 4) Coefficient of variation of R-R interval in ECG (CVR-R) was measured after 15-min-resting in supine position by using a R-R interval analyzer (Autonomic R 100, M.E.C.). The results of these examinations were compared with those of special examinations for the diagnosis of vibration disease. In patients with occupational vibration disease, MCV and SCV of the ulnar and median nerve were lower in value than those in age-matched healthy controls. In particular, MCV of the ulnar nerve, MCV and SCV of the median nerve were significantly lower in the patients than in the controls. Nerve conduction velocities were significantly correlated with skin temperature and nailpress test, though diminished nerve conduction velocities observed in vibration disease patients were considered to be attributable to peripheral circulatory disturbance.(ABSTRACT TRUNCATED AT 250 WORDS)