Dodecaborate Conjugates Targeting Tumor Cell Overexpressing Translocator Protein for Boron Neutron Capture Therapy.

We developed novel closo-dodecaborate ([B12H11]2-) anion-containing translocator protein (TSPO) ligand as a boron carrier for boron neutron capture therapy. This compound shows high water solubility and can deliver boron to TSPO highly expressed in breast cancer cells. We describe the synthesis and in vitro evaluation of a dodecaborate-based pyrazolopyrimidine.

Chemical structure of hydrolysates of cereulide and their time course profile.

Hydrolysates of an emetic toxin cereulide were found in the broth of Bacillus cereus. The ester cleaved depsipeptides of cereulide were synthesized using liquid phase fragment condensation method starting from commercially available amino acids. The chemical structure of hydrolysates was verified tetradepsipeptide l-O-Val-l-Val-D-O-Leu-d-Ala and dodecadepsipeptide (D-O-Leu-d-Ala-l-O-Val-l-Val)3 using LC-TOFMS. Quantitative analysis of cereulide in the broth revealed production of cereulide in the stationary phase and decomposition in the death phase. The increase in tetradepsipeptide continued after the stationary phase until decomposition occurred.

Change in smoking cessation stage over 1 year in patients with schizophrenia: a follow up study in Japan.

BACKGROUND: We performed a follow up study about willingness and behaviors to quit smoking among smokers with schizophrenia in Japan. METHODS: Participants were outpatients with schizophrenia aged 20-69 years who had been visiting the hospital for ≥1 year as of April 1, 2016, and had visited the hospital more than once in the previous 6 months. A baseline survey on smoking behaviors including current smoking status and smoking cessation stage, was administered in 420 participants that were randomly extracted from a patient pool (n = 680) in 2016, and a follow-up survey was administered in 2017. We calculated the distribution and change in smoking cessation stage, number of smokers and nonsmokers after 1 year, and quitting rate from a naturalistic 1-year smoking-cessation follow up. RESULTS: The number of baseline respondents was 350; 113 current smokers and 68 former smokers. Among the 113 current smokers, 104 (92.0%) were followed for 1 year, 79 (70.0%) were interested in smoking cessation, and only 7 had received smoking cessation treatments at baseline. Among the tracked 104 participants, only 6 (5.8%) stopped smoking after 1 year. Among the 25 participants who had intentions to quit smoking within 6 months at baseline, 6 (24.0%) maintained their intention to quit smoking for 1 year, and 16 (64.0%) did not maintain their intention to quit smoking. CONCLUSIONS: Our findings showed that many smokers with schizophrenia were interested in quitting smoking, but few patients received treatment and actually quit smoking. Timely intervention, including the option to receive smoking cessation treatment, is necessary for those patients with schizophrenia who smoke. TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN000023874, registered on August 31, 2016).

Synthesis of the reported structure of homocereulide and its vacuolation assay.

Homocereulide, isolated from marine bacterium Bacillus cereus, is an analog of emetic toxin cereulide. There is no report on its structure determination and involvement in B. cereus-associated food poisoning. Homocereulide is a cyclic dodecadepsipeptide composed of l-O-Val-l-Val-d-O-Leu-d-Ala and l-O-allo-Ile-d-Val-d-O-Leu-d-Ala. Here, we synthesized homocereulide using liquid phase fragment condensation. The NMR spectrum of synthesized homocereulide confirmed the intended structure and LC-MS results were consistent with natural products. Morphological evaluation using HEp-2 cells showed higher toxicity with homocereulide (1.39 nM) than cereulide (3.95 nM). Though cereulide is the main component in broth culture, homocereulide is also likely involved in B. cereus-associated food poisoning.

The 1st step initiation essential for allergen-specific IgE antibody production upon the 2nd step: Induction of non-specific IgE+ small B cells containing secondly-sensitized allergen-specific ones in mice firstly-sensitized with an allergen.

There was a significant amount of non-specific, but not of allergen (e.g., papain, mite feces and four kinds of pollen)-specific, IgE antibodies (Abs) in the sera of normal mice. An i.n. injection of each allergen without adjuvant into mice caused an increase in total IgE Ab titers with a similar time course in the serum. However, the stage of initiation of allergy varied from allergen to allergen. Submandibular lymph node cells from normal mice contained papain-, but not mite feces- or pollen-specific IgE+ cells and an i.n. injection of papain induced papain-specific IgE Abs in the serum. In contrast, one (i.n.) or two (i.n. and s.c) injections of mite feces induced neither mite feces-specific IgE+ cells in the lymph nodes nor mite feces-specific IgE Abs in the serum. I.n. sensitization with cedar pollen induced cedar pollen-specific IgE+ small B cells in the lymph nodes on Day 10, when non-specific IgE Ab titers reached a peak in the serum, implying induction of related allergen-specific IgE+ small cells as well. In fact, a second (s.c.) injection of ragweed (or cedar) pollen into mice sensitized i.n. once with cedar (or ragweed) pollen, but not with mite feces, induced a large amount of ragweed (or cedar) pollen-specific IgE Abs in the serum. These results indicate that when firstly-sensitized non-specific IgE+ small B cells in mouse lymph nodes include some secondly-sensitized allergen-specific ones, mice produce IgE Abs specific for the secondly-injected allergen.

Case of ovarian hyperstimulation and oocyte pick-up during very early period of unnoticed pregnancy followed by ongoing normal pregnancy.

We report a case of unnoticed pregnancy that was maintained during low estrogen and progesterone circumstances, that showed menses-like bleeding, and was then discovered after ovarian hyperstimulation during the next period. The patient was 39 years old and primigravid. She underwent intrauterine insemination, followed by luteal support with human chorionic gonadotrophin and progestin; however, she experienced menstruation-like bleeding 15 days later. As low estradiol and progesterone levels were confirmed on the 2nd day of bleeding, ovarian hyperstimulation of short protocol for in vitro fertilization was commenced. Although 13 mature follicles were observed, only six oocytes were retrieved and one developed into a blastocyst. Four days after oocyte pick-up, a gestational sac was seen in utero. The fetus is currently growing uneventfully. This case suggests that pregnancy can be maintained during ovarian hyperstimulation, even if menstruation-like bleeding is shown in low-progesterone circumstances.

Long-period ocean-bottom motions in the source areas of large subduction earthquakes.

Long-period ground motions in plain and basin areas on land can cause large-scale, severe damage to structures and buildings and have been widely investigated for disaster prevention and mitigation. However, such motions in ocean-bottom areas are poorly studied because of their relative insignificance in uninhabited areas and the lack of ocean-bottom strong-motion data. Here, we report on evidence for the development of long-period (10-20 s) motions using deep ocean-bottom data. The waveforms and spectrograms demonstrate prolonged and amplified motions that are inconsistent with attenuation patterns of ground motions on land. Simulated waveforms reproducing observed ocean-bottom data demonstrate substantial contributions of thick low-velocity sediment layers to development of these motions. This development, which could affect magnitude estimates and finite fault slip modelling because of its critical period ranges on their estimations, may be common in the source areas of subduction earthquakes where thick, low-velocity sediment layers are present.

Detection of boronic acid derivatives in cells using a fluorescent sensor.

The detection of boron-containing compounds requires very expensive facilities and/or tedious sample pretreatments. In an effort to develop a convenient detection method for boronic acid derivatives, boron chelating-ligands were synthesized for use as fluorescent sensors. In this paper, the synthesis and properties of fluorescent sensors for boronic acid derivatives are reported.

Insulin resistance in nonobese Japanese women with polycystic ovary syndrome is associated with poorer glucose tolerance, delayed insulin secretion, and enhanced insulin response.

Purpose: To determine the prevalence of insulin resistance (IR) and impaired glucose tolerance (IGT) in PCOS patients, the optimal screening method, and to compare our findings between nonobese and obese Japanese women with PCOS. Methods: Ninety-eight PCOS patients were included in this research from 2006 to 2013. Glucose tolerance test (OGTT) was performed. Serum glucose and insulin concentration were assayed before and 30, 60, and 120 min after taking 75 g of glucose. Results: All examined metabolic parameters were significantly favorable in the nonobese subjects, below 25 kg/m2. HOMA-IR, fasting insulin, glucose120, and insulin120 showed strong correlations with BMI. A total of 1.4 % of nonobese women had IR based on fasting insulin or HOMA-IR. However, 15.5 % (11/71) of nonobese women had IR as determined by a continuous increase of serum insulin level in OGTT. In comparison, the prevalence of IR among the obese women ranged from 41 to 59 %. AUCglucose, glucose60, glucose120, and insulin120 in nonobese women with a continuous insulin increase were higher than those without such a continuous increase. Conclusions: All examined metabolic parameters were significantly correlated with BMI. As the presence of a continuous increase of insulin level reflects to some degree poorer glucose tolerance, delayed insulin secretion, and enhanced insulin response compared with non-continuous insulin increase, OGTT might not been excluded to determine IR and IGT for nonobese women with PCOS.

Synthesis and in vitro evaluation of thiododecaborated α, α- cycloalkylamino acids for the treatment of malignant brain tumors by boron neutron capture therapy.

Boron-neutron capture therapy (BNCT) is an attractive technique for cancer treatment. As such, α, α-cycloalkyl amino acids containing thiododecaborate ([B12H11](2-)-S-) units were designed and synthesized as novel boron delivery agents for BNCT. In the present study, new thiododecaborate α, α-cycloalkyl amino acids were synthesized, and biological evaluation of the boron compounds as boron carrier for BNCT was carried out.

Japanese Guideline for Allergic Rhinitis 2014.

Like asthma and atopic dermatitis, allergic rhinitis is an allergic disease, but of the three, it is the only type I allergic disease. Allergic rhinitis includes pollinosis, which is intractable and reduces quality of life (QOL) when it becomes severe. A guideline is needed to understand allergic rhinitis and to use this knowledge to develop a treatment plan. In Japan, the first guideline was prepared after a symposium held by the Japanese Society of Allergology in 1993. The current 7th edition was published in 2013, and is widely used today. To incorporate evidence based medicine (EBM) introduced from abroad, the most recent collection of evidence/literature was supplemented to the Practical Guideline for the Management of Allergic Rhinitis in Japan 2013. The revised guideline includes assessment of diagnosis/treatment and prescriptions for children and pregnant women, for broad clinical applications. An evidence-based step-by-step strategy for treatment is also described. In addition, the QOL concept and cost benefit analyses are also addressed. Along with Allergic Rhinitis and its Impact of Asthma (ARIA), this guideline is widely used for various clinical purposes, such as measures for patients with sinusitis, childhood allergic rhinitis, oral allergy syndrome, and anaphylaxis and for pregnant women. A Q&A section regarding allergic rhinitis in Japan was added to the end of this guideline.

A retrospective study of 231 Japanese vitiligo patients with special reference to phototherapy.

Although the outcomes of various treatment modalities for vitiligo have been studied extensively, the influence of the participant's characteristics on treatment response has not been thoroughly investigated. Therefore, we retrospectively investigated treatment effects and their association with clinical characteristics in Japanese patients with vitiligo. The charts of patients with vitiligo treated in our institution were reviewed. Clinical response was evaluated as a marked response rate, defined as repigmentation in >75% of the initial lesional area. 162 patients were treated with phototherapy, while 69 were treated with topical mono-therapy. The patients treated with phototherapy and those treated with both phototherapy and topical treatment demonstrated significantly higher clinical response rates compared to patients treated solely with topical mono-therapy (marked response rate: 19.1% vs. 5.8%, P<0.05; and 23.5% vs. 5.8%, P<0.01, respectively). Among the phototherapy-treated patients, younger subjects (≤15 years old) were more responsive to phototherapy compared to older patients (37.0% vs. 15.6%; P=0.015). The disease subtypes did not affect treatment response. In conclusion, phototherapy appears to have a therapeutic effect superior to topical mono-therapy on both focal and generalized vitiligo, especially in younger patients. Thus, any type of psychosocially devastating lesions in a pediatric patient may be a good target for phototherapy.

Continuous 6-year follow-up study of sensitization to Japanese cedar pollen and onset in schoolchildren.

BACKGROUND: Intra individual longitudinal data has been lacking for IgE-mediated seasonal allergic rhinitis (SAR), especially in young children. Little is known about the development and natural course of SAR in terms of prevalence and incidence rates in schoolchildren. METHODS: In May or June each year from 1994 to 2007, schoolchildren were assessed for serum Japanese cedar pollen (JCP)-IgE and house dust mite (HDM)-IgE levels, and surveyed regarding nasal symptoms. RESULTS: Among the 220 children initially assessed in the first grade, 69 (31.4%) were already sensitized to JCP at first grade and 119 (54.1%) did not develop JCP sensitivity during the 6-year study at all. In the first grade children who were HDM-sensitized but JCP non-sensitized, JCP-IgE level was significantly elevated compared to the JCP and HDM non-sensitized group. This seems to indicate that HDM sensitization was very strongly associated with JCP sensitization. CONCLUSIONS: Elevated serum IgE is a consequence of specific sensitization to HDM and HDM sensitization appeared to develop prior to the start of primary school which distinguishes HDM sensitization from JCP sensitization.

Japanese Guideline for Allergic Rhinitis 2014.

Like asthma and atopic dermatitis, allergic rhinitis is an allergic disease, but of the three, it is the only type I allergic disease. Allergic rhinitis includes pollinosis, which is intractable and reduces quality of life (QOL) when it becomes severe. A guideline is needed to understand allergic rhinitis and to use this knowledge to develop a treatment plan. In Japan, the first guideline was prepared after a symposium held by the Japanese Society of Allergology in 1993. The current 7th edition was published in 2013, and is widely used today. To incorporate evidence based medicine (EBM) introduced from abroad, the most recent collection of evidence/literature was supplemented to the Practical Guideline for the Management of Allergic Rhinitis in Japan 2013. The revised guideline includes assessment of diagnosis/treatment and prescriptions for children and pregnant women, for broad clinical applications. An evidence-based step-by-step strategy for treatment is also described. In addition, the QOL concept and cost benefit analyses are also addressed. Along with Allergic Rhinitis and its Impact of Asthma (ARIA), this guideline is widely used for various clinical purposes, such as measures for patients with sinusitis, childhood allergic rhinitis, oral allergy syndrome, and anaphylaxis and for pregnant women. A Q&A section regarding allergic rhinitis in Japan was added to the end of this guideline.

Visual analog scale as a predictor of GINA-defined asthma control. The SACRA study in Japan.

OBJECTIVE: The assessment of asthma control is pivotal to treatment decisions. A questionnaire that assesses the Global Initiative for Asthma (GINA)-defined control requires four questions. A visual analog scale (VAS) to evaluate asthma control can be simply marked, but its correlation with GINA-defined control has been insufficiently evaluated. The purpose of this study is to evaluate whether VAS levels can predict GINA-defined asthma control with particular emphasis on the distinctions between "partly controlled" and "uncontrolled" and between "partly controlled" and "controlled" asthma, METHODS: A cross-sectional multicenter study was carried out throughout Japan (SACRA) from March to August 2009 among patients with a diagnosis and treatment of asthma. Asthma control was studied using the GINA questionnaire and a VAS measurement of asthma severity. Pulmonary function testing was not carried out, RESULTS: 1910 physicians enrolled 29,518 patients with asthma. 15,051 (51.0%) questionnaires were administered by physicians; patients filled out 14,076 (47.7%) questionnaires themselves. 28,225 (95.6%) of the patients were evaluable. VAS measurement of asthma symptoms was useful in predicting levels of GINA-defined control categories (the area under the receiver operating characteristic curve ranging from 0.704 to 0.837). Patients with "controlled," "partly controlled," and "uncontrolled" asthma were discriminated by VAS levels (1.50, 4.79, and 7.19). Similar results have been obtained with self- and physician-administered questionnaires showing the validity of results. CONCLUSION: Measurement of VAS levels is able to discriminate between patients with "controlled," "partly controlled," and "uncontrolled" asthma. The VAS score could be a simple guide in clinical situations requiring daily or regular evaluation of asthma control.

Examination, diagnosis and classification for Japanese allergic rhinitis: Japanese guideline.

Many countries throughout the world have experienced an increase in the prevalence of allergic rhinitis (AR), which has come to be a major cause of morbidity in developed countries. The pathology underlying AR is regarded as IgE-mediated type I allergy characterized by mucosal inflammation that occurs in response to allergen exposure. In Japan, AR caused by Japanese cedar pollen, the most common allergic disease, has become a salient public health challenge. Almost all primary care physicians and otorhinolaryngologists have been consulted by AR patients between February and April. Although most such patients have received treatment, numerous patients with AR have not received proper examinations for AR. Clinical guidelines are systematically developed statements that are designed to help practitioners make decisions about appropriate and effective health care. Guidelines in many countries including Japan have been published for AR. Unfortunately, those guidelines have remained untested. Moreover, they might be difficult for non-specialists to use. In this review, we specifically examine the present standard examination for diagnosis of AR and optimal classification for AR in Japan. We hope that this review would be used not only for the support of daily practice but also for selection of AR patients for clinical trials.

Essential role of macrophages in the initiation of allergic rhinitis in mice sensitized intranasally once with cedar pollen: regulation of class switching of immunoglobulin in B cells by controlling interleukin-4 production in T cells of submandibular lymph nodes.

The production of allergen-specific IgE antibodies (Abs) in allergen-sensitized patients or animals has a mutual relationship with the immunologic response leading to allergic rhinitis. We recently reported that, after an intranasal injection of cedar pollen into mice, an interleukin-4 (IL-4)-dependent increase in serum nonspecific IgE Abs was a prerequisite for the production of serum allergen-specific IgE Abs. Here, we explored which lymphoid organs were responsive to the intranasally injected allergen and how IL-4 and IgE Abs were produced in the lymphocytes. Time-dependent changes in the total cell numbers and in in vitro IgE Ab production in various lymphoid organs revealed that the submandibular lymph nodes were the main responsible organ. After treatment with allergen (for IgE production) or allergen and complete Freund's adjuvant (for IgG production), we separated submandibular lymph node cells into macrophage-, lymphocyte-, and granulocyte-rich populations by discontinuous Percoll density-gradient centrifugation. Unexpectedly, bulk cells, but not the lymphocyte- or macrophage-rich populations, produced significant amounts of IL-4, IgE, and IgG; whereas production was restored by addition of Mac-1(+) cells from the macrophage-rich to the lymphocyte-rich fraction. Furthermore, a combination of the lymphocyte-rich population (for IgG [or IgE]) production) and the macrophage-rich population (for IgE [or IgG]) production) produced a large amount of IgE (or IgG). These results indicate that, in the initiation of allergic rhinitis, macrophages in the submandibular lymph nodes are essential not only for IL-4 or immunoglobulin production, but also for class switching of immunoglobulin in lymphocytes.

Role of cytokines in lavage or drainage fluid after hemithyroidectomy in wound healing: involvement of histamine in the acceleration and delay of wound healing.

Wound healing is a sophisticated biologic process. In the case of hemithyroidectomy, the operation time is relatively short with small tissue damage and without skin excision, and bacterial contamination before, during, and after the operation is uncommon. Here, we explored which cytokine(s) affected the rates of healing of skin wounds after hemithyroidectomy of 29 patients. We assessed the amounts of cytokines (e.g., interleukin-6, platelet-derived growth factor, basic fibroblast growth factor, vascular endothelial growth factor, and tumor necrosis factor-α) in either the preoperative or postoperative lavage fluids, or in the drainage fluids on postoperative days (PODs) 1-8. All of these cytokines showed a similar pattern; after reaching a peak on POD1, the production fell sharply on POD2-8, revealing that wound healing commenced on POD1. The rates of wound healing were inversely related to the levels of histamine in six patients (i.e., those with the three largest and those with the three smallest total volumes of drainage fluid on POD1): high (or low) levels of histamine in the postoperative lavage fluids with low (or high) levels in the drainage fluids on POD1 caused earlier (or the delay of) wound healing, suggesting involvement of histamine in the acceleration and delay of wound healing.

Evaluating the effects of testing period on pollinosis symptoms using an allergen challenge chamber.

BACKGROUND: We previously built a pollen challenge test unit (allergen challenge chamber: ACC) to collect objective data about Japanese cedar pollinosis. In this study, we investigated adequate conditions for pollen challenge using the ACC. METHODS: The study consisted of two parts. The first part was conducted in November, which is not in pollen season. Subjects were exposed to Japanese cedar pollen at a concentration of 50,000 grains/m3 in the chamber for 120 min each day over the course of three consecutive days. The second part was conducted in April, which is just after pollen season. Subjects were exposed to Japanese cedar pollen at the same concentration (50,000 grains/m3) in the chamber for 90 min on a single day. Subjects recorded nasal and ocular symptoms before challenge and every 15 min after challenge initiation. The minimum cross-sectional area in the nasal cavity was measured using acoustic rhinometry before and after challenge as an indicator of nasal obstruction. Inflammatory markers in nasal lavage fluid and serum were also measured before and after challenge. RESULTS: Nasal and ocular symptoms were significantly exacerbated after challenge on all days of the single and 3-consecutive-day challenge tests, particularly on the third day of the consecutive challenge test. Nasal and ocular symptoms were also quickly induced with challenge immediately after the end of pollen season. No significant changes in inflammatory markers were seen. CONCLUSIONS: Care is needed with regard to pollen challenge conditions in the ACC, including timing of the challenge, to induce pollinosis symptoms that accurately reflect chronic inflammation.