Macrocyclic peptides II. Synthesis and structure of a novel dipeptide, (2S,3′S)-2-(2′-oxo-3′-methylpiperazin-1′-yl)-propanoic acid,and its use as the unit of cyclic peptides

A new cyclic compound [(2S,3′S)-2-(2′-oxo-3′-methylpiperazin-1′-yl)-propanoic acid] obtained using (2S,7S)-2,7-dimethyl-3,6-diazaoctanedioic acid as a starting material was derived from N-t-butyloxycarbonyl-(2S,3′S)-2-(2′-oxo-3′-methylpiperazin-1′-yl)-propanoic acid in order to determine the molecular structure by X-ray crystal analysis. Two new macrocyclic peptides were prepared using the above cyclic compound and sarcosine as peptide units.     

Actions of procaterol (OPC-2009), a new β2-adrenoceptor stimulant,on pulmonary resistance,contractions of the soleus muscle,and cardiovascular system of the anaesthetized cat

The β-adrenoceptor stimulant actions of procaterol hydrochloride [5-(1-hydroxy-2-iso-propylaminobutyl)-8-hydroxycarbostyril hydrochloride hemihydrate] were compared with those of isoprenaline, orciprenaline and salbutamol on pulmonary resistance, contractions of the soleus muscle, heart rate and diastolic blood pressure in the anaesthetized cat. All four drugs reduced the 5-HT-induced increase in pulmonary resistance, decreased the tension of incomplete tetanic contractions of the soleus muscle and the diastolic blood pressure, and increased the heart rate in a dose-related manner. The duration of the bronchodilator action of procaterol was far longer than that of orciprenaline or salbutamol while isoprenaline had the shortest duration. Procaterol was about 1·5 times more potent, and orciprenaline and salbutamol about 80 and 10 times less potent than isoprenaline in reducing the 5-HT-induced increase in pulmonary resistance and in decreasing the tension of incomplete tetanic contractions of the soleus muscle. Procaterol, orciprenaline and salbutamol were 3·5, 91·9 and 43·9 times less potent than isoprenaline in increasing the heart rate. Procaterol, orciprenaline and salbutamol were 3·4, 130·2 and 12·9 times less potent than isoprenaline in decreasing the diastolic blood pressure. Calculation of selectivity for bronchial vs cardiac β-adrenoceptors indicates that procaterol and salbutamol have a similar degree of selectivity for β₂-adrenoceptors mediating the bronchodilation, and that orciprenaline was an essentially unselective stimulant. Furthermore, the results support the suggestion that at present it is not possible to separate the bronchodilating and tremor-enhancing properties of β-adrenoceptor stimulants.     

Therapeutic effects of preferential induction of mite-specific T helper 0 clones

The predominance of Th2 cytokine-secreting pattern in allergic asthma has been known as a cause and an accelerating factor, and Th1 suppresses these allergic phenomena, but the role of Th0 clones is obscure. Because Th1/Th2 differentiation has been determined by cytokine environment, we investigated how mite-specific helper T cells stimulated in different cytokine environments actually influenced IgE and IgG4 synthesis, which are known to be regulatory immunoglobulins for allergic response. Th0 clones, which were mainly established in the presence of IL-12, provided a great deal of help for IgG4 and IgG1 synthesis, but did not provide help for IgE synthesis, whereas Th2 clones helped IgE synthesis prominently, and IgG4 and IgG1 synthesis marginally. These characteristics of Th0 clones were also true for Th0 clones obtained from patients who were successfully treated with desensitization therapy. Furthermore, the differences in helper activity between Th0 and Th2 clones were not ascribed solely to soluble factors. These data indicate that IgE and IgG4 synthesis is differentially regulated by antigen-specific T cells, and that conversion or selection from Th2 to Th0 by the addition of IL-12 may exhibit therapeutic effects.     

Immunohistochemistry of collagen types II and X, and enzyme-histochemistry of alkaline phosphatase in the developing condylar cartilage of the fetal mouse mandible

We investigated the immunohistochemical localisation of types II and X collagen as well as the cytochemical localisation of alkaline phosphatase in the developing condylar cartilage of the fetal mouse mandible on d 14–16 of pregnancy. On d 14 of pregnancy, although no immunostaining for types II and X collagen was observed, alkaline phosphatase activity was detected in all cells in the anlage of the future condylar process. On d 15 of pregnancy, immunostaining for both collagen types was simultaneously detected in the primarily formed condylar cartilage. Alkaline phosphatase activity was also detected in chondrocytes at this stage. By d 16 of pregnancy, the hypertrophic cell zone rapidly increased in size. These findings strongly support a periosteal origin for the condylar cartilage of the fetal mouse mandible, and show that progenitor cells for condylar cartilage rapidly or directly differentiate into hypertrophic chondrocytes.     

Return to the Original Work Activity Following the Full-endoscopic Lumbar Surgery under the Local Anesthesia

Transforaminal full-endoscopic spine (TF-FES) surgery is minimally invasive and can be performed under local anesthesia. Thus, it is expected that the patient can return to work (RTW) quickly. However, information in the literature regarding this is sparse. The purpose of this study is to review the timing of RTW after TF-FES surgery. This study involved 50 patients (14 women, 36 men; mean age 44.5 years, age range: 20–65 years) who underwent TF-FES surgery between January 2016 and April 2018. All the patients were active workers. Occupations varied widely (e.g., physician, nurse, helper, clerk, construction worker, chef, and schoolteacher). There were no surgery-related complications. Median time to RTW was 21 days. More than half of the patients could RTW within 21 days. In all, 12 cases (24%) could have RTW within 7 days. Occupations of 12 patients who achieved RTW within 7 days included physician, company owner, and restaurant owner, with 11 in the Light work, 1 was in the Medium work, and none in the Heavy work. All 12 had a quick RTW because their work was Light and they could not take prolonged sick leave. Prompt RTW is possible with TF-FES surgery. The biggest merit of TF-FES surgery is minimal invasiveness to the muscles of the back. Also, it can be performed under local anesthesia. Our findings reveal quicker RTW after surgery, depending on occupational type.     

Peripheral Blood Mononuclear Cells from Women with Recurrent Abortion Exhibit an Aberrant Reaction to Release Cytokines upon the Direct Contact of Human Leukocyte Antigen-G-Expressing Cells

PROBLEM: In search for pathogenesis of recurrent abortion, we examined whether lymphocytes/macrophages from women with recurrent abortion exhibited an aberrant ability to release cytokines upon the direct contact of human leukocyte antigen (HLA)-G. METHOD OF STUDY: The amounts of cytokines released from peripheral blood mononuclear cells (PBMCs) from women with recurrent abortion were compared with those from normal multiparous women or normal nulligravidous women when cocultured with or without HLA-G-expressing target cells. RESULTS: When cocultured with HLA-G-expressing target cells, the amount of interleukin-1β released from PBMCs was increased in recurrent aborters whereas it decreased in both normal multiparous and nulligravidous women. The amount of interleukin-3 released from PBMCs did not differ with or without HLA-G-expressing cells in recurrent aborters, whereas it increased in the presence of HLA-G-expressing cells in normal controls. The amount of tumor necrosis factor-α released from PBMCs was decreased in the presence of HLA-G-expressing cells in both recurrent aborters and normal controls. CONCLUSION: The aberrant reaction of maternal lymphocytes/macrophages in releasing cytokines upon the contact of HLA-G expressed on trophoblasts may impact negatively on trophoblastic growth, which may be pathogenic in recurrent abortion.     

Herbal Medicines, Sairei-to and Tokishakuyaku-san, Differently Modulate the Release of Cytokines from Decidual Versus Peripheral Blood Mononuclear Cells

PROBLEM AND METHOD OF STUDY: We have shown that Tokishakuyaku-san (Toki) and Sairei-to (Sai) enhance T helper-1 (Th1) cytokine release from peripheral blood mononuclear cells (PBMCs): thereby, they could be a therapeutic means in the treatment of autoimmunity related recurrent abortion in which T helper-2 (Th2) polarization is exaggerated, the condition purported to benefit from these herbal medicines. However, an open question is whether these medicines might enhance Th1 cytokine release in decidual tissues and thereby stimulate the killer activity, thus, working counterproductively by accelerating maternal alloimmune reactions toward fetal tissues. To address this, we examined the effects of these medicines on the release of cytokines from decidual mononuclear cells (DMCs) in comparison with PBMCs on the assumption that they might act differently on these cell types. The effects of these medicines were investigated as related to human leukocyte antigen (HLA)-G, a nonclassical HLA class I antigen expressed on trophoblasts and a putative crucial player involved in fetomaternal immune interplay. RESULTS: Regarding Th1 cytokines. Toki marginally increased the release of tumor necrosis factor (TNF)-alpha, but not interferon (IFN)-gamma from DMCs while Sai did not affect the release of both. Both Toki and Sai were without effect in modulating the release of interleukin (IL)-4, a member of Th2 cytokines. Interestingly, the presence of HLA-G reduced the release of Th1 cytokines from DMCs regardless of the addition of Toki, Sai or none. These findings are in sharp contrast with PBMCs on which these medicines seem to act so as to enhance Th1 polarization and attenuate Th2 polarization. CONCLUSION: Differential effects of Toki and Sai on the release of Th1/Th2 cytokines between DMCs and PBMCs may afford the rationale of these medicines in the treatment of autoimmunity-related recurrent abortion.