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RATIONALE: Modulating the low-grade chronic inflammation in chronic obstructive pulmonary disease remains challenging. Clarithromycin (CAM), a macrolide antibiotic, reportedly ameliorates chronic inflammation via mechanisms independent of its antibacterial activity. OBJECTIVES: The aim of this study was to examine whether CAM can prevent or reduce emphysema induced by chronic cigarette smoke exposure. METHODS: Mice were exposed to cigarette smoke daily for 6 months and treated with orally administered CAM at doses of 25 to 100 mg/kg twice a day throughout the course of the experiment to test the preventive effects. The administration of CAM at 50 or 100 mg/kg was performed during the second half of a 6-month exposure period to assess the therapeutic effects. Histologic analysis was performed to evaluate the effect of CAM. MEASUREMENTS AND MAIN RESULTS: CAM treatment for 6 months decreased airspace enlargement and the destruction of the alveolar walls and impaired the accumulation of macrophages in bronchoalveolar lavage fluid in a dose-related fashion. The administration of clarithromycin at 100 mg/kg in the therapeutic protocol reduced emphysema compared with the smoke-exposed group without treatment. An immunohistologic analysis revealed that CAM reduced the number of F4/80-positive macrophages in the lung parenchyma. In an in vitro test, CAM at 5 to 20 microM directly suppressed the activation of macrophages stimulated with tumor necrosis factor-alpha. CONCLUSIONS: Our data demonstrated that CAM at a clinically achievable dose prevented cigarette smoke-induced emphysema by modulating lung inflammation. This study supports the possibility that low-dose CAM treatment might provide a new therapeutic strategy for chronic obstructive pulmonary diseases. [ABSTRACT FROM AUTHOR]

The antigenic determinant of thermally denatured DNA reactive with systemic lupus erythematosus (SLE) sera was examined by hapten inhibition assay. We used oligonucleotides with different chain lengths (2-8) derived from DNase I digests of salmon sperm DNA in Farr's radioimmunoassay with thermally denatured mouse embryo 3H-DNA as antigen, and the effect of dextran sulphate addition to the assay mixture on the inhibitory activity of oligonucleotides was examined, A characteristic oligonucleotide inhibition pattern on DNA binding by SLE sera was observed in the assay system without dextran sulphate. Di- and/or trinucleotide inhibited the binding more effectively than tetra- and/or pentanucleotide. These patterns were also observed in DNA-normal serum interaction. When dextran sulphate was added to the mixture, the inhibition pattern changed; the inhibitory activity of oligonucleotides increased with chain length in both serum groups. The inhibitory potency of di- and trinucleotide was higher on DNA-SLE sera than on DNA normal sera interaction. The high potency of short-chain oligomers in SLE sera is obviously different from that in experimentally elicited anti-DNA sera suggesting that different mechanism(s) are involved In antibody production in normal individuals and SLE patients. [ABSTRACT FROM AUTHOR]

Abstract: The kinetics of the oxidation in hypo-stoichiometric MOX with 30%Pu content was investigated using thermal gravity and differential thermal analysis to evaluate the variation of oxygen-to-metal ratio (O/M) in the fuel fabrication process. In the isothermal oxidation examination, the O/M ratio of the MOX gradually approached 2.00 at temperatures below 200°C. Therefore it was considered that the oxidation reaction below 200°C proceeded by increasing the amount of fcc phase with O/M=2.00. Finally, the oxidation rate of hypo-stoichiometric MOX was evaluated, and the effective oxygen chemical diffusion coefficient was estimated. [Copyright &y& Elsevier]

Background: More than 30 years have passed since the Japanese government announced its International Student 100,000 Plan in 1983. Today, the number of international students in the country exceeds 300,000. This study examines the relationship between factors affecting the mental health of international students and their satisfaction with having studied abroad in Japan., Methods: An online-questionnaire was given to 82 former Japanese government scholarship students who studied in Japan in the 1980s. The survey consisted of items related to the basic personal attributes of the participants, their lives in Japan during their period of study (20 items), their satisfaction level at having studied in Japan (10 items), and their current happiness level (4 items)., Results: A significant relationship was observed between the level of satisfaction at having studied in Japan and a number of the statements relating to respondents' lives in Japan as students, including: "I felt that the differences between Japan and my home country were interesting, and enjoyed these differences," and "Whenever I encountered a difficult situation, I attempted to find different approaches to deal with the problem." A similar relationship was also observed between these statements and subjective happiness., Conclusions: International students who were able to accept the differences and difficulties they confronted positively and respond to situations flexibly tended to report higher levels of satisfaction with their studies in Japan and higher levels of happiness, suggesting that individual psychological factors, such as situation perception and associated coping behaviors, have a defining impact on mental health.

Background: Studies of alexithymia have primarily targeted adult populations. Although some recent studies of alexithymia have focused on children and young adolescents, the literature is not sufficient for development of an assessment tool. The aim of this study was to develop, and evaluate the psychometric properties of, a new scale to measure alexithymia-like features in young adolescents., Methods: A total of 1,444 Japanese junior high school students (701 males, 743 females; age range 12-15; mean [SD] age, 13.37 [0.98] years) participated in 2 surveys conducted at their own schools., Results: First, exploratory factor analysis of the first survey data (n=981) demonstrated that this new scale had a unifactor structure, as determined by minimum average partial analysis and parallel analysis. Second, confirmatory factor analysis of the second survey data (n=463) confirmed the unifactor structure of this new scale and acceptable goodness of model fit. The new scale had modest internal consistency., Conclusions: The correlations of this new alexithymia scale with related variables were weak but significant, in accordance with our hypothesis. The scale had acceptable reliability and convergent validity and thus might be useful for measuring alexithymic tendency in young adolescents.

This study investigated the feasibility of a cognitive behavioral therapy (CBT) program for improving mood and quality of life in an older woman with mild cognitive impairment (MCI), depression, and anxiety. The program comprised eight 30-minute weekly sessions; interventions included behavioral activation, relaxation, and cognitive reconstruction, in which the patient's caregiver also participated. The patient's condition was assessed before and immediately after the intervention. After 3 and 12 months, the caregiver reported the patient's behavioral and psychological symptoms by using self-reported psychological scales for depression, anxiety, and quality of life. Although CBT helped to improve mood and quality of life in the short term (3 months), the results were not sustained over the long term (12 months). Even though improvement in psychological symptoms did not persist and only one patient with MCI was evaluated, these results suggest that CBT is a feasible nonpharmacological treatment option and provide preliminary support for wider use of CBT in Japan. CBT programs should be tailored to the needs of patients with MCI and dementia, and regular follow-up sessions should be used to evaluate program feasibility and improvement in patient mental health.

A 70-year-old man visited our emergency department, whose laboratory test results revealed leucocytosis, anaemia, thrombocytopenia and high levels of serum lactate dehydrogenase. In addition, the peripheral blood smear revealed neutrophilic granulocytes with nuclear hypolobation (pseudo-Pelger-Hüet anomaly), hypogranulation and no myeloperoxidase reactivity. Genetic testing of the peripheral blood sample was as follows: G-band, 46XY,t(9;22)(q34;q11.2) (20/20); fluorescence in situ hybridisation BCR/ABL fusion signal, 97%; and analysis of exons 5-9 of the p53 gene, mutation (Pro72Arg) in exon 4 protein. On the basis of these findings, the patient was diagnosed with chronic myelogenous leukaemia (CML) in chronic phase with a p53 mutation and treated with hydroxyurea, dasatinib and nilotinib. Neutrophilic granulocytes with the anomalies were no longer observed after achieving cytogenetic remission. To the best of our knowledge, this is the first report of CML case with the anomalies, in which a p53 mutation without chromosome 17 abnormalities was identified., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

It is predicted that in the near future robot simulated patients (SPs) will come into use. Through the impressions of five SPs about robot SPs, we explored their vision of the future of medical education as an indicator of what ordinary citizens think. The opinions of SPs were collected using a semi-structured focus group interview, after which the perspectives provided were explored using a qualitative research method called Steps for Coding and Theorization (SCAT). Although SPs accepted the introduction of robot SPs, they regard them as potential substitutes. The use of robot SPs raised concerns about the level of response to human diversity and the level of emotional intelligence. The problem of how much diversity among patients and doctors is acceptable in the field of education was identified. On the part of citizens, there is not much expectation that artificial intelligence (AI) will lead to sophisticated machines capable of human conversation. However, looking ahead to the AI era, real SPs anticipate that, along with the evolution of AI, the next generation of SPs will have thought deeply about their role within a program employing both humans and robots.

Glycosphingolipids (GSLs) are abundant in plasma membranes of mammalian cells, and their synthesis is strictly regulated in the Golgi apparatus. Disruption of GSL homeostasis is the cause of numerous diseases. Hundreds of molecular species of GSLs exist, and the detailed mechanisms underlying their homeostasis remain unclear. We investigated the physiological significance of isoform production for β1,4-N-acetyl-galactosaminyl transferase 1/B4GALNT1 (B4GN1), an enzyme involved in synthesis of ganglio-series GSLs GM2/GD2/GA2. We discovered a new mRNA variant (termed variant 2) of B4GN1 through EST clone search. A new isoform, M1-B4GN1, which has an NH 2 -terminal cytoplasmic tail longer than that of previously-known isoform M2-B4GN1, is translated from variant 2. M1-B4GN1 has R-based motif (a retrograde transport signal) in the cytoplasmic tail. M1-B4GN1 is partially localized in the endoplasmic reticulum (ER) depending on the R-based motif, whereas M2-B4GN1 is localized in the Golgi. Stability of M1-B4GN1 is higher than that of M2-B4GN1 because of the R-based motif. M2-B4GN1 forms a homodimer via disulfide bonding. When M1-B4GN1 and M2-B4GN1 were co-expressed in CHO-K1 cells, the two isoforms formed a heterodimer. The M1/M2-B4GN1 heterodimer was more stable than the M2-B4GN1 homodimer, but the heterodimer was not transported from the Golgi to the ER. Our findings indicate that stabilization of M1-B4GN1 homodimer and M1/M2-B4GN1 heterodimer by R-based motif is related to prolongation of Golgi retention, but not to retrograde transport from the Golgi to the ER. Coexistence of several B4GN1 isoforms having distinctive characteristics presumably helps maintain overall enzyme stability and GSL homeostasis., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Epidemiological studies suggest that hyponutrition during the fetal period increases the risk of mental disorders such as attention deficit hyperactivity disorder and autism-spectrum disorder, which has been experimentally supported using animal models. However, previous experimental hyponutrition or protein-restricted (PR) diets affected stages other than the fetal stage, such as formation of the egg before insemination, milk composition during lactation, and maternal nursing behavior., Results: We conducted in vitro fertilization and embryo transfer in mice and allowed PR diet and folic acid-supplemented PR diet to affect only fetal environments. Comprehensive phenotyping of PR and control-diet progenies showed moderate differences in fear/anxiety-like, novelty-seeking, and prosocial behaviors, irrespective of folic-acid supplementation. Changes were also detected in gene expression and genomic methylation in the brain., Conclusions: These results suggest that epigenetic factors in the embryo/fetus influence behavioral and epigenetic phenotypes of progenies. Significant epigenetic alterations in the brains of the progenies induced by the maternal-protein restriction were observed in the present study. To our knowledge, this is first study to evaluate the effect of maternal hyponutrition on behavioral phenotypes using reproductive technology.

Aims: This study investigated the efficacy of structured writing on reducing self-harm ideations and enhancing emotion regulation., Methods: Japanese university students (N=22) participated in the study. Participants were randomly assigned to the structured writing group (n=10; 70% female), or an assessment only control group (n=12; 67% female). For three consecutive days, participants in the intervention group performed structured writing that included psycho-education and self-reflection about emotions. The Self-Harm Ideation Scale, the Generalized Expectancy for Negative Mood Regulation Scale, and the Acceptance and Action Questionnaire-II were used to assess outcomes., Results: Structured writing had a short-term effect on expectancies for self-regulation of negative moods and acceptance of negative emotions, but had a limited effect on self-harm ideations., Conclusion: This study presents preliminary evidence that increasing awareness, learning, and reflection about emotions resulting from using a structured writing program is particularly useful for regulating emotions. J. Med. Invest. 64: 74-78, February, 2017.

In the Golgi maturation model, the Golgi cisternae dynamically mature along a secretory pathway. In this dynamic process, glycosyltransferases are transported from the endoplasmic reticulum (ER) to the Golgi apparatus where they remain and function. The precise mechanism behind this maturation process remains unclear. We investigated two glycosyltransferases, ST3Gal5 (ST3G5) and B4GalNAcT1 (B4GN1), involved in ganglioside synthesis and examined their signal sequences for ER export and Golgi retention. Reports have suggested that the [R/K](X)[R/K] motif functions as an ER exporting signal; however, this signal sequence is insufficient in stably expressed, full-length ST3G5. Through further analysis, we have clarified that the (2)R(3)R(X)(5) (9)K(X)(3) (13)K sequence in ST3G5 is essential for ER export. We have named the sequence the R/K-based motif. On the other hand, for ER export of B4GN1, the homodimer formation in addition to the R/K-based motif is required for ER export suggesting the importance of unidentified lumenal side interaction. We found that ST3G5 R2A/R3A and K9A/K13A mutants localized not only in Golgi apparatus but also in endosomes. Furthermore, the amounts of mature type asparagine-linked (N)-glycans in ST3G5 R2A/R3A and K9A/K13A mutants were decreased compared with those in wild-type proteins, and the stability of the mutants was lower. These results suggest that the R/K-based motif is necessary for the Golgi retention of ST3G5 and that the retention is involved in the maturation of N-glycans and in stability. Thus, several basic amino acids located on the cytoplasmic tail of ST3G5 play important roles in both ER export and Golgi retention., (© The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Sirh7/Ldoc1 [sushi-ichi retrotransposon homolog 7/leucine zipper, downregulated in cancer 1, also called mammalian retrotransposon-derived 7 (Mart7)] is one of the newly acquired genes from LTR retrotransposons in eutherian mammals. Interestingly, Sirh7/Ldoc1 knockout (KO) mice exhibited abnormal placental cell differentiation/maturation, leading to an overproduction of placental progesterone (P4) and placental lactogen 1 (PL1) from trophoblast giant cells (TGCs). The placenta is an organ that is essential for mammalian viviparity and plays a major endocrinological role during pregnancy in addition to providing nutrients and oxygen to the fetus. P4 is an essential hormone in the preparation and maintenance of pregnancy and the determination of the timing of parturition in mammals; however, the biological significance of placental P4 in rodents is not properly recognized. Here, we demonstrate that mouse placentas do produce P4 in mid-gestation, coincident with a temporal reduction in ovarian P4, suggesting that it plays a role in the protection of the conceptuses specifically in this period. Pregnant Sirh7/Ldoc1 knockout females also displayed delayed parturition associated with a low pup weaning rate. All these results suggest that Sirh7/Ldoc1 has undergone positive selection during eutherian evolution as a eutherian-specific acquired gene because it impacts reproductive fitness via the regulation of placental endocrine function., (© 2014. Published by The Company of Biologists Ltd.)

International accreditation of medical education was introduced in Japan in 2013 and is planning to be applied in late 2014 or 2015. Students will need to cope with the resulting changes and to recognize by what route they will learn medicine. Therefore, a freshman orientation course, which was based on problem-based learning (PBL) and had been held for first-year students, was modified as an awareness reform program in which students would learn "how to learn medicine." We investigated whether this program has led to useful changes in students' recognition of the way of learning in medical school and their directions as learners. The program was held for 114 first-year medical school students in 2013 and consisted of PBL tutorials, large-classroom lectures, simulation learning using role-play with simulated patients, and team-based learning (TBL), presented in this order. Learning modules that is made with an integration of the clinical sciences with the basic biomedical and the behavioral and social sciences were provided. A nonanonymous questionnaire survey asking" what learning methods are effective for you?" was conducted before and after completion of the course. Furthermore, group answers obtained in TBL were investigated. The score for the question" To what extent can you imagine your route of learning during your 6 years?" significantly increased from 3.1±0.99 (mean±SD) before the course to 3.5±0.88 (p<0.01) after the course. The score for the question" To what extent is the small-group learning, such as PBL, useful for you?" significantly increased from 3.9±0.73 to 4.2±0.71 (p<0.05). Group responses in TBL sessions indicated that students desired classes that presented tasks and regarded" emphasis on reflection" and" observation of senior physicians as role models" as the most important methods for learning interview skills. We believe students should acquire active learning attitudes as adults early in their 6 years of medical school. The level of understanding of" how to learn as adults" was 3.7 and indicated a moderate result. This course employed many educational strategies, and we believe it helped students understand what they learn and how to learn during their 6 years of medical and to get an overview of the learning roadmap.

Background: Subthreshold depression is highly prevalent in the general population and causes great loss to society especially in the form of reduced productivity while at work (presenteeism). We developed a highly-structured manualized eight-session cognitive-behavioral program with a focus on subthreshold depression in the workplace and to be administered via telephone by trained psychotherapists (tCBT)., Methods: We conducted a parallel-group, non-blinded randomized controlled trial of tCBT in addition to the pre-existing Employee Assistance Program (EAP) versus EAP alone among workers with subthreshold depression at a large manufacturing company in Japan. The primary outcomes were depression severity as measured with Beck Depression Inventory-II (BDI-II) and presenteeism as measured with World Health Organization Health and Work Productivity Questionnaire (HPQ). In the course of the trial the follow-up period was shortened in order to increase acceptability of the study., Results: The planned sample size was 108 per arm but the trial was stopped early due to low accrual. Altogether 118 subjects were randomized to tCBT+EAP (n = 58) and to EAP alone (n = 60). The BDI-II scores fell from the mean of 17.3 at baseline to 11.0 in the intervention group and to 15.7 in the control group after 4 months (p<0.001, Effect size = 0.69, 95%CI: 0.32 to 1.05). However, there was no statistically significant decrease in absolute and relative presenteeism (p = 0.44, ES = 0.15, -0.21 to 0.52, and p = 0.50, ES = 0.02, -0.34 to 0.39, respectively)., Conclusion: Remote CBT, including tCBT, may provide easy access to quality-assured effective psychotherapy for people in the work force who present with subthreshold depression. Further studies are needed to evaluate the effectiveness of this approach in longer terms. The study was funded by Sekisui Chemicals Co. Ltd., Trial Registration: ClinicalTrials.gov NCT00885014.

The objectives of the present study were to evaluate whether a schedule-dependent pharmacokinetic and/or pharmacodynamic interaction exists between two sequences of docetaxel and doxorubicin administration and to determine the maximal tolerated dose (MTD) of this combination. Patients with chemotherapy-naïve metastatic or recurrent advanced breast cancer were enrolled. In the crossover design, tandem dose escalation of docetaxel and doxorubicin was performed. Docetaxel, in doses ranging from 50-70 mg/m2, was administered for 1 h by drip infusion either just before or after a 5-min bolus i.v. injection of doxorubicin at dosages from 40-50 mg/ m2. The sequence of drug administration was switched after the first course in each patient, and the sequence of drug administration thereafter depended on the patient's choice. Twenty-five patients were initially assessable for toxicity. The MTD in the sequence of doxorubicin after docetaxel was 40 and 50 mg/m2, respectively, with the dose-limiting toxicity of neutropenia. On the other hand, the MTD of the sequence of docetaxel after doxorubicin was 70 and 50 mg/m2, respectively. The dose-limiting toxicities in this sequence were neutropenia and diarrhea. Duration of grade 4 neutropenia in the sequence of docetaxel followed by doxorubicin was significantly longer than that in the alternate sequence (P = 0.0062). However, there was no difference in pharmacokinetic parameters of docetaxel, doxorubicin, and doxorubicinol between the two sequences. The sequence of 50 mg/m2 doxorubicin followed by 60 mg/m2 docetaxel is recommended for subsequent clinical trials for practical reasons.

To explore the pathogenesis in placental dysfunction and abruptio placentae, we analyzed the occurrence of placental cell apoptosis and the role of Fas and Fas ligand (L) in that process in an inflammatory placental dysfunction model of pregnant mice, using lipopolysaccharides (LPS). In the present study, Day 13 pregnant mice were injected i.p. with LPS (50 microg/kg) or saline as a control, and the placentas were isolated at various time points after the injection. Analysis of the isolated DNA in agarose-gel electrophoresis revealed a typical ladder pattern of bands consisting of 180-200 base pairs (bp), which is regarded as a hallmark of apoptosis. The intensity of the bands increased time-dependently, reaching a maximum level at 12 h after LPS injection. In accord with the biochemical data, histochemical analysis using terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) revealed that nuclei positive for double-stranded DNA breaks were found in decidua, diploid trophoblasts in the basal zone, and spongiotrophoblasts. The number of positive nuclei was maximized at 12 h after LPS injection. As a next step, we investigated the possible involvement of Fas and Fas L in the induction of apoptosis of the placental cells after LPS injection. Western blot analysis indicated that LPS increased the expression of Fas and Fas L in the placenta by about 4-fold at 12 h and 18 h, respectively, after injection. The cells expressing Fas and Fas L were identified, using immunohistochemistry and nonradioactive in situ hybridization, as decidua, diploid trophoblasts in the basal zone, and spongiotrophoblasts. Furthermore, when the expression of 4-hydroxy-2-nonenal (HNE)-modified proteins was assessed to evaluate the relation of oxidative stress elicited by LPS to the induction of apoptosis, once again decidua, diploid trophoblasts in the basal zone, and spongiotrophoblasts were positive. Therefore, the placental dysfunction by LPS may be brought about by the Fas-mediated apoptosis of various placental cells in a paracrine/autocrine fashion, possibly under the influence of oxidative stress.

We describe 3 patients with acute myeloblastic leukemia (AML), who received rhG-CSF for infections such as pneumonia or for prophylaxis of infection, and who achieved complete remission. They had not received any antileukemic therapy before or during the administration of rhG-CSF. These findings suggest the possibility that complete remission can be brought about by G-CSF itself in some patients with AML.

Pregnancy in a woman with active acromegaly is very rare, because amenorrhea, due to hyperprolactinemia and disturbed pituitary gonadotropin secretion may cause infertility. We report a 28-year-old pregnant woman with untreated acromegaly, who was followed up from early pregnancy to delivery. Her pregnancy was uneventful, and she went into spontaneous labor at 38 weeks and delivered a normal infant. Her serum GH levels were further increased in late pregnancy, followed by decreased in postpartum periods, which may be associated with enlargement of pituitary adenoma during pregnancy. In contrast with serum GH, her serum insulin-like growth factor-1 (IGF-1) levels were dissociated with her serum GH levels during late pregnant and postpartum period. Her serum GH and IGF-1 levels in late pregnancy were different from the levels in pregnant women with acromegaly reported previously.

Adriamycin (ADR) has been considered to target mainly DNA metabolism in the nucleus. Recently, we observed the nuclear translocation of heat shock protein 70 (HSP70) after ADR treatment. We examined which intranuclear changes might be related to this alteration of HSP70 localization. We found considerable alternations in the nucleolar morphology and function in ADR-treated tumor cells, i.e., a ring-shaped segregation of granular components of almost all nucleoli and a dramatic reduction of nucleolar 45S ribosomal precursor RNA biosynthesis in HeLa cells exposed to 100 microM ADR for 2 h. Concomitantly with these changes, HSP70 was concentrated into the nucleoli, as in the case of heat shock treatment. These results indicate a novel anticancer effect of ADR via the suppression of cellular protein biosynthesis, in addition to its effect on DNA.

We describe a patient who has a chronic polyclonal B lymphocyte proliferation with a hairy-cell appearance. A 48-year-old Japanese woman with marked splenomegaly, systemic lymphadenopathy, and leukocytosis was referred to out hospital. Laboratory examination revealed marked polyclonal IgG hypergammaglobulinemia. Morphologic examination of the patient's peripheral blood, including May-Giemsa staining and scanning electron microscopy, showed a monotonous proliferation of hairy-appearing mature lymphocytes. An immunophenotypic study revealed an expansion of cells with mature B cell antigens positive for CD11c; however, light-chain restriction was not seen. The lack of both immuno-globulin heavy-chain and T cell receptor gene rearrangements by Southern blot analysis indicated the polyclonal nature of the proliferating B cells. This was confirmed further by a clonal analysis of the patient's lymphocytes using an X-chromosome-linked restriction fragment polymorphism within the X-linked phosphoglycerate kinase (PGK) gene. Since chronic B cell lymphoproliferation with a hairy cell appearance has not been described previously, this case might be extremely rare, and has important implication for the pathogenesis of mature B cell lymphoproliferative diseases, including hairy cell leukemia.

In order to develop new-generation macrolide antibiotics active against erythromycin (EM)-resistant strains, a series of 6-O-methyl EM 9-O-substituted oxime derivatives was synthesized and evaluated for antibacterial activity against EM-resistant (S. aureus J-109) and susceptible (S. aureus 209P) strains. To understand how substituents affect the biological activity, the quantitative structure-activity relationships (QSAR) was analyzed using the Hansch-Fujita method. With the EM-resistant strain, the positive coefficient for log P may indicate that higher hydrophobicity of molecules is favorable for antibacterial activity. The negative coefficients of the Sterimol parameters L, B1, and B5 may indicate that long, bulky substituents are unfavorable. With the EM-susceptible strain, the negative coefficient for log P may indicate that hydrophilicity is important for antibacterial activity. A short substituent is also required to improve the activity. Based on the QSAR model, a derivative (87) having an anthracenylmethyl moiety was synthesized to reinforce and confirm the correlation. The activity of 87 against the EM-resistant strain was significant. In QSARs of 6-O-methyl EM-A 9-O-substituted oxime derivatives, the difference of the contribution of log P to the antibacterial activity between EM-resistant and susceptible strains was clearly recognized.

We describe siblings with the non-salt-losing form of 21-hydroxylase deficiency who had hypersecretion of aldosterone and plasma renin activity (PRA). Blood pressure and serum electrolytes in both cases were normal despite the aldosterone hypersecretion. Aldosterone secretion was elevated markedly with ACTH administration and with sodium deprivation and/or volume depletion during ACTH suppression by dexamethasone. With suppression by dexamethasone, aldosterone hypersecretion was decreased with lowering of the steroids proximal to the block in the biosynthetic pathway. However, urinary sodium excretion was decreased. These results suggest that the biosynthetic pathway for aldosterone production was preserved. Furthermore, aldosterone hypersecretion and high PRA may serve to compensate for the sodium loss which results in turn from the overproduction of the sodium-losing steroids, such as progesterone and 17 alpha-hydroxyprogesterone which are aldosterone antagonists.

A new method for differentiation of specific DNA-binding by human sera from non-specific binding was evaluated with sera from patients with systemic lupus erythematosus in different stages of the disease. An addition of dextran sulfate or calcium chloride to Farr's radioimmunoassay mixture reduced non-specific binding of thermally denatured [3H]DNA of the patient sera without much effect on the specific binding. The measurement of DNA-binding value by the sera in these addition systems provides accurate information with regard to the pathophysiological state of the disease.

The antigenic determinant of thermally denatured DNA reactive with systemic lupus erythematosus (SLE) sera was examined by hapten inhibition assay. We used oligonucleotides with different chain lengths (2-8) derived from DNase I digests of salmon sperm DNA in Farr's radioimmunoassay with thermally denatured mouse embryo 3H-DNA as antigen, and the effect of dextran sulphate addition to the assay mixture on the inhibitory activity of oligonucleotides was examined. A characteristic oligonucleotide inhibition pattern on DNA binding by SLE sera was observed in the assay system without dextran sulphate. Di-and/or trinucleotide inhibited the binding more effectively than tetra-and/or pentanucleotide. These patterns were also observed in DNA-normal serum interaction. When dextran sulphate was added to the mixture, the inhibition pattern changed; the inhibitory activity of oligonucleotides increased with chain length in both serum groups. The inhibitory potency of di- and trinucleotide was higher on DNA-SLE sera than on DNA-normal sera interaction. The high potency of short-chain oligomers in SLE sera is obviously different from that in experimentally elicited anti-DNA sera suggesting that different mechanism(s) are involved in antibody production in normal individuals and SLE patients.

A non-specific DNA binding by human sera was measured in 60 male and female healthy subjects in different ages. Farr assay using thermally denatured mouse embryo [3H]DNA proved a high DNA binding level of 47.9 +/- 5.8% (mean +/- S.D.) on an average of these sera. The addition of dextran sulfate and CaCl2 significantly decreased the mean binding value to 14.7 +/- 4.8% and 6.5 +/- 3.2%, respectively. No significant difference was observed between men and women, or between any age groups from twenties to sixties. The measurement of complement activity in the serum gave no evidence for the participation of complement in the non-specific DNA binding.

Spleens of normal structure were obtained in surgery on nine patients with gastric cancer. The freeze-cracked surfaces of the organ as well as the vascular casts of methacrylate resin were examined by scanning electron microscopy. Penicillar arteries were confirmed to terminate in the cords of Billroth, representing the open circulation. Labyrinthine channels of arterial capillaries were found in restricted regions in the red pulp neighboring pulp arteries and veins. They characteristically possessed in their lumen spanning trabecullae covered with endothelial cells. In some places, the flat endothelium of a channel continued to the lattice-like endothelium of a thin sinus, representing closed circulation. The occurrence and distribution of the arteriolar labyrinths were confirmed by SEM observation of the vascular casts. Their continuation to the thin sinuses was also demonstrated in the casts. The present study evidences that in the human spleen, specialized arteriolar terminals provide a closed circulation route in restricted regions, besides the hitherto known, predominant route of open circulation.