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Background: The safety and efficacy of an oral anticoagulant (OAC) treatment and the difference between direct OACs (DOACs) and warfarin in nonsevere frail elderly patients with AF are unclear., Methods: This was a retrospective and observational study of 354 patients over 80 years of age with nonsevere frailty who were diagnosed with AF and treated with OACs. Nonsevere frailty was defined as a clinical frailty scale score of <7. Bleeding and thromboembolic events during the OAC treatment were followed up., Results: Of 354 patients enrolled, 273 (77.1%) received DOACs and 81 (22.9%) received warfarin. Of 273 patients receiving DOACs, there were 210 (76.9%) prescribed with appropriate doses of DOACs. Of 81 warfarin-treated patients, 53 (65.4%) were prescribed an appropriate dose of warfarin. During a follow-up of 33.1 (14.0-51.0) months, 15 patients (1.5/100 person-years) had bleeding events and 10 (1.0/100 person-years) had thromboembolic events while on an OAC treatment. The incidence ratio of bleeding events in patients receiving DOACs was lower than that in those receiving warfarin (1.0/100 person-years vs 2.9/100 person-years, hazard ratio [HR]: 0.26, 95% confidence interval [CI]: 0.07-0.91, P  = .036). There was no significant difference in the incidence of thromboembolic events between the DOAC and warfarin treatment groups (0.88/100 person-years vs 1.4/100 person-years, HR: 0.63, 95% CI: 0.16-2.57, P  = .52)., Conclusions: OACs are substantially safe and effective for preventing thromboembolic events in nonsevere frail patients over 80 years of age. Particularly, DOACs can be used more safely than warfarin., Competing Interests: TI has received grant support through his institution from Daiichi Sankyo and Bayer Healthcare and honoraria for lectures from Bayer Healthcare, Bristol‐Myers Squibb, Pfizer, Daiichi Sankyo, and Ono Pharmaceutical. Regarding this study, all authors declare that there are no potential conflicts of interest., (© 2019 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Heart Rhythm Society.)

Background: Pilsicainide, a pure Na + channel blocker, is a popular antiarrhythmic drug for the management of atrial tachyarrhythmias (AT), in Japan. However, serious drug-induced proarrhythmias (DIPs) may unexpectedly occur. We assessed the clinical background of AT patients presenting with DIPs caused by pilsicainide., Methods: This study retrospectively enrolled 874 consecutive patients (543 men, 63.6±15.3 years old, and 57.9±16.5 kg of body weight), who were orally administered pilsicainide for AT management. We evaluated the relationship between DIPs and serum pilsicainide concentration, renal dysfunction (estimate glomerular filtration rate, eGFR), and electrocardiogram (ECG) parameters., Results: Among the patients, 154 (17.6%) had renal dysfunction (eGFR<50 mL/min), including 12 (1.4%) on hemodialysis. DIPs were present in 10 patients (1.1%): all had renal dysfunction, and one was on hemodialysis. The eGFR in DIP patients was significantly lower than that in the non-DIP patients (32.2±15.1 vs. 68.4±22.1 mL/min, p <0.001). Among the clinical factors measured, only renal dysfunction (eGFR<50 mL/min) was significantly associated with DIPs (OR 44.6; 95% CI 5.61-335.0, p <0.001). Interestingly, among the ECG parameters, the corrected QT (QTc) intervals in DIP patients were longer than those in non-DIP patients (555.8±37.6 vs. 430.7±32.6 ms, p <0.001). As pilsicainide concentration increased, both QRS and QTc intervals prolonged. The latter were improved by discontinuing pilsicainide administration, and additional treatments., Conclusions: DIPs caused by pilsicainide administration were strongly associated with renal dysfunction. Hence, confirmation of renal function would be necessary prior to and/or during the pilsicainide administration.

The potential applications of non-proteinogenic amino acids have increased continuously since the introduction of these molecules into a ribosomal translation system. An increasing number of studies concerning topics, such as the addition of an artificial function to a protein, cellular expression of a protein with an artificial residue, and development of an artificial peptide with a novel function, have been done using these molecules. Here, we describe recent studies that elucidate the compatibility of non-proteinogenic amino acids with ribosomal translation. We also describe the development of a simple and high-speed selection method and its potential application for the creation of a novel functional peptide with non-proteinogenic amino acids. As these studies have expanded the diversity of the artificial peptide library and increased the speed of novel functional peptide selection, they will significantly facilitate the development of new molecules, such as pharmaceutical drug candidates and bioassay probes., (© 2016 The Chemical Society of Japan & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Click chemistry has provided us with access to DNA and RNA analogues with non-natural triazole internucleoside linkages. The bond periodicity of the oligonucleotides was designed to enforce duplex formation with natural congeners, and the non-cleavable linkages protect the oligomers against nuclease digestion. This account reviews the progress of the triazole-linked analogues over the past five years. Reinforced by their synthetic robustness, these analogues may find various utilities as tools for exploratory research.

Effects of the prostanoids on the growth of cultured aortic vascular smooth muscle cells (VSMCs) were examined using mice lacking prostanoid receptors. Proliferation of VSMCs was assessed by measuring [(3)H]-thymidine incorporation and the cell number, and their hypertrophy by [(14)C]-leucine incorporation and protein content. In VSMCs from wild-type mice, expressions of mRNAs for the EP(4) and TP were most abundant, followed by those for the IP, EP(3) and FP, when examined by competitive reverse transcriptase-PCR. Those for the EP(1), EP(2) and DP, however, could not be detected. AE1-329, an EP(4) agonist, and cicaprost, an IP agonist, inhibited platelet derived growth factor (PDGF)-induced proliferation of VSMCs from wild-type mice; these inhibitory effects disappeared completely in VSMCs from EP(4)(-/-) and IP(-/-) mice, respectively. In accordance with these effects, AE1-329 and cicaprost stimulated cAMP production in VSMCs from wild-type mice, which were absent in VSMCs from EP(4)(-/-) and IP(-/-) mice, respectively. Effects of PGE(2) on cell proliferation and adenylate cyclase were almost similar with those of AE1-329 in VSMCs from wild-type mice, which disappeared in VSMCs from EP(4)(-/-) mice. PGD(2) inhibited PDGF-induced proliferation of VSMCs from both wild-type and DP(-/-) mice to a similar extent. This action of PGD(2) was also observed in VSMCs from EP4(-/-) and IP(-/-) mice. In VSMCs from wild-type mice, I-BOP, a TP agonist, showed potentiation of PDGF-induced hypertrophy. I-BOP failed to show this action in VSMCs from TP(-/-) mice. The specific agonists for the EP(1), EP(2) or EP(3), and PGF(2)alpha showed little effect on the growth of VSMCs. These results show that PGE(2), PGI(2) and TXA(2) modulate PDGF-induced proliferation or hypertrophy of VSMCs via the EP(4), IP and TP, respectively, and that the inhibitory effect of PGD(2) on PDGF-induced proliferation is not mediated by the DP, EP(4) or IP.

Background: The prognostic factors of adult granulosa cell tumor (AGCT) have not been well defined., Methods: In 27 AGCT patients, we examined clinical stage, microscopic patterns, mitotic index (MI), and lymph-vascular space invasion (LVSI) to determine whether these factors were related to disease-free survival (DFS) of patients with AGCT. We also performed immunohistochemical examination for p53., Results: Seventeen cases represented stage I tumors, four stage II, five stage III, and one stage IV. Patients with stage I disease had more favorable prognosis than those with stage II to IV disease (p=0.034). There was no relation between the microscopic patterns and the DFS. The MI, which was categorized into < or =3/10 high power field (HPF) and > or =4/10 HPF, was significantly related to patients DFS (p<0.0005). The DFS time for patients with moderate or prominent LVSI was significantly shorter than that for patients with no or minimal LVSI (p<0.0001). By multivariate analysis, MI and LVSI were shown to be independent prognostic factors. Five of seven patients with recurrent tumor had extrapelvic spread; two in the abdominal cavity and three in the liver., Conclusion: The results of this study suggest that prognosis for patients with AGCT depends on the MI and LVSI. During the follow-up period of patients, they need to be examined for distant metastasis including liver.

Background: Noncancerous cells simulating adenocarcinoma cells may interfere with the analysis of peritoneal cytology (PC) in patients with endometrial carcinoma. Immunocytochemistry (ICC) may improve the diagnosis of PC., Methods: PC slides from 115 patients with endometrial carcinoma were reviewed. Suspicious or positive cell clusters were recovered with a cell transfer method and were subjected to ICC for MOC-31, cytokeratin 5/6, and p53. Conventional Papanicolaou staining and ICC results were compared directly on the same cells., Results: By combined conventional and immunocytochemical PC (CONV-ICC-PC), cytodiagnosis was positive in 18 of 115 patients (15.7%) and suspicious in 3 of 115 patients (2.6%). According to a multivariate Cox regression analysis of patients with tumors confined to the uterus that included grade, myometrial invasion, cervical involvement, and CONV-ICC-PC, only CONV-ICC-PC was an independent prognostic factor (P < 0.05). A multivariate analysis for all of the patients studied that compared CONV-ICC-PC with staging variables revealed that only peritoneal metastasis (P < 0.0001) and lymph node metastasis (P < 0.01) were independent prognostic factors. When peritoneal metastases were excluded, CONV-ICC-PC (P < 0.01) and lymph node metastasis (P < 0.0025) were the independent prognostic factors. By cell transfer and p53 immunostaining in samples from 14 patients with malignant cells in their peritoneal washings, no deaths occurred among 5 patients with negative p53, whereas 5 of 9 patients with positive p53 died of disease at the time of data analysis., Conclusions: MOC-31 immunostaining improves the diagnosis of PC in endometrial carcinoma. Positive PC is an important prognostic factor for patients with endometrial carcinoma confined to the uterus. The p53 positive cells in PC have possible prognostic significance.

Background: Leptin might affect bone metabolism. This study was performed to investigate the relationship of leptin to bone metabolism in detail in premenopausal and postmenopausal healthy women., Methods: The relationships between serum leptin level and bone mineral density of several regional sites of the body as well as whole body, along with bone metabolic markers, were examined in 47 premenopausal and 29 postmenopausal healthy women., Results: Serum leptin level was weakly correlated with bone mineral density of pelvis (Pearson's correlation coefficient r=0.39, p<0.05) and left leg (r=0.41, p<0.01) in the premenopausal women, although the correlation decreased after adjustment for BMI. There was no significant relationship between serum leptin level and whole body bone mineral density both in the premenopausal and postmenopausal women. Serum leptin level was correlated with serum alkaline phosphatase (r=0.56, p<0.001) and urinary deoxypyridinoline/cr (r=-0.32, p<0.05) by Pearson's correlation test in the premenopausal women; the relationships were maintained even after adjustment for BMI (r=0.50 and -0.48, respectively)., Conclusions: Leptin is not a key regulator of bone metabolism, although it may have some effects on bone metabolic markers and BMD regionally in premenopausal women.

Background: The serous adenocarcinoma (SA) and clear cell adenocarcinoma (CCA) of endometrium have been shown to be associated with high relapse rate and poor survival. It is not clear whether prognostic significance of these specific cell types of tumor is independent of retroperitoneal lymph node metastasis and other histopathologic prognostic factors in endometrial carcinoma., Methods: We examined 240 consecutive patients with clinical stage I to stage III endometrial carcinoma who were treated prospectively with radical surgery and/or platinum-based chemotherapy. Surgery included extended hysterectomy, bilateral salpingo-oophorectomy, and systematic pelvic and paraaortic lymph node dissection. Prognostic significance of various histopathologic factors was determined by Cox regression analysis., Results: SA/CCA were more frequently associated with deep myometrial invasion, high nuclear grade (G3), lymph-vascular space invasion (LVSI), and pelvic lymph node metastasis when compared to endometrioid adenocarcinoma (EMA). Of 216 clinically staged stage I or II disease, seven of 12 cases of SA/CCA had extrauterine disease. This incidence was much higher than that for EMA (46/204) (p<0.01). A multivariate Cox regression analysis revealed that cell type, grade, LVSI, and paraaortic node metastasis (PANM) were independent prognosticators., Conclusions: Prognosis of patients with endometrial carcinoma depends on cell type, grade, LVSI, and PANM. Poor prognosis for patients with SA/CCA is independent of lymph node metastasis and other histopathologic prognostic factors. The SA/CCA should be strictly discriminated from EMA.

Background: The incidence and distribution pattern of retroperitoneal lymph node metastasis in patients with cervical carcinoma should be investigated based on data from systematic pelvic lymph node (PLN) and paraaortic lymph node (PAN) dissection, so that a basis can be established for determining the site of selective lymph node dissection or sampling., Methods: A total of 208 patients with Stages IB, IIA, and IIB cervical carcinoma who underwent radical hysterectomy and systematic pelvic and PAN dissection were investigated for lymph node metastasis and histopathologic risk factors for lymph node metastasis., Results: Fifty-three patients (25.5%) had lymph node metastasis. The obturator lymph nodes were most frequently involved, with a rate of 18.8% (39/208). Forty-nine of 53 node-positive patients had lymph node metastasis in the obturator, internal iliac, or common iliac lymph nodes. Of 26 solitary lymph node metastases confined to one node group, 18 were in the obturator, 3 in the internal iliac, 3 in the parametrial, and 2 in the common iliac lymph nodes. A multiple logistic regression analysis revealed that deep cervical stromal invasion and lymph-vascular space invasion were related to PLN metastasis. It was also shown that metastasis to bilateral PLNs (excluding the common iliac lymph nodes) as well as metastasis to the common iliac lymph nodes were significantly related to PAN metastasis., Conclusions: The results of this study suggest that the obturator lymph nodes can be sentinel lymph nodes of cervical carcinoma. PAN metastasis appears to occur secondarily to wide-spread PLN metastasis. These results provide a basis for determining the site of selective lymph node dissection and for estimating the existence of PAN metastasis from the pattern of metastasis in PLN in patients with cervical carcinoma.

We report a case of mos 45,X/46,X,+mar, diagnosed prenatally by amniocentesis, whose physical examination, including external and internal organs, along with serum testosterone values were normal five years after delivery. The mosaic karyotype was seen in 146 of 240 cells examined (amniotic fluid cells, 110/65; placental chorionic villi: 5/4; cord blood, 21/81; cultured skin fibroblasts, 10/90) from 386 metaphases, and the marker chromosome appeared as a small non-fluorescent acrocentric chromosome. All autosomes appeared normal, and no normal Y chromosome could be demonstrated. Analysis of 26 Y-chromosome loci by molecular techniques such as PCR, Southern analysis using multiple Y-specific DNA probes, and Hae III restriction endonuclease assessment of male-specific repeated DNA in the heterochromatic region of the Y chromosome, and fluorescence in situ hybridization (FISH), revealed the marker was derived from a Y chromosome including p terminal to q11.23, and paracentric inversion in the remaining Y long arm. The formation of testes can be considered as existence of SRY (sex-determining region of Y) as a testis-determining factor. The present report illustrates the importance of FISH and molecular techniques as a complement to cytogenetic methods for accurate identification and characterization of chromosome rearrangements in prenatal diagnosis.

Background: Prenatal exposure to the synthetic estrogen diethylstilbestrol (DES) is associated with the subsequent development of clear cell adenocarcinoma of the lower reproductive tract in young women, and data concerning the molecular genetic alterations involved in the etiology of this tumor type have not previously been reported. Such knowledge would be of potential value by providing insight into the molecular mechanisms of hormonal carcinogenesis in general, as well as by suggesting molecular markers for risk assessment in the estrogen-exposed population., Methods: A total of 24 samples of clear cell adenocarcinoma of the vagina or cervix, 16 associated with exposure in utero to DES and 8 with no history of DES exposure, were obtained as archival fixed and embedded tissue specimens. DNA was purified from these tissues and used to examine a number of biologically plausible molecular genetic endpoints for tumor specific alterations., Results: No evidence was found for mutations in the K-ras or H-ras protooncogenes, the Wilms' tumor (WT1) tumor suppressor gene, or the estrogen receptor gene. Sporadic overexpression of the p53 tumor suppressor gene was detected in some tumor cell nuclei by immunohistochemistry, but in the absence of detectable p53 gene mutation. Genetic instability as manifested by somatic mutation of microsatellite repeats was widespread in these tumors, with evidence of microsatellite instability in all DES-associated tumors examined, and in 50% of those tumors not associated with DES exposure., Conclusions: These data are consistent with the hypothesis that the induction of genomic instability may be an important mechanism of DES-induced carcinogenesis.

Hypercalcemia developed in a 34-year-old woman with a clear cell carcinoma of the ovary. Osseous involvement with the tumor cells was not present. Primary hyperparathyroidism was absent. Operative partial resection of the metastatic supraclavicular lymph node, followed by radiation therapy, decreased her serum calcium concentrations. This case belongs to the category of humoral hypercalcemia of malignancy (HHM). Detection of a significant quantity of immunoreactive parathyroid hormone-related protein (PTH-rP) in the metastatic lymph node suggested that the HHM of the patient was induced by PTH-rP produced by the tumor. From a review of 17 cases of ovarian tumors showing HHM-like morbidity, it was found that clear cell carcinoma and cystadenocarcinoma were the major types of ovarian tumors associated with HHM.

A double-antibody radioimmunoassay method was used for serial determinations of a tumor-antigen (TA-4) of cervical squamous cell carcinoma, and the correlation of serum antigen levels with the disease progess was investigated in 23 patients with cervical squamous cell carcinoma. Ten cases with widespread metastases received radiotherapy and/or chemotherapy. Nine of these cases who showed progression of the disease had a corresponding increase in serum antigen levels, while one case who had regression of the disease showed a corresponding decrease in serum antigen levels. Thirteen patients received radical surgery, and in all of these, high pretreatment antigen levels declined to undetectable levels 1 or 2 weeks after surgery. A panel of coded sera from the NCI-Mayo Clinic Serum Bank was also studied for evaluating the specificity of the assay. Thirteen of 25 patients (52%) with cervical squamous cell carcinoma showed positive serum antigen levels, while only one of 58 control cases (1.7%) showed false-positive result. These results suggest that serial TA-4 determinations may provide a useful method for evaluating regression or progression of the disease.