A Case of Dupilumab-Induced Diffuse Alveolar Hemorrhage.

Eosinophilic pneumonia is a known side effect of dupilumab; however, diffuse alveolar hemorrhage has not yet been reported in association with dupilumab. We herein report a case of diffuse alveolar hemorrhage caused by dupilumab. A 57-year-old man with severe asthma was unable to discontinue oral steroids and thus was prescribed dupilumab. The patient was admitted to the hospital four weeks after treatment because of suspected eosinophilic pneumonia. Bronchoscopy revealed diffuse alveolar hemorrhage characterized by hemosiderin-phagocytic macrophages in the bronchoalveolar lavage fluid without eosinophils. The steroid dosage improved the respiratory status and resolved the infiltrate shadow. Dupilumab may thus cause diffuse alveolar hemorrhage, which can be differentiated using bronchoscopy.

Guidelines for office gynecology in Japan: Japan Society of Obstetrics and Gynecology (JSOG) and Japan Association of Obstetricians and Gynecologists (JAOG) 2017 edition.

Six years after the first edition of The Guideline for Gynecological Practice, which was jointly edited by The Japan Society of Obstetrics and Gynecology and The Japan Association of Obstetricians and Gynecologists, the third revised edition was published in 2017. The 2017 Guidelines includes 10 additional clinical questions (CQ), which brings the total to 95 CQ (12 on infectious disease, 28 on oncology and benign tumors, 27 on endocrinology and infertility and 28 on healthcare for women). Currently a consensus has been reached on the Guidelines and therefore the objective of this report is to present the general policies regarding diagnostic and treatment methods used in standard gynecological outpatient care that are considered appropriate. At the end of each answer, the corresponding recommendation level (A, B, C) is indicated.

Japan Society of Obstetrics and Gynecology and Japan Society for Menopause and Women's Health 2017 guidelines for hormone replacement therapy.

Hormone replacement therapy (HRT) plays a large part in maintaining and improving the quality of life (QOL) of postmenopausal women. Despite this obvious role, the use of HRT has stagnated in Japan as well as the United States, since the interim report of the HRT trial of Women's Health Initiative study was published in 2002. The Japan Society of Obstetrics and Gynecology and Japan Society for Menopause and Women's Health formulated the Guidelines for Hormone Replacement Therapy in 2009, which was subsequently revised in 2012, with the aim of organizing perceptions about HRT and allowing people to provide or receive HRT with a sense of security. Later on, in light of changes in indications for HRT and attitudes toward its impact on cancer risks, amendments were made again in 2017. With the establishment of the 2017 guidelines, practitioners in Japan are able to address various issues related to HRT with more appropriate judgment. Moreover, the practice of reliable, safe and effective HRT is expected to promote further efforts toward improvement or maintenance of QOL in patients.

Uterine leiomyomata: a retrospective study of correlations with hypertension and diabetes mellitus from the Japan Nurses' Health Study.

We performed a scrutiny survey of self-reported uterine leiomyomata (UL) to investigate the associations of parental history with hypertension and personal history of hypertension in the UL cases in Japanese women. Questionnaires that included items on the sites of UL determined by imaging techniques and surgical procedure were mailed to 2015 women with a self-reported UL at a baseline survey of the Japan Nurses' Health Study (n = 15,019). We found that women with a past history and a maternal history of hypertension had an increase in their risk of UL. A maternal history of hypertension was significantly associated with an increase in the risk of UL in women without a past history of hypertension but not in the women with a past history of hypertension. A past history and a parental history of diabetes mellitus were not associated with an increase in the risk of UL. Women of reproductive age with a maternal history of hypertension may be at a higher risk for hypertension and UL. Impact Statement What is already known on this subject? A positive association of uterine leiomyomata (UL) with a past history of hypertension has been found but the association of a parental history of hypertension with UL has not yet been clarified. What do the results of this study add? Maternal hypertension, as well as a personal history of hypertension, was associated with an increased risk of UL and a past history and a parental history of diabetes mellitus were not associated with an increase in the risk of UL. What are the implications of these findings for clinical practice and/or further research? Women of a reproductive age with a maternal history of hypertension may be at a higher risk for hypertension and UL.

[Calcium and bone metabolism across women's life stages. The effects of oral contraceptives/low dose estrogen-progestin on bone metabolism, bone mass and geometry in adolescent and young adult women.]

Estrogens have a biphasic action on pubertal and/or adolescent skeletal growth. Low levels of estrogen may increase the periosteal expansion through the increase in the sensitivity of bone for mechanical stimuli and the secretion of IGF-1. On the other hand, high estrogen concentrations may inhibit periosteal bone formation. To use OC/LEP(oral contraceptive/low dose estrogen-progestin) during adolescence, meaning exposure to high levels of estrogen, may prevent the acquisition of physiologic peak of bone mass.

Patient preference for monthly bisphosphonate versus weekly bisphosphonate in a cluster-randomized, open-label, crossover trial: Minodroate Alendronate/Risedronate Trial in Osteoporosis (MARTO).

Minodronate is a potent nitrogen-containing bisphosphonate that can be administered according to a monthly (every 4 weeks) dosing regimen. A 6-month, cluster-randomized, open-label, multicenter, crossover trial was conducted to test the preference of Japanese patients with osteoporosis for monthly bisphosphonate versus weekly bisphosphonate. One hundred and forty-seven patients (postmenopausal women and men) with primary osteoporosis were recruited at eight outpatient clinics. The clinics were randomized into two groups according to the dosing protocol-monthly minodronate followed by weekly alendronate or risedronate for a total of 24 weeks, or weekly alendronate or risedronate followed by monthly minodronate for 24 weeks. Patient preference for either the monthly or weekly bisphosphonate regimen was evaluated using a preference questionnaire. One hundred and fifteen patients (78.2 %) who completed the trial were processed for the analyses. Significantly more patients preferred the monthly bisphosphonate regimen (65.2 %) than the weekly bisphosphonate regimen (15.7 %) (P = 0.007). 'Dosing schedule fits lifestyle better' was the most common reason given for the patient preference for both the monthly (32.0 %) and weekly bisphosphonate (33.3 %) regimens. Significantly more patients found the monthly bisphosphonate regimen to be more convenient (73.0 %) than the weekly bisphosphonate regimen (13.9 %) (P < 0.0001). The safety profiles of the two regimens were similar. The present trial demonstrated a strong patient preference for and the convenience of the monthly bisphosphonate regimen over the weekly bisphosphonate regimen in Japanese patients with osteoporosis.

Survey of the utility of once-monthly bisphosphonate treatment for improvement of medication adherence in osteoporosis patients in Japan.

Prescription of a bisphosphonate (BP) with monthly dosing has recently been approved in Japan. The value of this approach for improvement of medication adherence was investigated in patients undergoing drug therapy for osteoporosis. A questionnaire was distributed to patients receiving treatment for osteoporosis at 8 medical facilities (5 orthopedic, 2 gynecology, and one internal medicine). Responses were collected from 1,300 patients. After exclusion of those who missed an item on the questionnaire or took drugs other than oral drugs, responses from 1,151 patients were analyzed. The most frequently used drug for treatment of osteoporosis was a once-weekly BP. Of the 1,151 patients, 38.4 % reported forgetting to take their current drug. The most frequent concern was 'I cannot feel an effect', but 73.2 % answered 'I have no concerns'. Regarding the most appropriate dosing regimen for long-term treatment, 60.3 % selected once-weekly and 24 % selected once every 4 weeks. Based on a recommendation by a physician of a drug to be taken monthly, 32.5 % wanted to switch, 31.8 % were undecided, and 35.7 % wanted to continue with their current drug. The desire for a change was higher among patients currently taking a once-weekly BP (52.3 %) than among patients taking a daily BP (29.5 %) or a SERM (19.4 %). This survey revealed patients' preferences in osteoporosis drug therapy. It is important to select a drug for osteoporosis based on the efficacy and the drug regimen preferred by the individual patient.

Variations in circulating osteoprotegerin and soluble RANKL during diurnal and menstrual cycles in young women.

BACKGROUND/AIMS: Physiological bone turnover shows diurnal variations and changes within the menstrual cycle. The aim of this study was to assess the variability of osteoprotegerin (OPG) and soluble RANKL (sRANKL) serum levels during diurnal and menstrual cycles. METHOD: Blood was collected from 15 young women at 6-hour intervals between 08.00 and 20.00 h during the follicular phase. Moreover, to compare the follicular and luteal phases, blood was also collected at 14.00 h during the luteal phase. Serum bone-specific alkaline phosphatase (BAP), N-telopeptide of type I collagen (NTX), OPG and free sRANKL were measured. RESULTS: No diurnal variations in BAP, OPG, sRANKL and sRANKL/OPG ratio were detected. NTX was significantly higher in the morning than in the afternoon and at night (p = 0.02). There were no menstrual variations in either. CONCLUSIONS: The consistent absence of diurnal variations in circulating OPG and sRANKL levels may reflect the absence of diurnal variation in their expression in the bone microenvironment. In this case, the nocturnal rise and the fall in bone resorption in the luteal phase should be accounted for by other factors than RANKL/OPG-mediated factors. Timing of sampling is unlikely to influence the results of circulating OPG and sRANKL measurement.

Influence of maternal genetic and lifestyle factors on bone mineral density in adolescent daughters: a cohort study in 387 Japanese daughter-mother pairs.

We conducted a cross-sectional study in a cohort of Japanese adolescent schoolgirls (12-18 years of age) and their mothers (387 pairs). Age, lumbar bone mineral density (BMD), birth and menarche-related status, height, body weight and lifestyles were surveyed in the participants. The values of BMD, height and body weight were converted to standard deviation (SD) by age. There were 49 (12.7%) pre-menarche and 338 (87.3%) post-menarche daughters. BMD-SD, height-SD, vitamin D intake and vitamin K intake were significantly correlated between the pre-menarche daughters and mothers (P < 0.05), while BMD-SD, birth weight, age at menarche and all lifestyle-related factors were significantly correlated between the post-menarche daughters and mothers (P < 0.05). BMD-SD in the pre-menarche daughters was affected by BMD-SD in mothers (R (2) = 0.069, P = 0.033) and their own height-SD (R (2) = 0.199, P = 0.001) (model R (2) = 0.340), independently. BMD-SD in the post-menarche daughters was affected by BMD-SD in mothers (R (2) = 0.073, P < 0.001) as well as by their own age at menarche (R (2) = 0.020, P = 0.001), height-SD (R (2) = 0.022, P < 0.001), body weight-SD (R (2) = 0.081, P < 0.001) and intensity of exercise (R (2) = 0.015, P = 0.045) (model R (2) = 0.372), independently. The results suggest that BMD is strongly correlated between daughters and mothers and that a greater age at menarche leads to lower peak bone mass. It was also suggested that maintaining high-intensity physical activity and adequate body weight is important in achieving maximum BMD as factors amenable to intervention in post-menarche daughters.

Ovarian cystadenofibroma with solid nodular components masqueraded as ovarian cancer.

INTRODUCTION: The histological features and image findings on computed tomography (CT) and magnetic resonance imaging (MRI) for ovarian cystadenofibroma mimicking malignant ovarian tumor are reported. CASE: A 62-year-old woman was diagnosed as an ovarian cancer on abdominal CT. However, it was diagnosed as a cystadenofibroma on magnetic resonance T2-weighted images that showed the solid components of the tumor with very low intensity. Although ovarian cystadenofibroma is a relatively rare benign tumor, its ultrasonographic feature of cystic lesions with solid components resembles that of malignant ovarian tumor. CONCLUSION: MRI was considered to be useful modality for ovarian cystadenofibroma to be effectively diagnosed preoperatively.

Association between lumbar bone mineral density and vascular stiffness as assessed by pulse wave velocity in postmenopausal women.

Recent studies have showed a significant correlation between vascular calcification and bone mineral density (BMD). Therefore, an investigation was carried out on the association between arterial stiffness, lumbar BMD and bone metabolic markers in Japanese postmenopausal women. Brachial-ankle PWV (baPWV) and BMD of the lumbar spine and serum bone-specific alkaline phosphatase (BAP) levels in 143 postmenopausal women were measured, where there was a significant negative correlation between baPWV and BMD (r = -0.21; P = 0.0135). An additional analysis included the remaining 75 subjects, but excluded subjects with hypertension and obesity. Here, a more negative correlation between baPWV and BMD (r = -0.315; P = 0.006), and a positive correlation between baPWV and BAP (r = 0.248; P = 0.032) were also significant. A group analysis, where the women were age matched and stratified into three groups of different bone density, i.e., normal BMD, osteopenic and osteoporotic, were further made. This showed lower PWV values in the normal BMD group than in the other two groups. A study also showed that the tertile with the highest BAP was associated with significantly higher PWV values than the other tertiles. However, when the multiple linear regression analysis was carried out, there was no correlation between PWV and BAP values. Low BMD and arterial stiffness show some correlation, suggesting that BAP may reflect the degree of arterial stiffness present.

Possible risk factor for postmenopausal women: postprandial hypertriglyceridemia.

AIM: To explore the clinical implications of postprandial hypertriglyceridemia in postmenopausal Japanese women. METHODS: Postprandial blood samples were collected from 91 women at their initial visit, with fasting blood samples collected within the following month to examine their lipid profiles. These women were grouped into normotriglyceridemia (fasting/postprandial triglycerides [TG] < 150; n = 36), mild postprandial hypertriglyceridemia (fasting TG < 150, postprandial TG > or = 150, < 225; n = 27), moderate postprandial hypertriglyceridemia (fasting TG < 150, postprandial TG > or = 225; n = 19) and hypertriglyceridemia (fasting TG > or = 150; n = 9) by using 225 mg/dL as the cut-off value for postprandial hypertriglyceridemia. RESULTS: The subjects were 54.1 +/- 7.8 years old; their duration of menopause, 6.0 +/- 7.7 years; body mass index, 21.4 +/- 4.0 kg/m(2); postprandial TG concentration, 189 +/- 110 mg/dL; and fasting TG concentration, 109 +/- 50 mg/dL. Approximately 50% (n = 46) of the women had normal fasting TG (fasting TG < 150), but high postprandial TG (postprandial TG > or = 150). Approximately 10% (n = 9) of the women had hypertriglyceridemia (fasting TG > or = 150 mg/dL). In those with postprandial hypertriglyceridemia (n = 46), postprandial TG negatively correlated with high-density lipoprotein cholesterol (HDL-C), while fasting TG showed no such correlation with HDL-C. CONCLUSION: Postprandial TG may provide a better understanding of lipid metabolism in postmenopausal women.

Differential effects of chronic treatment with estrogen receptor ligands on regulation of nitric oxide synthase in porcine aortic endothelial cells.

In cultured endothelial cells, estrogen increases expression and activity of endothelial nitric oxide synthase (eNOS). This study was designed to determine whether estrogenic treatments increase eNOS similarly in vivo. Aortic endothelial cells were collected from adult ovariectomized pigs which were untreated (8wk-OVX) or treated with oral 17beta-estradiol (E2, 2 mg/day), conjugated equine estrogen (CEE, 0.625 mg/day), or raloxifene (60 mg/day) for 4 weeks. Plasma NOx, estrogen receptors (ERalpha and ERbeta), eNOS, eNOS regulatory proteins, and eNOS mRNA in endothelial cells were determined by Griess reaction, Western blot, and real-time polymerase chain reaction, respectively. Ovariectomy decreased, whereas all treatments restored plasma NO(x) to pre-OVX levels. On the contrary, eNOS protein and mRNA increased with ovariectomy; E2 and CEE but not raloxifene reduced mRNA; eNOS protein was reduced by CEE and raloxifene treatments. Tyrosine phosphorylation of eNOS and expression of calmodulin increased, but Hsp90 decreased with all treatments and only raloxifene treatment increased caveolin-1 compared with OVX. Expression of ERalpha/ERbeta increased with ovariectomy and was reversed by treatments such that raloxifene>CEE>E2. Three clinically relevant estrogen treatments restore plasma NO after ovariectomy, but do not affect eNOS mRNA, posttranslational regulation of eNOS or expression of estrogen receptors in the same way.

Placenta previa totalis complicated with pulmonary embolism during cesarean section: a case report.

Venous thromboembolism is believed to be rare in Japan, whereas increases in occurrence of pulmonary embolism have been drawing attention because it has become the most common cause of maternal death in recent years. A 36-year-old woman at 33 weeks of pregnancy was transferred to our hospital because of placenta previa totalis and treated with emergency cesarean section on the same day. Soon after the delivery of the fetus, the patient developed pulmonary embolism. The condition of pulmonary embolism was suspected when abnormal values were noted in respiratory and circulatory parameters and then confirmed by intraoperative transesophageal echocardiography, which revealed a thrombus in the right atrium. Anticoagulant treatment with unfractionated heparin started during the operation caused a tendency to bleed during and after the operation, and subsequently required a second laparotomy to control bleeding. After insertion of an inferior vena cava filter, a third laparotomy was performed to remove a giant hematoma. Heparin discontinuation intended to decrease the tendency to bleed was followed by two recurrences of pulmonary embolism, resulting in a dangerous condition. Despite these difficult complications, our interventions successfully saved the patient's life and restored her health. We report changes observed in her conditions along with treatment and management we provided, and describe the specificity of pulmonary embolism occurring during the operation.

Differential effects of 17beta-estradiol, conjugated equine estrogen, and raloxifene on mRNA expression, aggregation, and secretion in platelets.

Changes in platelet functions could contribute to thrombotic risk associated with estrogen treatments. This study was designed to test the hypothesis that three clinically relevant estrogenic treatments affect platelet function comparably. Adult female pigs were ovariectomized and randomized to either no treatment or treatment with oral 17 beta-estradiol (2 mg/day), conjugated equine estrogen (0.625 mg/day), or raloxifene (60 mg/day) for 4 wk. Platelet turnover, aggregation, and secretion were assessed before and after treatment. Platelet turnover and mRNA increased significantly only in pigs treated with 17 beta-estradiol. Expression of estrogen receptors increased with ovariectomy and decreased with all treatments. Platelet aggregation and secretion of ATP, platelet-derived growth factor, and matrix metalloproteinase-2 increased with ovariectomy. All treatments reduced both aggregation and secretion. Expression of mRNA for constitutive endothelial nitric oxide synthase (eNOS), but not eNOS protein, increased with ovariectomy. Only eNOS mRNA decreased with all treatments, but only treatment with 17 beta-estradiol increased secretion of nitric oxide from intact platelets. Platelets from 17 beta-estradiol-treated animals caused relaxation of coronary arteries, which was sensitive to inhibition of nitric oxide. Although three different estrogenic treatments reversed increases in platelet aggregation caused by ovariectomy, only 17 beta-estradiol increased platelet RNA and release of platelet-derived nitric oxide. These differences reflect transcriptional and posttranscriptional regulation of protein synthesis in bone marrow megakaryocytes and circulating platelets.

Sex-specific changes in platelet aggregation and secretion with sexual maturity in pigs.

Cardiovascular disease may begin early in adolescence. Platelets release factors contributing to vascular disease. Experiments were designed to test the hypothesis that hormonal transitions associated with sexual maturity differentially affect platelet aggregation and secretion in males and females. Platelets were collected from juvenile (2-3 mo) and sexually mature (adult; 5-6 mo) male and female pigs (n=8/group). Maturation was evidenced by increased weight of reproductive tissue and changes in circulating levels of gonadal hormones. Aggregation to ADP (10 microM) and collagen (6 microg/ml) and ATP secretion to 50 nM thrombin were determined by turbidimetric analysis and bioluminescence, respectively. Total platelet counts, platelet turnover, and mean platelet volume did not change with maturity. Platelet aggregation and ATP secretion decreased in females but increased in males with maturity, whereas total ATP content remained unchanged in platelets from females but increased in platelets from males. Platelet fibrinogen receptor, P-selectin expression, and receptors for sex steroids did not change with sexual maturation. Plasma C-reactive protein and brain-type natriuretic peptide also did not change. Results indicate that changes in platelet aggregation and secretion change with sexual maturity differently in females and males. These observations provide evidence on which clinical studies could be designed to examine platelet characteristics in human children and young adults.

Early and definitive diagnosis of toxic shock syndrome by detection of marked expansion of T-cell-receptor VBeta2-positive T cells.

We describe two cases of early toxic shock syndrome, caused by the superantigen produced from methicillin-resistant Staphylococcus aureus and diagnosed on the basis of an expansion of T-cell-receptor VBeta2-positive T cells. One case-patient showed atypical symptoms. Our results indicate that diagnostic systems incorporating laboratory techniques are essential for rapid, definitive diagnosis of toxic shock syndrome.

One-year spinal bone change in pre- and perimenopausal Japanese women. A prospective observational study.

BACKGROUND: This prospective observational study was designed to determine whether the bone mineral density (BMD) of the lumbar spine decreases before menopause. METHODS: The change in BMD of the second through fourth lumbar vertebrae (delta%L2-4BMD) over the course of 12 months was measured in 197 pre- and perimenopausal Japanese women aged 48.2 +/- 2.3 (mean +/- SD) years. RESULTS: Overall, delta%L2-4BMD decreased significantly, with a greater decrease seen in perimenopausal women. This group also had a significantly higher level of FSH (p < 0.05, t = 7.356), a significantly lower level of estradiol (p < 0.05, t = 4.245), and significantly higher levels of the bone metabolic markers, alkaline phosphatase (p < 0.05, t = 3.841), calcium (p < 0.05, t = 3.939), and osteocalcin (p < 0.05, t = -3.295). Overall, there was a significant positive correlation between osteocalcin and delta%L2-4BMD (r = -0.194, p = 0.0479). CONCLUSION: A subset of perimenopausal women with transient decreases in ovarian function that do not respond to increased FSH may be at increased risk for abnormally low BMD, and may benefit from early management of bone mass.

Premature infant with severe periventricular leukomalacia associated with a large placental chorioangioma: a case report.

We present the first reported case of severe periventricular leukomalacia associated with a large placental chorioangioma. We believe that the large chorioangioma near the point of umbilical cord insertion was not only disrupting fetoplacental circulation but may also have led to the periventricular leukomalacia lesions.