Substitute parameters of exercise-induced pulmonary hypertension and usefulness of low workload exercise stress echocardiography in mitral regurgitation.

In asymptomatic patients with mitral regurgitation (MR), data of exercise-induced pulmonary hypertension (EIPH) are limited, and feasibility of evaluating EIPH is not high. We aimed to investigate prognostic impact of EIPH and its substitute parameters. Exercise stress echocardiography (ESE) were performed in 123 consecutive patients with moderate to severe degenerative MR. The endpoint was a composite of death, hospitalization for heart failure, and worsening of symptoms. EIPH [tricuspid regurgitation peak gradient (TRPG) at peak workload ≥ 50 mmHg] was shown in 57 patients (46%). TRPG at low workload was independently associated with TRPG at peak workload (ß = 0.67, p < 0.001). Early surgical intervention (within 6 months after ESE) was performed in 65 patients. Of the remaining 58 patients with the watchful waiting strategy, the event free survival was lower in patients with EIPH than in patients without EIPH (48.1 vs. 97.0% at 1-year, p < 0.001). TRPG at low workload ≥ 35.0 mmHg as well as EIPH were associated with poor prognosis in patients with the watchful waiting strategy. In conclusion, the importance of ESE and evaluating EIPH in patients with MR was re-acknowledged. TRPG at peak workload can be predicted by TRPG at low workload, and TRPG at low workload may be useful in real-world clinical settings.

Diagnostic value of vena contracta area measurement using three-dimensional transesophageal echocardiography in assessing the severity of aortic regurgitation.

PURPOSE: Transthoracic echocardiography (TTE) provides noninvasively quantitative assessment of aortic regurgitation (AR) severity, but its diagnostic accuracy depends on image quality. Two-dimensional transesophageal echocardiography (TEE) is a semi-invasive procedure that is excellent in evaluating AR mechanism. However, quantitative assessment may be challenging due to restrictions in probe manipulation. This study aimed to investigate the diagnostic value of three-dimensional TEE to measure the vena contracta area (3DVCA) of AR. METHODS: The subjects comprised 62 patients (age, 65 ± 16 years) whose AR was evaluated using TEE. The 3DVCA and semi-quantitative TEE parameters, such as the ratio of AR jet width to left ventricular outflow tract (jet/LVOT) and the vena contracta width (VCW) of AR jet, were compared using angiography grade and quantitative TTE measurements including regurgitant volume (RVol) and effective regurgitant orifice area (EROA). The diagnostic accuracy was determined using receiver operating characteristic (ROC) analysis, and the reproducibility of 3DVCA was also evaluated. RESULTS: In 3DVCA, less overlap between angiography grades were observed. Correlation with RVol or EROA was better in 3DVCA than in Jet/LVOT or VCW. The area under the ROC curve was .737 for jet/LVOT, .773 for VCW, and .849 for 3DVCA, respectively. The optimal cutoff value of 3DVCA was ≥.31 cm2 for grading severe AR. Inter- and intra-observer reproducibility of 3DVCA were .92 and .97, respectively. CONCLUSIONS: The 3DVCA method using TEE showed high diagnostic accuracy and reproducibility. 3DVCA deserves use in accurately assessing AR severity, especially in patients who present difficulty in quantitative Doppler assessment using TTE.

Prevalence, determinants, and prognostic significance of exercise-induced pulmonary hypertension in patients with hypertrophic cardiomyopathy.

Exercise-induced pulmonary hypertension (EIPH) is associated with worse outcomes in patients with heart failure or valvular heart disease. However, little is known regarding the implications of EIPH in hypertrophic cardiomyopathy (HCM) patients. We retrospectively reviewed data of consecutive HCM patients who underwent clinically indicated exercise echocardiography using a semi-supine bicycle ergometer at our hospital. EIPH was defined as pulmonary artery systolic pressure ≥ 60 mmHg during exercise. The incidences of HCM-related mortality and HCM-related morbidity during follow-up period were evaluated. Of 42 patients (mean age 59 ± 21 years; 4 with resting obstruction, 19 with provoked obstruction, and 19 without obstruction), 16 (38%) developed EIPH. Patients with EIPH had significantly longer resting E wave deceleration time (271 ± 116 vs. 213 ± 66 ms; P = 0.04), higher resting pulmonary artery systolic pressure (35 ± 6 vs. 31 ± 5 mmHg; P = 0.04), and higher B-type natriuretic peptide level (283 [222, 465] vs. 142 [54, 423] pg/ml; P = 0.04) than those without EIPH. Kaplan-Meier curve analysis demonstrated that EIPH was significantly associated with HCM-related morbidity (log-rank; P = 0.01). In Cox regression analysis, EIPH was a significant predictor of HCM-related morbidity (hazard ratio: 5.98, 95% confidence interval 1.36-41.07; P = 0.02). In conclusion, EIPH was documented in about one-third of HCM patients. EIPH was a significant predictor of HCM-related morbidity in patients with HCM.

Impact of central and peripheral estrogen treatment on anxiety and depression phenotypes in a mouse model of postmenopausal obesity.

Obesity and diabetes increase the risk of depression, and the incidence of these conditions increases rapidly after menopause, but few animal models of postmenopausal obesity have been available. We developed a mouse model of postmenopausal obesity that exhibited anxiety and depressive phenotypes in behavioral tests. To examine the effect of estradiol (E2) in the model, we prepared 4 experimental groups: 1) control, sham-operated female C57BL/6 mice fed a regular diet; 2) OVX-HF, ovariectomized (OVX) mice fed a high-fat diet (HF); 3) E2-SC, OVX-HF mice administered subcutaneous (SC) E2 (50 µg/kg/day); and 4) E2-ICV, OVX-HF mice administered intracerebroventricular (ICV) E2 (1 µg/kg/day). OVX-HF mice exhibited anxiety phenotypes in the open field test, but not in the light-dark box test, and E2 treatment via both routes effectively ameliorated it. OVX-HF mice demonstrated depressive phenotypes in the tail suspension test and forced swim test. Both E2 treatments achieved significant improvement in the tail suspension test, but not in the forced swim test. Serum corticosterone levels did not differ among the groups. Hippocampal expression of glucocorticoid receptor mRNA and serotonin 1A receptor mRNA was significantly increased in OVX-HF mice and was decreased in E2-treated mice. The hypothalamic level of pro-brain-derived neurotrophic factor (proBDNF) protein was tended to decrease in OVX-HF mice, but neither E2 treatment increased it. Since this mouse model exhibited anxiety and depressive phenotypes in relatively short experimental periods without genetic manipulations, it would be useful for further exploring psychiatric phenotypes or screening of therapeutic candidates in postmenopausal obesity.

Teneligliptin improves metabolic abnormalities in a mouse model of postmenopausal obesity.

A decrease in serum estrogen levels in menopause is closely associated with the development of visceral obesity and the onset of type 2 diabetes in women. In the present study, we demonstrated the therapeutic effects of the novel DPP4 inhibitor, teneligliptin, on the features of postmenopausal obesity in mice. In the control group, female C57BL/6 mice were sham-operated and maintained on a standard diet. In the postmenopausal obese group, ovariectomized (OVX) mice were maintained on a high-fat diet, and were referred to as OVX-HF. In the treated group, teneligliptin at 60 mg/kg per day was administrated to OVX-HF, and were referred to as Tene. After a 12-week food challenge, the metabolic phenotypes of these mice were analyzed. Body weight, fat accumulation, and glucose intolerance were greater in OVX-HF than in control, while these abnormalities were markedly improved without alterations in calorie intake in Tene. Teneligliptin effectively ameliorated the characteristics of metabolic abnormalities associated with postmenopausal obesity. Regarding chronic inflammation in visceral adipose tissue, the numbers of F4/80(+)CD11c(+)CD206(-) M1-macrophages in flow cytometry, crown-like structure formation in immunohistochemistry, and proinflammatory cytokine expression were significantly attenuated in Tene. Hepatic steatosis was also markedly improved. Furthermore, decreased energy consumption in the dark and light phases, reduced locomotor activity in the dark phase, and lowered core body temperature in OVX-HF were ameliorated in Tene. Since obesity and reduced energy metabolism are a common physiology of menopause, teneligliptin appears to be beneficial as a treatment for type 2 diabetes in postmenopausal obesity.

Accurate Prediction of the Stage of Histological Chorioamnionitis before Delivery by Amniotic Fluid IL-8 Level.

OBJECTIVE: To estimate the stage of histological chorioamnionitis (h-CAM) antenatally using clinical data. MATERIALS AND METHODS: Four hundred and twenty-eight singleton mothers were recruited. Clinical data including the levels of white blood cell count (WBC), C-reactive protein (CRP), amniotic fluid interleukin-8 (AF-IL-8) at Cesarean section, and maternal body temperature (MBT) were collected. RESULTS: Histological chorioamnionitis was present in 45.3% of the cases. Poor neonatal prognosis was highest (59.1%) in cases with h-CAM stage III. AF-IL-8 (odds ratio: 8.5, 95% CI: 5.1-14.8, P < 0.0001) and MBT (odds ratio: 2.3, 95% CI: 1.13-4.1, P = 0.0192) were independent risk factors for h-CAM. The cutoff value of AF-IL-8 for predicting each stage of h-CAM (stage I or higher, stage II or higher, and stage III) were ≥9.9 ng/mL, ≥17.3 ng/mL, and ≥55.9 ng/mL, respectively. CONCLUSION: The stage of h-CAM was able to be predicted accurately by the level of AF-IL-8 before delivery.

Intestinal microbiota is different in women with preterm birth: results from terminal restriction fragment length polymorphism analysis.

Preterm birth is a leading cause of perinatal morbidity and mortality. Studies using a cultivation method or molecular identification have shown that bacterial vaginosis is one of the risk factors for preterm birth. However, an association between preterm birth and intestinal microbiota has not been reported using molecular techniques, although the vaginal microbiota changes during pregnancy. Our aim here was to clarify the difference in intestinal and vaginal microbiota between women with preterm birth and women without preterm labor. 16S ribosomal ribonucleic acid genes were amplified from fecal and vaginal DNA by polymerase chain reaction. Using terminal restriction fragment length polymorphism (T-RFLP), we compared the levels of operational taxonomic units of both intestinal and vaginal flora among three groups: pregnant women who delivered term babies without preterm labor (non-PTL group) (n = 20), those who had preterm labor but delivered term babies (PTL group) (n = 11), and those who had preterm birth (PTB group) (n = 10). Significantly low levels of Clostridium subcluster XVIII, Clostridium cluster IV, Clostridium subcluster XIVa, and Bacteroides, and a significantly high level of Lactobacillales were observed in the intestinal microbiota in the PTB group compared with those in the non-PTL group. The levels of Clostridium subcluster XVIII and Clostridium subcluster XIVa in the PTB group were significantly lower than those in the PTL group, and these levels in the PTL group were significantly lower than those in non-PTL group. However, there were no significant differences in vaginal microbiota among the three groups. Intestinal microbiota in the PTB group was found to differ from that in the non-PTL group using the T-RFLP method.

Kami-shoyo-san, Kampo (Japanese traditional medicine), is effective for climacteric syndrome, especially in hormone-replacement-therapy-resistant patients who strongly complain of psychological symptoms.

AIM: Hormone replacement therapy (HRT) for climacteric symptoms is effective for vasomotor symptoms, such as hot flushes and sweating, but not for various psychological symptoms, such as anxiety, depression, and irritability. In such cases, prescribing Kampo, traditional herbal medicine, is sometimes considered. However, the effectiveness of Kampo has not been clearly shown. We examined the clinical effect of Kami-shoyo-san, a herbal formula commonly prescribed for climacteric symptoms in a Japanese Kampo clinic. METHODS: There were 180 patients who initially consulted our Kampo Outpatient Clinic due to the absence of a response to HRT or unsatisfactory improvement. Out of 180 patients, 45 patients received a Kami-shoyo-san extract for 4 weeks based on patient-centered Kampo diagnosis. We evaluated the severity of climacteric symptoms based on the visual analogue scale (VAS) score before and after 4 weeks of Kami-shoyo-san administration. Furthermore, the severity of each symptom before treatment was compared between the responders and non-responders. RESULTS: Kami-shoyo-san was effective in 33 (73.3%) of the 45 patients. After treatment, on the whole, the VAS score significantly decreased (P < 0.0001). Concerning vasomotor symptoms and psychological symptoms, each VAS score significantly decreased (P<0.0001). When comparing the severity of pretreatment symptoms between responders and non-responders, symptoms, such as 'insomnia', 'depression', and 'vertigo' were significantly more marked in the responders (P<0.05). CONCLUSION: The results of this study suggest that Kami-shoyo-san relieved both vasomotor and psychological symptoms, and especially in patients with marked psychological symptoms, it exhibited potent effects.

Central versus peripheral impact of estradiol on the impaired glucose metabolism in ovariectomized mice on a high-fat diet.

Age-related loss of ovarian function promotes adiposity and insulin resistance in women. Estrogen (E(2)) directly enhances insulin sensitivity and suppresses lipogenesis in peripheral tissues. Recently, the central actions of E(2) in the regulation of energy homeostasis are becoming clearer; however, the functional relevance and degree of contribution of the central vs. peripheral actions of E(2) are currently unknown. Therefore, we prepared and analyzed four groups of mice. 1) CONTROL: sham-operated mice fed a regular diet, 2) OVX-HF: ovariectomized (OVX) mice fed a 60% high-fat diet (HF), 3) E2-SC: OVX-HF mice subcutaneously treated with E(2), and 4) E2-ICV: OVX-HF mice treated with E(2) intracerebroventricularly. OVX-HF mice showed increased body weight with both visceral and subcutaneous fat volume enlargement, glucose intolerance, and insulin resistance. Both E2-SC and E2-ICV equally ameliorated these abnormalities. Although the size of adipocytes and number of CD11c-positive macrophages in perigonadal fat in OVX-HF were reduced by both E(2) treatments, peripherally administered E(2) decreased the expression of TNFα, lipoprotein lipase, and fatty acid synthase in the white adipose tissue (WAT) of OVX-HF. In contrast, centrally administered E(2) increased hormone-sensitive lipase in WAT, decreased the hepatic expression of gluconeogenic enzymes, and elevated core body temperature and energy expenditure with marked upregulation of uncoupling proteins in the brown adipose tissue. These results suggest that central and peripheral actions of E(2) regulate insulin sensitivity and glucose metabolism via different mechanisms, and their coordinated effects may be important to prevent the development of obesity and insulin resistance in postmenopausal women.

Stage I ovarian cancer cases during early, mid and late pregnancy periods: three case reports and review of the literature.

Since ovarian cancer during pregnancy is rare, the decisions regarding pregnancy discontinuation or fertility preservation are often difficult. We report three ovarian cancer cases detected at early, mid and late pregnancy periods in which both babies and mothers were saved. In particular, case 2 is the first reported instance of a sertoliform endometrioid carcinoma of the ovary during pregnancy. In addition, we review the clinical characteristics of previously reported patients with stage I ovarian cancer diagnosed during pregnancy. Even with stage Ia ovarian cancer, restaging laparotomy at cesarean section or post-delivery may be important to determine the treatment plan because staging during pregnancy is rarely complete.