Reduced longitudinal cardiac strain in asthma patients.

OBJECTIVE: There is limited knowledge about the potential relationship between asthma and heart function. Aim of our present study was to examine if asthma may be associated with manifest or subclinical heart dysfunction. METHODS: Seventy-two allergic mild-to-moderate and severe asthma patients and 20 matched controls were enrolled in the study. Depending on the anti-asthmatic therapy, four subgroups of asthma patients were created: patients under long-acting beta2-agonists (LABA) and inhaled cortisone without oral cortisone treatment with (1a) versus without (1b) additional omalizumab therapy; patients with LABA, inhaled cortisone and omalizumab treatment with (2a) versus without (2b) oral cortisone. Standard echocardiographic parameters as well as global longitudinal left and right ventricular strains as determined by ultrasound-based speckle-tracking method were evaluated. Furthermore, NT-pro-brain natriuretic peptide (NT-pro-BNP), immunoglobulin E (IgE), C-reactive protein (CRP), and blood count were assessed in asthma and control groups. RESULTS: There were no relevant differences in standard echocardiographic measures between both asthma groups and the control collective. Longitudinal left ventricular strain values were reduced significantly in severe and mild-to-moderate asthma groups (-12.91 ± 0.84% and -13.92 ± 1.55%, respectively), whereas longitudinal right ventricular strain values were additionally relevantly decreased in severe asthma (-10.35 ± 1.04%) compared to the control (-16.55 ± 0.49% and -18.48 ± 1.90%, respectively). Cardiac strains were similar in subgroups 1a and 1b. In contrast, patients from subgroup 2a presented reduced heart strains and decreased lung function compared to those from 2b. CRP, IgE, and eosinophils were significantly increased in asthma versus control individuals. CONCLUSIONS: Allergic asthma, especially severe asthma is associated with subclinical impaired left and right ventricular function as determined by speckle-tracking analysis.

Efficacy, safety and regulatory status of SGLT2 inhibitors: focus on canagliflozin.

Prevalence of diabetes mellitus is inc6reasing, with a burden of 382 million patients worldwide at present (more than the entire US population). The International Diabetes Federation anticipates an increase up to 592 million patients by 2035. Another major problem arises from the fact that just 50% of patients with type 2 diabetes mellitus are at target glycaemic control with currently available medications. Therefore, a clear need for new therapies that aim to optimize glycaemic control becomes evident. Renal sodium-linked glucose transporter 2 inhibitors are new antidiabetic drugs with an insulin-independent mechanism of action. They pose one remarkable advantage compared with already established antidiabetics: increasing urinary glucose excretion without inducing hypoglycaemia, thereby promoting body weight reduction due to loss of ~300 kcal per day. This review focuses on canagliflozin, which was the first successful compound of this class to be approved by both the US Food and Drug Administration and the European Medicines Agency in 2013. Clinical trials showed promising results: enhancing glycaemic control was paralleled by reducing body weight and systolic and diastolic blood pressure. Nevertheless, some safety concerns remain, such as genital mycotic infections, urinary tract infections and cardiovascular risks in vulnerable patients, which will be closely monitored in several post-authorization safety studies.

[Platinum-based chemotherapy in triple negative breast cancer]. / Platin-basierte Therapie beim dreifach negativen Mammakarzinom.

Since its first market authorisation 40 years ago, cisplatin is an important constituent of cytostatic chemotherapy regimens. Some tumour entities even lost their fright after introduction of cisplatin into the therapeutic armamentarium. For instance, cure rates of up to 95 % are reported for testicular cancer depending on the tumour-stage at the time of diagnosis. In the first-line breast cancer therapy cisplatin is regarded only a cytostatic reserve at present. However, platinum-based therapy regimes are widely used in anthracyclin- and/or taxan-refractory situations. In addition, platinum-based therapy is well-established in the palliative treatment of breast cancer.Breast cancer is the most common female cancer type and triple negative breast cancer (TNBC) has the poorest prognosis. Therapy options are limited to surgery, radiotherapy, and polychemotherapy since targeted therapies, which are based on a molecular interaction with a target protein, are not amenable at present. However, triple negative breast cancer specimens show good initial response to platinum-based chemotherapy. Therefore, clinical research of cisplatin therapy in BRCA-mutated triple negative breast cancer is currently intensified. However, despite successful first treatment, the tumour often reappears quickly, a phenomenon designated as the triple negative paradox. Throughout this article, current indications and possible future development to a potentially new indication is outlined.

In vitro differentiation of human dental follicle cells with dexamethasone and insulin.

The dental follicle is an ectomesenchymally derived connective tissue harboring precursor cells for the tooth supporting apparatus. In this study, we examined gene expression of freshly isolated human dental follicle cells during osteogenic differentiation in vitro. These plastic adherent fibroblastic cells express Notch-1, nestin and vimentin. We differentiated dental follicle cells with dexamethasone or insulin-based protocols into membrane-like structures containing mineralizing foci. An analysis of mineralized tissue with atomic force microscopy illustrated a bone and cementum-like structure. A real-time RT-PCR analysis was developed to investigate expression of typical osteoblast or cementoblast related genes during differentiation. Gene expressions of osteocalcin (OCN), bone morphogenic protein (BMP)-2 and nestin were increased during the both differentiation approaches. Our work demonstrates differentiation of dental follicle cells with an insulin-based protocol for the first time.

Hormonal regulation of peripheral benzodiazepine receptor binding properties is mediated by subunit interaction.

The peripheral benzodiazepine receptor (PBR) is composed of three subunits with molecular masses of 18, 30, and 32 kDa. Many physiological functions have been attributed to the PBR, including regulation of steroidogenesis. Furthermore, the PBR itself is under hormonal regulation. In the current study, we investigated the role of female gonadal sex hormones in the regulation of PBR expression in steroidogenic and nonsteroidogenic tissues. To accomplish this, adult female rats were pharmacologically castrated using chronic administration of the gonadotropin-releasing hormone agonist decapeptyl (triptorelin-D-Trp(6)-LHRH). Half of these rats received 17beta-estradiol as hormone replacement, while a control group received daily injections of vehicle only. We found that PBR binding capacity dropped by 40 and 48% in ovaries and adrenals, respectively, following decapeptyl administration, as opposed to no change in the kidney. This down-regulation of PBR densities was prevented by estradiol replacement. We did not find evidence for transcriptional, posttranscriptional, and translational mechanisms in this decapeptyl-induced down-regulation. In contrast, immunoprecipitation of the PBR complex, using antibodies against the 18- and 32-kDa subunits of the complex, demonstrated that there were changes in PBR subunit interactions, consistent with the down-regulation of PBR binding capacity. These findings represent a novel hormone-dependent posttranslational regulatory mechanism.

Hormone replacement therapy enhances postprandial lipid metabolism in postmenopausal women.

Postmenopausal estrogen therapy reduces cardiovascular morbidity and mortality, except in women with advanced coronary disease. This beneficial effect is partly attributed to a reduction of fasting plasma total and low-density lipoprotein cholesterol (LDL-C) and an elevation of plasma high-density lipoprotein cholesterol (HDL-C) concentrations. Since postprandial lipemia seems to play a role in the pathogenesis of coronary artery disease, we evaluated the effect of hormone replacement therapy (HRT) on postprandial lipoprotein metabolism in 14 normolipemic postmenopausal women. A vitamin A fat-loading test before and after three cycles of treatment with a sequential combination of conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA) was used to label chylomicrons and chylomicron remnants with retinyl palmitate (RP), and RP clearance was assessed over an 8-hour period postprandially. Following 3 months of HRT, fasting total cholesterol and LDL-C levels were reduced 9.8% (P = .049) and 16.5% (P = .023), respectively. Fasting HDL-C levels increased 18.9% (P = .001). Fasting triglycerides (TGs) increased, but not significantly. Postprandial integrated plasma TGs did not change significantly. The integrated RP levels in whole plasma and chylomicron (Svedberg flotation units [Sf] > 1,000) and nonchylomicron (Sf < 1,000) fractions were reduced 58% (P = .043), 78% (P = .041), and 75% (P = .001), respectively, after hormonal treatment. Enhanced clearance of chylomicrons and chylomicron remnants by HRT may contribute to the protective effect of estrogens against cardiovascular disease in normolipemic postmenopausal women.

Effect of estradiol on rat ileum.

1. Sex hormones may influence gastrointestinal motility and thus may be responsible for symptoms that are common during pregnancy or hormone replacement therapy. The purpose of this study was to evaluate the effect of estradiol on the gut. 2. Segments of rat ileum (n=9) were suspended in an organ bath and exposed to increasing concentrations of carbachol, in the presence or absence of 17beta-estradiol. 17beta-estradiol markedly reduced the force developed by the ileum in response to carbachol. 3. These results suggest that estradiol reduces gastrointestinal motility.

Fluctuations of lipid and lipoprotein levels in hyperlipidemic postmenopausal women receiving hormone replacement therapy.

BACKGROUND: Fluctuations in lipid and lipoprotein levels are encountered quite often in hyperlipidemic patients. We examined the possibility that lipid and lipoprotein levels fluctuate due to the different effects of estrogen and progestogen in postmenopausal hyperlipidemic women receiving combined hormonal replacement therapy. METHODS: In an open-label study conducted during 3 consecutive hormonal cycles (3 months), levels of fasting total cholesterol, triglycerides, and low (LDLC)- and high-density lipoprotein cholesterol (HDLC) were determined in 36 postmenopausal hyperlipidemic women on day 13 of conjugated equine estrogen (1.25 mg/d) therapy and on day 25 after 12 days of receiving estrogen plus medroxyprogesterone acetate (5 mg/d). RESULTS: While receiving estrogen and combined therapies, means +/- SD total cholesterol levels increased from 6.50 +/- 0.97 mmol/L (251 +/- 37 mg/dL) to 6.88 +/- 1.42 mmol/L (266 +/- 54 mg/dL) (P<.001); LDLC levels, from 4.05 +/- 1.14 mmol/L (156 +/- 44 mg/dL) to 4.62 +/- 1.36 mmol/L (178 +/- 52 mg/dL) (P<.001). Mean +/- SD HDLC cholesterol levels decreased from 1.44 +/- 0.32 mmol/L (55 +/- 12 mg/dL) to 1.29 +/- 0.28 mmol/L (50 +/- 10 mg/dL) (P<.001); triglyceride levels, from 2.23 +/- 1.03 mmol/L (197 +/- 91 mg/dL) to 2.06 +/- 1.04 mmol/L (182 +/- 92 mg/dL) (P<.001). CONCLUSIONS: Hyperlipidemic postmenopausal women receiving combined sequential estrogen and progestogen replacement therapy demonstrate very significant fluctuations in their lipid and lipoprotein levels. These fluctuations depend on the hormonal phase, ie, estrogen alone or combined with progestogen.

The effects of sublingual estradiol on left ventricular function at rest and exercise in postmenopausal women: an echocardiographic assessment.

OBJECTIVE: To evaluate the acute hemodynamic effects of 4 mg estradiol given sublingually. DESIGN: Rest and exercise echocardiographies were performed prior to estradiol administration. Then, another set of tests was done post-dose: rest examination at 1 h post-dose, isometric exercise at 65 min post-dose, and dynamic exercise at 100 min post-dose. RESULTS: The administration of 4 mg sublingual estradiol to 24 postmenopausal women (aged 48-58 years) was followed 60 min post-dose by a surge in mean estradiol serum levels (1759 +/- 704 pg/ml). At rest a slight drop in systolic and diastolic blood pressure was measured after estrogen ingestion: 132 +/- 24 mm Hg versus 127 +/- 21 mm Hg, p < 0.05; 83 +/- 11 mm Hg versus 78 +/- 10 mm Hg, p < 0.02. There were no changes in resting heart rate, double product, or vascular resistance. The left heart cavities became smaller: the left atrium diameter decreased from 33.7 +/- 4 mm to 32.3 +/- 4 mm, p < 0.01; the end-systolic diameter decreased from 24.9 +/- 3 mm to 23.6 +/- 4 mm, p < 0.01; the end-diastolic diameter decreased from 44.5 +/- 4 mm to 42.7 +/- 4 mm, p < 0.01. The peak aortic blood flow velocity fell from 120 +/- 19 cm/s to 116 +/- 22 cm/s (p < 0.05), and the flow velocity integral fell from 26.3 +/- 4 cm to 24.9 +/- 5 cm (p < 0.01); the cardiac output underwent a small change, with borderline significance: 7 +/- 2 L/min versus 6.7 +/- 2 L/min, p = 0.06. Only minor changes in the hemodynamic and echocardiographic parameters were recorded after estrogen for both isometric and dynamic exercises. Analyses were also made for two subgroups: 13 normotensive women were compared with 11 hypertensive women. The post-estrogen decreases in resting blood pressure and in peak blood velocity were observed only in the hypertensive subjects, whereas the changes in heart dimensions and in flow velocity integral were the same in both subgroups. CONCLUSIONS: Sublingual estradiol was associated with acute hemodynamic alterations mainly at rest but also after exercise.

Hormone replacement and simvastatin in the therapy of hypercholesterolemic postmenopausal women.

OBJECTIVES: To prospectively investigate the effect of cholesterol lowering diet, hormone replacement therapy and simvastatin on plasma lipid levels using a 3-month stepwise protocol. METHODS: Participants were postmenopausal women under the age of 60 with hypercholesterolemia (plasma total cholesterol > 240 mg/dl). The study started with 3 months of Step-One diet (phase I) followed by 3 months of diet and hormone replacement therapy (0.625 mg conjugated estrogens daily combined with 5 mg medroxyprogesterone acetate at days 13-25 of each cycle) (phase II). In women whose total cholesterol remained above 240 mg/dl or LDL-cholesterol above 160 mg/dl by the end of phase II, simvastatin at 10 mg daily was added (phase III). Plasma cholesterol levels as well as safety measurements were closely monitored. RESULTS: Sixteen (21%) of 75 patients who entered the study had satisfactory cholesterol levels by the end of 6 months. Another 25 patients (33%) dropped out of the study for various reasons by that time. In the 34 patients who started simvastatin, plasma total cholesterol levels did not significantly change during phase I and II, however, LDL-cholesterol significantly decreased (204 +/- 31 to 187 +/- 26 mg/dl, p = 0.04) and HDL increased (53 +/- 12 to 62 +/- 16 mg/dl, p = 0.04). A dramatic decrease occurred in both total and LDL-cholesterol levels after one month of phase III (281 +/- 26 to 213 +/- 30 mg/dl 187 +/- 26 to 122 +/- 30 mg/dl respectively, p < 0.0001), with no further changes during the rest of the study period. No significant changes occurred in HDL-cholesterol and triglyceride plasma levels at this phase. Adverse effects were few and minor throughout the study. CONCLUSIONS: Some of the hypercholesterolemic postmenopausal women will benefit from hormone replacement therapy as a single cholesterol lowering treatment in addition to diet (21% in our series). Nevertheless, combination therapy of estrogens and low dose simvastatin proved to be extremely effective in lowering cholesterol levels with no significant side effects. Such therapeutic regimen may also have a synergistic anti-atherogenic effect.

Exercise echocardiography in postmenopausal hormone users with mild systemic hypertension.

Rest and exercise echocardiography (at dynamic and isometric exercise) were performed in 30 postmenopausal women (aged 54 +/- 4 years) with borderline to mild hypertension. They were then divided into 2 groups: 17 women who started oral hormone replacement therapy (0.625 mg/day conjugated estrogens or 2 mg/day estradiol) and a control group of 13 nonusers. After 6 to 9 months, a second echocardiography was performed in 26 women (4 withdrew). There were only a few changes in values obtained in the 12 controls at the end of follow-up compared with baseline. Primarily, these changes included a slight decrease in systolic blood pressure at rest and on exercise. Several significant morphologic and hemodynamic alterations appeared in 14 hormone users. Left ventricular cavity dimensions and mass became smaller: mean end-diastolic diameter decreased from 45.9 +/- 3 mm at baseline to 44.4 +/- 3 mm at study termination (p = 0.007). The corresponding values for end-systolic diameter were 25.8 +/- 4 mm and 23.9 +/- 4 mm (p = 0.006); for left atrium diameter, it was 34.5 +/- 4 mm and 32.5 +/- 4 mm (p = 0.001); for left ventricular wall width, it was 19.9 +/- 2 mm and 19.3 +/- 2 mm (p = 0.02); for left ventricular mass, it was 197 +/- 28 g and 179 +/- 32 g (p = 0.006). The resting aortic blood flow velocity and acceleration increased: 119 +/- 18 cm/s before therapy versus 129 +/- 23 cm/s while on hormone substitution (p = 0.04), and 13.6 +/- 3 m/s2 versus 16.5 +/- 4 m/s2 (p = 0.008), respectively. Mean rest to peak exercise systolic blood pressure difference became smaller after hormones: 39 +/- 19 mm Hg versus 28 +/- 13 mm Hg (p = 0.03) during dynamic exercise, and 43 +/- 22 mm Hg versus 25 +/- 13 mm Hg (p = 0.004) during isometric exercise. The above data probably indicate that with hormone replacement therapy, there is an improvement in cardiac function both at rest and during exercise.

Genetic relationship between dopamine transporter gene and schizophrenia: linkage and association.

This study explores the genetic relationship between schizophrenia and the dopamine transporter gene (DAT) by a variety of methods. In a sample of 48 families--each family containing at least one nuclear family with a pair of affected siblings--we performed linkage analysis using the maximum likelihood (LOD score) method as well as sibpair analysis (identity by descent). In addition, we investigated a sample of 108 nuclear families--index case affected with schizophrenia/chronic schizoaffective disorder--for association using the haplotype relative risk method. Linkage between schizophrenia and DAT using two- and three-point linkage analysis was excluded with all disease models employed. No evidence for association between haplotypes of the VNTR-probe of the DAT and schizophrenia has been detected. Thus, a contribution of the DAT gene to the genetic diathesis of schizophrenia is unlikely in the families studied.

A case of hypergonadotrophinaemia associated with very high isolated concentrations of immunologically and biologically active luteinizing hormone.

A very rare case of a menstruating infertile woman with isolated luteinizing hormone (LH) hypergonadotrophinaemia is presented. There were no signs indicating the presence of a pituitary microadenoma, and LH had normal bioactivity and normal molecular weight. Likewise, no mutation was detected in the coding region of the LH beta-chain gene. In a non-stimulated cycle and a clomiphene citrate cycle, the patient developed an unruptured cyst. The patient ovulated and conceived twice following the addition of human chorionic gonadotrophin. A partial resistance at the ovarian LH receptor site, perhaps caused by a mutation, is a possible explanation for these findings. Another possibility is a malfunction in the signal transduction system of LH beyond the receptor level.

Acute effects of 17 beta-estradiol on the rat heart.

OBJECTIVE: Our purpose was to study the acute effects of 17 beta-estradiol on mechanical and electrical activities of cardiac function and on coronary arteries in the rat heart. STUDY DESIGN: The effects of 17 beta-estradiol were studied on perfused working heart isolated from Charles River male rats. Heart rates, coronary flow, aortic flow, and left ventricular pressure were measured. To avoid coronary interaction, chronotropic and inotropic effects were also tested on isolated atria. Data were analyzed with the paired Student t test. RESULTS: 17 beta-Estradiol produced a dose-dependent negative chronotropic effect in right atria but did not affect the contractility of left atria. A decrease in heart rate was also observed in perfused hearts treated with 5 x 10(-6) mol/L 17 beta-estradiol. 17 beta-Estradiol (5 x 10(-6) mol/L) significantly increased coronary flow (p < 0.005) but had a negligible effect on cardiodynamic index values. A significant effect of 17 beta-estradiol on cardiac function was observed when coronary arteries were precontracted with acetylcholine. CONCLUSION: Both the experimental coronary vasodilatory effect and the negative chronotropic effect of 17 beta-estradiol support the clinical observations that suggest that this hormone may have an important role in prevention of cardiovascular diseases.

The effect of the hypoestrogenic state, induced by gonadotropin-releasing hormone agonist, on Doppler-derived parameters of aortic flow.

The effect of the hypoestrogenic state, induced by a GnRH agonist (GnRH-a), on cardiac function in healthy young women, was evaluated by Doppler echocardiography performed before treatment and when serum 17 beta-estradiol levels were suppressed by GnRH-a to 36.7 pmol/L. The following parameters of aortic flow were measured: peak flow velocity, ejection time, and acceleration time. Additional parameters calculated were flow velocity integral, cardiac index, and mean acceleration. The study group included 15 menstruating women, aged 25-42 yr (mean, 33 yr), with symptomatic fibroids, endometriosis, or scheduled for in vitro fertilization, who were treated with a GnRH-a. There were significant decreases in peak flow velocity (99 +/- 11 vs. 86 +/- 11 cm/s; P = 0.0004) and cardiac index (3.0 +/- 0.7 vs. 2.5 +/- 0.5 L/min.m2; P = 0.002). A decrease that did not reach statistical significance was noted in flow velocity integral (18.9 +/- 2.7 vs. 16.5 +/- 3.4 cm; P = 0.07). Mean acceleration was decreased significantly (12.6 +/- 2.6 vs. 10.8 +/- 1.8 m/s.s; P = 0.01), but no significant changes in acceleration time (81 +/- 16 vs. 83 +/- 10 ms; P = 0.7) or ejection time (296 +/- 25 vs. 295 +/- 27 ms; P = 0.8) were observed. These results indicate that estrogen deprivation is associated with smaller stroke volume and flow acceleration and might suggest that hypoestrogenism has a direct effect on cardiovascular performance.

Inhibitory effect of a highly potent antagonist of LH releasing hormone (SB-75) on the pituitary gonadal axis in the intact and castrated rat.

The biological potency of the new, highly potent antagonist [AC-D-Nal (2)1, D-Phe(4Cl)2, D-Pal(3)3, D-Cit6, D-Ala10] LH-RH (SB-75) on the pituitary-gonadal system of female castrated and intact ovulating rats was tested. Administration of a single dose (50-100 micrograms/kg BW) of the antagonist SB-75 inhibited effectively the elevated gonadotrophin levels for 48 h. Pituitary LH and FSH content was not affected by SB-75 treatment. When administered in the early afternoon of the proestrus to intact cycling rats, SB-75 blocked the preovulatory LH surge as well as the primary and secondary FSH surges. However, the secondary FSH surge was not affected by SB-75 treatment when administered on the evening of proestrus suggesting its independence from the LH-RH mechanism. A group of ovariectomized rats was chronically treated with D-Trp6-LH-RH after having been pretreated by administration of a single dose of the antagonist. The initial stimulatory release of LH and FSH initiated by injection of the LH-RH agonist was significantly reduced by pretreatment with the LH-RH antagonist. We conclude that the LH-RH antagonist SB-75 may be used effectively in the field of reproductive dysfunction and endocrinological oncology and may become an invaluable physiological probe in studying the hormonal dynamics of the reproductive endocrine axis.

Combined transvaginal tubal catheterization and adhesiolysis of filmy uterine synechiae performed with a newly developed device under the guidance of digital road mapping fluoroscopy.

Transcervical fallopian tube catheterization is rapidly gaining favor as a minimally invasive diagnostic and therapeutic technique. On occasion, the presence of filmy adhesions not identified on HSG obstruct the passage of the cannula to the cornual angle. We describe the design and operative characteristics of a new transcervical adhesiolysis device that if used under the guidance of DRM mapping, can restore the shape of the uterine cavity and allow completion of the procedure during the same session.

Another look at co-treatment with growth hormone and human menopausal gonadotrophins in poor ovarian responders.

The objective of this study was to evaluate whether a combined human growth hormone (HGH) and human menopausal gonadotrophin (HMG) treatment can improve ovulation induction in poor ovarian responders. Ten patients aged 28-43 years and requiring > 25 ampoules of HMG for ovulation were admitted to the study. Pituitary growth hormone reserve was evaluated by clonidine stimulation and insulin tolerance tests before commencement of treatment. The patients underwent one treatment cycle with D-tryptophan-6-luteinizing hormone-releasing hormone (D-Trp6-LHRH) and HMG and another cycle with D-Trp6-LHRH, HMG and HGH. Serum HGH, insulin-like growth factor (IGF)-I and oestradiol were measured throughout the two treatment cycles and follicular maturation was assessed by ultrasonographic studies. All patients tested showed no elevation of their serum HGH concentration during a clonidine test, but showed an adequate response during insulin tolerance tests. No significant difference was found in the number of HMG ampoules, duration of treatment, number of leading follicles, and serum oestradiol concentration between the two treatment cycles. Co-treatment with HGH and HMG did not improve ovarian performance in poor ovarian responders. No correlation was found between the results of HGH pituitary function tests and the ovarian response to gonadotrophins.