Comparison of ovarian stimulation response in patients with breast cancer undergoing ovarian stimulation with letrozole and gonadotropins to patients undergoing ovarian stimulation with gonadotropins alone for elective cryopreservation of oocytes†

The primary objective of this study is to compare the oocyte yield in breast cancer patients undergoing controlled ovarian stimulation (COS) using letrozole and gonadotropins with patients undergoing COS with standard gonadotropins for elective cryopreservation of oocytes. Odds ratios (OR) for the number of mature oocytes were estimated. Pregnancy outcomes for breast cancer patients undergoing frozen-thawed 2-PN embryo transfers (FETs) after oncologic treatment were also noted. 220 and 451 cycles were identified in the breast cancer and the elective cryopreservation groups, respectively. Patients in the former group had lower peak estradiol levels [464.5 (315.5–673.8) pg/mL] compared to the latter [1696 (1058–2393) pg/mL; p?<?0.01]. More oocytes were retrieved in the breast cancer group (12.3?±?3.99) compared to the elective cryopreservation group (10.9?±?3.86; p?<?0.01). The odds for mature oocytes with letrozole and gonadotropins was 2.71 (95% CI 1.29–5.72; p?=?0.01). Fifty-six FETs occurred in the breast cancer group. The clinical pregnancy and live birth rates per FET cycle were 39.7%, and 32.3%, respectively. Our findings suggest that COS with letrozole and gonadotropins yield more mature oocytes at lower estradiol levels compared to COS with gonadotropins alone. Breast cancer patients undergoing FET after oncologic treatment have live birth rates comparable to age-matched counterparts.     

Diethylstilbesterol has gender-specific effects on weight gain and bone development in mice

Neonatal exposure to diethylstilbesterol (DES) in female mice programs estrogen-sensitive tissues, resulting in greater body weight gain and positive effects on bone architecture at adulthood. Using the CD-1 mouse model, the objective of the present study was to examine how short-term neonatal exposure to DES modulates weight gain as well as bone mineral density (BMD), bone strength, and bone microarchitecture in both males and females at adulthood. Male and female offspring (n = 8-12 pups/treatment/gender) were randomized to DES (2 mg/kg bw/d) or control (corn oil) from postnatal day 1 to 5 (subcutaneous injection, once daily) and sacrificed at 4 mo of age. Body weight was measured weekly, while bone mineral, strength, and microarchitecture were measured at 4 mo of age. DES treatment resulted in significantly higher body weight in females but lower weight in males at 4 mo of age. In DES-treated females, markedly higher BMD of lumbar vertebrae (LV1-LV3) was translated into significantly stronger LV2 that was more resistant to fracture; similar effects were observed at the femur midpoint. At the spine, males had a markedly lower BMD and peak load, suggesting an adverse effect. Microstructural analyses demonstrated that functional changes in femurs, i.e., peak load, were primarily due to modulation of cortical bone. In conclusion, neonatal exposure to DES exerted gender-specific effects on body weight gain and bone health.     

Protein repellent properties of covalently attached PEG coatings on nanostructured SiO(2)-based interfaces

In this study, we report the systematic comparison of different poly(ethylene glycol) (PEG) self-assembled monolayers on glass with respect to their protein adsorption and cell adhesion resistance. Combining PEGylation with micellar nanolithography allowed the formation of gold nanoparticle arrays on glass and selective coverage of the free glass area by PEG. The gold nanoparticles serve as anchor points for the attachment of individual proteins and peptides such as the cell-matrix adhesion promoting cyclic RGDfK motif or the kinesin motor protein Eg5. The capability of the motor protein to bind microtubules remained unaffected by the immobilization. It was shown that the film thickness of a water swollen PEG layer is crucial to maximize the interaction between proteins and peptides with the nanostructures. Non-specific interaction between cells or microtubules and the surface was minimized. The optimum PEG layer thickness correlated with the size of gold nanoparticles which was approximately 5 nm.     

Prostaglandin E2 suppresses human group 2 innate lymphoid cell function

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Early life exposure to genistein and daidzein disrupts structural development of reproductive organs in female mice

In mice, exposure to isoflavones (ISO), abundant in soy infant formula, during the first 5 d of life alters structural and functional development of reproductive organs. Effects of longer exposures are unknown. The study objective was to evaluate whether exposure to a combination of daidzein and genistein in the first 10 compared to 5 d of life results in greater adverse effects on ovarian and uterine structure in adult mice. Thirteen litters of 8-12 pups were cross-fostered and randomized to corn oil or ISO (2 mg daidzein + 5 mg genistein/kg body weight/d) for the first 5 or 10 d of life. The 10-d protocol mimicked the period when infants are fed soy protein formula (SPF) but avoids the time when suckling pups can consume mother's diet. Body and organ weights, and histology of ovaries and uteri were analyzed. There were no differences in the ovary or uterus weight, number of ovarian follicles, number of multiple oocyte follicles, or percent of ovarian cysts with 5 or 10 d ISO intervention compared to respective controls. The 10-d ISO group had higher body weights from 6 d to 4 mo of age and a higher percent of hyperplasia in the oviduct than the respective control. Lower number of ovarian corpus lutea and a higher incidence of abnormal changes were reported in the uteri of both ISO groups compared to their respective controls. Five and 10-d exposure to ISO had similar long-lasting adverse effects on the structure of ovaries and uterus in adult mice. Only the 10-d ISO exposure resulted in greater body weight gain at adulthood.     

Benzodiazepine-induced spatial learning deficits in rats are regulated by the degree of modulation of α1 GABAA receptors

Despite significant advances in understanding the role of benzodiazepine (BZ)-sensitive populations of GABA_A receptors, containing the α₁, α₂, α₃ or α₅ subunit, factual substrates of BZ-induced learning and memory deficits are not yet fully elucidated. It was shown that α₁-subunit affinity-selective antagonist β-CCt almost completely abolished spatial learning deficits induced by diazepam (DZP) in the Morris water maze. We examined a novel, highly (105 fold) α₁-subunit selective ligand—WYS8 (0.2, 1 and 10 mg/kg), on its own and in combination with the non-selective agonist DZP (2 mg/kg) or β-CCt (5 mg/kg) in the water maze in rats. The in vitro efficacy study revealed that WYS8 acts as α₁-subtype selective weak partial positive modulator (40% potentiation at 100 nM). Measurement of concentrations of WYS8 and DZP in rat serum and brain tissues suggested that they did not substantially cross-influence the respective disposition. In the water maze, DZP impaired spatial learning (acquisition trials) and memory (probe trial). WYS8 caused no effect per se, did not affect the overall influence of DZP on the water-maze performance and was devoid of any activity in this task when combined with β-CCt. Nonetheless, an additional analysis of the latency to reach the platform and the total distance swam suggested that WYS8 addition attenuated the run-down of the spatial impairment induced by DZP at the end of acquisition trials. These results demonstrate a clear difference in the influence of an α₁ subtype-selective antagonist and a partial agonist on the effects of DZP on the water-maze acquisition.     

Cardiac autonomic dysfunction in patients with gastroesophageal reflux disease

AIM: To investigate autonomic nervous function in patients with a diagnosis of gastroesophageal reflux disease(GERD).METHODS: The investigation was performed on 29patients(14 men), aged 18-80 years(51.14 ± 18.34),who were referred to our Neurocardiology Laboratory at the Clinical and Hospital Center "Bezanijska Kosa"with a diagnosis of GERD. One hundred sixteen healthy volunteers matched in age and sex with the examinees served as the control group. The study protocol included the evaluation of autonomic function and hemodynamic status, short-term heart rate variability(HRV) analysis, 24 h ambulatory ECG monitoring with long-term HRV analysis and 24 h ambulatory blood pressure monitoring.RESULTS: Pathologic results of cardiovascular reflex test were more common among patients with reflux compared to the control group. Severe autonomic dysfunction was detected in 44.4% of patients and in7.9% of controls(P 0.001). Parameters of short-term analysis of RR variability, which are the indicators ofvagal activity, had lower values in patients with GERD than in the control group. Long-term HRV analysis of time-domain parameters indicated lower values in patients with reflux disease when compared to the control group. Power spectral analysis of long-term HRV revealed lower low- and high-frequency values.Detailed 24 h ambulatory blood pressure analysis showed significantly higher values of systolic blood pressure and pulse pressure in the reflux group than in the control group.CONCLUSION: Patients with GERD have distortion of sympathetic and parasympathetic components of the autonomic nervous system, but impaired parasympathetic function appears more congruent to GERD.     

The Carbohydrate Threshold in Pregnancy and Gestational Diabetes: How Low Can We Go?

The original nutrition approach for the treatment of gestational diabetes mellitus (GDM) was to reduce total carbohydrate intake to 33–40% of total energy (EI) to decrease fetal overgrowth. Conversely, accumulating evidence suggests that higher carbohydrate intakes (60–70% EI, higher quality carbohydrates with low glycemic index/low added sugars) can control maternal glycemia. The Institute of Medicine (IOM) recommends ≥175 g/d of carbohydrate intake during pregnancy; however, many women are consuming lower carbohydrate (LC) diets (<175 g/d of carbohydrate or <40% of EI) within pregnancy and the periconceptual period aiming to improve glycemic control and pregnancy outcomes. This report systematically evaluates recent data (2018–2020) to identify the LC threshold in pregnancy in relation to safety considerations. Evidence from 11 reports suggests an optimal carbohydrate range of 47–70% EI supports normal fetal growth; higher than the conventionally recognized LC threshold. However, inadequate total maternal EI, which independently slows fetal growth was a frequent confounder across studies. Effects of a carbohydrate intake <175 g/d on maternal ketonemia and plasma triglyceride/free fatty acid concentrations remain unclear. A recent randomized controlled trial (RCT) suggests a higher risk for micronutrient deficiency with carbohydrate intake ≤165 g/d in GDM. Well-controlled prospective RCTs comparing LC (<165 g/d) and higher carbohydrate energy-balanced diets in pregnant women are clearly overdue.     

A1/A2 polymorphism of the glycoprotein IIIa gene and diabetic retinopathy in Caucasians with type 2 diabetes

Background: A PlA1/A2 polymorphism of glycoprotein IIIa is known to be involved in the pathogenesis of arterial thrombosis, myocardial infarction, stroke and type 2 diabetes, but there is no evidence of association with diabetic retinopathy. The aim of this study was to examine the role of the PlA1/A2 polymorphism of the glycoprotein IIIa gene in the development of diabetic retinopathy in Caucasians with type 2 diabetes. Design: Cross‐sectional case–control study. Participants: Totally 222 patients with diabetic retinopathy and 120 diabetic subjects without clinical signs of diabetic retinopathy from the Eye Clinic, University Medical Centre Ljubljana were enrolled in the study. Methods: Fundus examination and blood biochemical analysis were performed. The polymerase chain reaction and restriction fragment length polymorphism were used. Main Outcome Measures: The total cholesterol, triglyceride, high‐density lipoprotein levels, fasting blood glucose and HbA_1c were measured, and the genotypes of the PlA1/A2 polymorphism were determined. Results: Patients with diabetic retinopathy had earlier onset, longer duration of type 2 diabetes and a higher incidence of insulin therapy compared to the diabetic patients without diabetic retinopathy. A significantly lower frequency of the A2A2 genotype of glycoprotein IIIa was found in diabetic patients with retinopathy compared to those without retinopathy (odds ratio = 0.49, 95% confidence interval = 0.28–0.89; P = 0.018). Conclusions: The A2A2 genotype of the glycoprotein IIIa polymorphism was associated with lower risk for diabetic retinopathy in Caucasians with type 2 diabetes. Further studies are needed to elucidate its protective role in the development of diabetic retinopathy in Caucasians.