Filamin-A as a Balance between Erk/Smad Activities During Cardiac Valve Development

Mitral valve prolapse (MVP) affects 2.4% of the population and has poorly understood etiology. Recent genetic studies have begun to unravel the complexities of MVP and through these efforts, mutations in the FLNA (Filamin-A) gene were identified as disease causing. Our in vivo and in vitro studies have validated these genetic findings and have revealed FLNA as a central regulator of valve morphogenesis. The mechanisms by which FLNA mutations result in myxomatous mitral valve disease are currently unknown, but may involve proteins previously associated with mutated regions of the FLNA protein, such as the small GTPase signaling protein, R-Ras. Herein, we report that Filamin-A is required for R-Ras expression and activation of the Ras–Mek–Erk pathway. Loss of the Ras/Erk pathway correlated with hyperactivation of pSmad2/3, increased extracellular matrix (ECM) production and enlarged mitral valves. Analyses of integrin receptors in the mitral valve revealed that Filamin-A was required for β1-integrin expression and provided a potential mechanism for impaired ECM compaction and valve enlargement. Our data support Filamin-A as a protein that regulates the balance between Erk and Smad activation and an inability of Filamin-A deficient valve interstitial cells to effectively remodel the increased ECM production through a β1-integrin mechanism. As a consequence, loss of Filamin-A function results in increased ECM production and generation of a myxomatous phenotype characterized by improperly compacted mitral valve tissue. Anat Rec, 302:117–124, 2019. © 2018 Wiley Periodicals, Inc.     

Sex-specific effects of ketogenic diet after pre-exposure to a high-fat,high-sugar diet in rats

Background and aimsThe objectives were to evaluate the relationship between ketogenic diets, the ketone body beta-hydroxybutyrate (BHB), parameters known to increase risk for cardiovascular and metabolic diseases in both sexes, using a pre-clinical model of obesity.Methods and resultsRats had access to a diet high in fat and sugar (HFS) for 12 weeks. After HFS, they switched to chow (HFS–CH) or ketogenic diet (HFS-KD) for 3 weeks to model a dietary intervention. Body weight, adiposity, and food intake were measured. Glucose tolerance and corticosterone response to stress were measured after HFS, then again after the intervention. Both sexes increased body weight, food intake, and adiposity compared to control (CTL) while on HFS. HFS females showed impaired glucose tolerance. HFS males developed a dampened corticosterone to stress, whereas HFS females developed an exacerbated response. The effects of HFS on adiposity and corticosterone were reversed in HFS–CH males. These same improvements were observed in HFS–CH females, although they still had impaired glucose tolerance. HFS-KD males showed some improvements, however, they still had higher body weight and adiposity than CTL. The same pattern was observed in females. These beneficial effects of KD correlated with plasma BHB levels in females but not in males.ConclusionsThese data model effects reported in clinical literature and serve as a valuable translational tool to further test causal mechanisms that lead to desirable outcomes of KD. These sex-specific relationships are important, as KD could potentially affect endocrine mechanisms differently in males and females.     

Addressing Oncofertility Needs: Views of Female Cancer Patients in Fertility Preservation

A total of 41 questionnaires were returned from 64 respondents who consented to receive a questionnaire through the mail. Almost all valued the opportunity to receive consultation to address their fertility concerns and discuss fertility preservation options. Psychological stress, time pressure, and costs were identified as main factors affecting respondents’ decision to proceed with in-vitro fertilization to cryopreserve oocytes or embryos. About one third indicated that the discussion of fertility matters was initiated by themselves, their friends, and families rather than their health care providers. The findings have identified several major barriers encountered by female cancer patients when seeking fertility preservation services.     

Bone Tissue Composition in Postmenopausal Women Varies With Glycemic Control From Normal Glucose Tolerance to Type 2 Diabetes Mellitus

The risk of fragility fracture increases for people with type 2 diabetes mellitus (T2DM), even after controlling for bone mineral density, body mass index, visual impairment, and falls. We hypothesize that progressive glycemic derangement alters microscale bone tissue composition. We used Fourier-transform infrared (FTIR) imaging to analyze the composition of iliac crest biopsies from cohorts of postmenopausal women characterized by oral glucose tolerance testing: normal glucose tolerance (NGT; n = 35, age = 65 ± 7 years, HbA1c = 5.8 ± 0.3%), impaired glucose tolerance (IGT; n = 26, age = 64 ± 5 years, HbA1c = 6.0 ± 0.4%), and overt T2DM on insulin (n = 25, age = 64 ± 6 years, HbA1c = 9.13 ± 0.6). The distributions of cortical bone mineral content had greater mean values (+7%) and were narrower (−10%) in T2DM versus NGT groups (p < 0.05). The distributions of acid phosphate, an indicator of new mineral, were narrower in cortical T2DM versus NGT and IGT groups (−14% and −14%, respectively) and in trabecular NGT and IGT versus T2DM groups (−11% and −10%, respectively) (all p < 0.05). The distributions of crystallinity were wider in cortical NGT versus T2DM groups (+16%) and in trabecular NGT versus T2DM groups (+14%) (all p < 0.05). Additionally, bone turnover was lower in T2DM versus NGT groups (P1NP: −25%, CTx: −30%, ucOC: −24%). Serum pentosidine was similar across groups. The FTIR compositional and biochemical marker values of the IGT group typically fell between the NGT and T2DM group values, although the differences were not always statistically significant. In summary, worsening glycemic control was associated with greater mineral content and narrower distributions of acid phosphate, an indicator of new mineral, which together are consistent with observations of lower turnover; however, wider distributions of mineral crystallinity were also observed. A more mineralized, less heterogeneous tissue may affect tissue-level mechanical properties and in turn degrade macroscale skeletal integrity. In conclusion, these data are the first evidence of progressive alteration of bone tissue composition with worsening glycemic control in humans. © 2020 American Society for Bone and Mineral Research (ASBMR).     

Attachment and Sexual Functioning: Understanding the Mediating Role of Body Image Among LGB and Non-LGB Women

IntroductionDespite studies showing that individuals with insecure attachment suffer from poor body image, and that poor body image is a main risk factor for sexual dysfunction, the mediating role of body image between attachment insecurities and sexual functioning has not been assessed. Moreover, differences in body self-consciousness among sexual minority women have not been examined, even though LGB individuals have been found to be more conscious of stigma and the disapproval of others.AimTo fill this gap, the current study examines the mediating role of body image self-consciousness between insecure attachment and sexual functioning among LGB and non-LGB women.MethodsThe study sample consisted of 1,001 women; of them, 808 defined themselves as heterosexual (80.7%), and 193 (19.3%) identified as LGB. The sample was a convenience sample of women who responded to ads on social media. Participants completed an online questionnaire (via Qualtrics) about their attachment orientation, body-image self-consciousness, and sexual functioning.Main OutcomeBody image self-consciousness mediated the relationship between insecure attachment and sexual dysfunction among women in general and LGB women in particular.ResultsResults indicated that among LGB women, the relationship between attachment and sexual functioning was fully mediated by body image self-consciousness. For non-LGB women, a full model with statistically significant direct and indirect effects was revealed. Both avoidant attachment and anxious attachment were related to body image self-consciousness which was, in turn, related to sexual functioning. A statistically significant direct path from avoidant attachment to sexual functioning was also revealed.ConclusionThe study findings contribute to the literature by revealing the mediating role that body image self-consciousness plays between insecure attachment and sexual dysfunction among women in general and LGB women in particular.Clinical ImplicationsThis study provides support for the negative relationship between body image self-consciousness and sexual functioning of women regardless of sexual orientation, and suggests that women affected by body image concerns might be prone to more sexual dysfunction. Therefore, body image self-consciousness should be brought up in sex therapy sessions and future interventions. Clinicians should also be cognizant of differences between LGB and non-LGB women in terms of this effect, taking into account the history of stigma that LGB women may have endured and how this history affects their body image.Gewirtz-Meydan A, Mitchell KJ, Spivak-Lavi Z. Attachment and Sexual Functioning: Understanding the Mediating Role of Body Image Among LGB and Non-LGB Women. J Sex Med 2021;18:1245–1257.     

Disease burden and treatment outcomes in second-line therapy of patients with estrogen receptor-positive (ER+) advanced breast cancer: A review of the literature

ObjectiveTo determine the variable burden of disease of patients with advanced estrogen receptor-positive (ER+) breast cancer and assess the current treatment landscape after failure of first-line endocrine therapy.MethodsA comprehensive literature review was performed (2000–2011) by searching Medline via PubMed, and Embase and Cochrane databases, to assess disease burden (i.e. societal, humanistic, and/or economic burden) and treatment landscape for second-line therapy of ER+ advanced breast cancer in postmenopausal women.ResultsOnly 1 study was identified that evaluated burden of disease based on ER status (ER+, ER-negative, or ER-unknown); this study was a subgroup analysis assessing the impact of breast cancer recurrence over 10 years. The investigators reported that only minor differences in survival and medical costs were noted based on ER status in relapsing patients. Regardless of ER status, patients with breast cancer recurrence consumed more healthcare resources and were associated with more costly care than those without recurrence. A total of 7 studies were identified related to treatment outcomes of second-line therapy in ER+ patients. A combined international population totaled >3800 patients who had progressed on prior hormonal therapy, including tamoxifen and aromatase inhibitors. Three trials performed a comparative efficacy/safety assessment of an ER antagonist vs. aromatase inhibitor, 1 trial compared an aromatase inhibitor to megestrol acetate, and 1 trial compared 2 aromatase inhibitors. Among each of the studies evaluated, no significant differences were observed in the primary efficacy endpoint, and the safety profiles were similar. Two additional studies demonstrated a similar or better efficacy and safety profile based on different dosing evaluations.ConclusionsCurrently, there is insufficient evidence on the economic and humanistic burden associated with ER status, and this gap warrants further research. With increasing drug resistance and greater economic burden associated with breast cancer recurrence, there is an unmet medical need for improved treatment in this patient population.     

Impulsive or Depressive Personality Traits Do Not Impede Behavioral Change After Brief Alcohol Interventions

ABSTRACT

The authors investigated whether impulsivity and depression affect the success of interventions to reduce alcohol use. Unadjusted and adjusted regression models were constructed to analyze the effect of impulsivity and depression on 12-month outcomes of participants of a trauma center based randomized trial of brief personalized motivational interventions versus information and advice. Of 497 problem drinkers enrolled in the program, 248 completed the 12-month follow-up. Impulsivity, male gender, being older than 35, and intentional mechanism of injury had a direct association with drinking. After interventions, a decrease in drinking was found that was unaffected by the presence of impulsivity or depression indicators.     

Birth plans—Impact on mode of delivery,obstetrical interventions,and birth experience satisfaction: A prospective cohort study

Objective

To examine whether the presence of a birth plan was associated with mode of delivery, obstetrical interventions, and patient satisfaction.

Methods

This was a prospective cohort study of singleton pregnancies greater than 34 weeks’ gestation powered to evaluate a difference in mode of delivery. Maternal characteristics, antenatal factors, neonatal characteristics, and patient satisfaction measures were compared between groups. Differences between groups were analyzed using chi‐squared for categorical variables, Fisher exact test for dichotomous variables, and Wilcoxon rank sum test for continuous or ordinal variables.

Results

Three hundred women were recruited: 143 (48%) had a birth plan. There was no significant difference in the risk of cesarean delivery for women with a birth plan compared with those without a birth plan (21% vs 16%, adjusted odds ratio [adjOR] 1.11 [95% confidence interval (CI) 0.61‐2.04]). Women with a birth plan were 28% less likely to receive oxytocin (P < .01), 29% less likely to undergo artificial rupture of membranes (P < .01), and 31% less likely to have an epidural (P < .01). There was no difference in the length of labor (P = .12). Women with a birth plan were less satisfied (P < .01) and felt less in control (P < .01) of their birth experience than those without a birth plan.

Conclusion

Women with and without a birth plan had similar odds of cesarean delivery. Though they had fewer obstetrical interventions, they were less satisfied with their birth experience, compared with women without birth plans. Further research is needed to understand how to improve childbirth‐related patient satisfaction.