Beta cyclodextrins bind,stabilize, and remove lipofuscin bisretinoids from retinal pigment epithelium

Accumulation of lipofuscin bisretinoids (LBs) in the retinal pigment epithelium (RPE) is the alleged cause of retinal degeneration in genetic blinding diseases (e.g., Stargardt) and a possible etiological agent for age-related macular degeneration. Currently, there are no approved treatments for these diseases; hence, agents that efficiently remove LBs from RPE would be valuable therapeutic candidates. Here, we show that beta cyclodextrins (β-CDs) bind LBs and protect them against oxidation. Computer modeling and biochemical data are consistent with the encapsulation of the retinoid arms of LBs within the hydrophobic cavity of β-CD. Importantly, β-CD treatment reduced by 73% and 48% the LB content of RPE cell cultures and of eyecups obtained from Abca4-Rdh8 double knock-out (DKO) mice, respectively. Furthermore, intravitreal administration of β-CDs reduced significantly the content of bisretinoids in the RPE of DKO animals. Thus, our results demonstrate the effectiveness of β-CDs to complex and remove LB deposits from RPE cells and provide crucial data to develop novel prophylactic approaches for retinal disorders elicited by LBs.The retinal pigment epithelium (RPE), strategically situated between the neural retina and the choroid blood vessels, is essential for photoreceptor (PR) function. It recycles vitamin A, which is required for the visual cycle and clears debris generated by the circadian shedding of PR outer segments (1, 2). Each RPE cell phagocytoses and digests the material produced by 30–50 overlying PRs, which shed 10% of their mass daily. The intense and continual phagocytic activity of RPE cells results in the progressive accumulation of indigestible products or “lipofuscin” in their lysosomal compartment (3, 4). Unlike lipofuscins found in other body tissues, which are composed mainly of protein, RPE lipofuscin consists predominantly of lipid-bisretinoids and only 2% protein (5). Lipofuscin bisretinoids (LBs) are vitamin A-derived side products of the visual cycle. Light converts 11-cis-retinal (11CR), the visual pigment chromophore, into all-trans-retinal (ATR), which is immediately flipped by the ATP-binding cassette transporter 4 (Abca4) transporter from the lumen of the outer segment discs to the cytoplasm, where it is reduced to inert all-trans-retinol by retinol dehydrogenase 8 (Rdh8), in mice (6, 7). Small fractions of 11CR and ATR are converted into N-retinylidine-N-ethanolamine (A2E) and other less abundant bisretinoids, which once accumulated in the lysosomes of RPE cells are refractory to all known lysosomal hydrolases (8, 9). The concept that LB accumulation causes retinal degeneration is supported by in vitro and in vivo data that show that excessive LBs are toxic for cultured RPE cells (10, 11), that photoreceptors overlying A2E-laden RPE are more prone to degeneration (12) and that excessive accumulation of LBs in Stargardt’s disease precedes macular degeneration (13). Mice carrying null mutations in Abca4 and Rdh8 develop blindness, basal laminar deposits, and focal accumulations of extracellular debris between the RPE and the Bruch membrane (drusen) (6).Here we report that a family of modified cyclic oligosaccharides, beta cyclodextrins (β-CDs), formed by seven d-glucose units, can encapsulate the hydrophobic arms of A2E within their nonpolar cavity, protect A2E from oxidation, and remove A2E from RPE cells. Our data demonstrate a direct correlation between the ability of β-CDs to perform these protective functions and their affinity for A2E.     

Associations of Adolescent Hopelessness and Self-Worth With Pregnancy Attempts and Pregnancy Desire

Objectives. We examined the associations of pregnancy desire (ambivalence or happiness about a pregnancy in the next year) and recent pregnancy attempts with hopelessness and self-worth among low-income adolescents.Methods. To evaluate independent associations among the study variables, we conducted gender-stratified multivariable logistic regression analyses with data derived from 2285 sexually experienced 9- to 18-year-old participants in the Mobile Youth Survey between 2006 and 2009.Results. Fifty-seven percent of youths reported a desire for pregnancy and 9% reported pregnancy attempts. In multivariable analyses, hopelessness was positively associated and self-worth was negatively associated with pregnancy attempts among both female and male youths. Hopelessness was weakly associated (P = .05) with pregnancy desire among female youths.Conclusions. The negative association of self-worth and the positive association of hopelessness with pregnancy attempts among young men as well as young women and the association of hopelessness with pregnancy desire among young women raise questions about why pregnancy is apparently valued by youths who rate their social and cognitive competence as low and who live in an environment with few options for material success.Rates of adolescent pregnancy and childbearing in the United States are among the highest in the developed world.1 Each year, approximately 750 000 women younger than 20 years become pregnant,2 and about 400 000 give birth.3 In the United States, adolescent pregnancy rates are about two thirds higher among non-White young women than among White young women, and childbearing rates are approximately one third higher2; 57% of births to adolescents in 2010 were to African American or Hispanic/Latino mothers.3 Surveillance data for 9th- to 12th-grade US students show that Blacks and Hispanics are more likely than Whites to engage in risk behaviors associated with pregnancy (e.g., vaginal intercourse at an early age, nonuse of hormonal contraceptives).4Race and ethnicity do not, in themselves, explain adolescent pregnancy risk. Kirby identified more than 100 antecedents of adolescent pregnancy, primarily related to the types of physical and social environments in which minority youths in the United States are disproportionately represented.5 He concluded that most risk factors, including poor school performance6 and residence in a socioeconomically disadvantaged neighborhood,7–9 reflected dysfunction, disadvantage, or disorganization. Offspring of adolescent parents or sisters of women who began childbearing in adolescence are at high risk for adolescent parenthood, suggesting a cultural or intergenerational component.8–10 Family quality, especially parent characteristics and relationships9,11–16; the quality of relationships with one’s school, residential community, and peers6,7,9,12,14; and substance use and mental health,9,17–22 are associated with pregnancy or pregnancy risk behaviors among both female and male adolescents.Youths who live in challenging social and physical environments typically have negative psychological and cognitive responses to their surroundings (e.g., low self-worth and hopelessness).23,24 Although the evidence is mixed,20–22,25,26 it is generally assumed that poor self-image, poor self-worth, and poor self-esteem in girls are associated with pregnancy or pregnancy risk markers, including early age at first vaginal intercourse and an inability to negotiate condom use. Hopelessness reflects negative expectations about future desired or valued outcomes and helplessness with respect to one’s ability to change the odds that negative outcomes will occur.27 Hopelessness has been identified as a risk marker for youth violence and self-harm and poor adult social trajectories.24,28–31 In industrialized countries, adolescent pregnancy (and the decision to continue a pregnancy) may be a consequence of a lack of hope and the perception of too few positive life options,32,33 although only a limited number of studies have directly examined hopelessness and pregnancy risk.Kogan et al. examined a related phenomenon, conventional future orientation, and found associations with decreased sexual risk taking at age 16 and avoidance of pregnancy at age 19 years.34 A 2013 study of Mobile Youth Survey (MYS) participants showed that having a positive feeling about the future was marginally associated with older age at first intercourse, a risk factor for adolescent pregnancy.35 Neither study examined female and male youths separately. Despite the health, social, and economic burdens associated with pregnancy involvement among boys,9,36,37 little is known about the psychological or cognitive correlates of adolescent paternity risk.Adolescent pregnancy and childbearing disproportionately occur among historically marginalized youths and present significant, and often lifelong, social and health risks to parents and their offspring.37 Many known antecedents, including poverty, neighborhood quality, and quality of the parental relationship, may be intractable. However, learned cognitive factors such as hopelessness and low self-worth may be modifiable.27Because of our overarching interest in identifying potentially intervenable correlates of pregnancy involvement among high-risk youths, we examined the hypotheses that hopelessness is positively associated and self-worth is negatively associated with 2 known risk markers of adolescent pregnancy: pregnancy attempts and pregnancy desire.15,26,38–42 Our analyses involved a cross-sectional sample of adolescent female and male participants in the MYS,43 a study of primarily African American and impoverished young people with little variation in their social risk for pregnancy. Because there may be gendered cultural meanings or consequences associated with early pregnancy and parenting (especially in communities where rates of adolescent pregnancy are disproportionately high) and because the psychological or cognitive correlates of pregnancy risk may vary according to gender,21,22 we examined female and male youths separately.     

Warmed,humidified carbon dioxide insufflation versus standard carbon dioxide in laparoscopic cholecystectomy: a double-blinded randomized controlled trial

Background

During laparoscopic cholecystectomy (LCHE), the insufflation with warmed and humidified carbon dioxide (CO₂) may reduce postoperative pain. The aim of the study was to evaluate the positive effects of heated and humidified carbon dioxide gas on patients with regard to postoperative pain after LCHE.

Patients and methods

This is a prospective, randomized, double-blinded, controlled clinical trial. 148 patients (female = 98, male = 50) scheduled for elective LCHE were randomized into two groups: receiving either heated humidified carbon dioxide, or standard gas. Intraoperative core temperature was measured. The perioperative management was identical for both groups. Postoperative pain intensity was assessed using a visual analog pain scale, and the amount of analgesic consumption was recorded. The postoperative pain management was also standardized and equal for both groups.

Results

67 out of 148 received standard gas (group A), and 81 received warmed, humidified gas (group B). The groups were comparable demographically. The amount of analgesic consumption was recorded. Intraoperative core temperature was significant higher in group B than in group A. Pain was significantly less in group B (p = 0.025) 6 h postoperatively. On the first postoperative day, no significant difference in pain between the two groups was detectable (p = 0.437).

Conclusion

The use of warmed and humidified carbon dioxide during LCHE reduces postoperative pain at the day of operation.     

Older women with diabetes have an increased risk of fracture: a prospective study

To determine whether type 2 diabetes is associated with fracture in older women, we analyzed data from 9654 women, age 65 yr or older, in the Study of Osteoporotic Fractures. Diabetes with age at onset 40 yr or older was reported by 657 women, of whom 106 used insulin. A total of 2624 women experienced at least one nonvertebral fracture during an average follow-up of 9.4 yr, and 388 had at least one vertebral fracture during an average interval of 3.7 yr. Although diabetes was associated with higher bone mineral density, it was also associated with a higher risk of specific fractures. Compared with nondiabetics, women with diabetes who were not using insulin had an increased risk of hip [relative risk (RR), 1.82; 95% confidence interval (CI), 1.24-2.69] and proximal humerus (RR, 1.94; 95% CI, 1.24-3.02) fractures in multivariate models controlling for age, body mass index, bone density, and other factors associated with fractures and diabetes. Insulin-treated diabetics had more than double the risk of foot (multivariate adjusted RR, 2.66; 95% CI, 1.18-6.02) fractures compared with nondiabetics. This study indicates that diabetes is a risk factor for hip, proximal humerus, and foot fractures among older women, suggesting that fracture prevention efforts should be a consideration in the treatment of diabetes.     

Simple Nutrient-Based Rules vs. a Nutritionally Rich Plant-Centered Diet in Prediction of Future Coronary Heart Disease and Stroke: Prospective Observational Study in the US

To better understand nutrition paradigm shift from nutrients to foods and dietary patterns, we compared associations of a nutrient-based blood cholesterol-lowering diet vs. a food-based plant-centered diet with risk of coronary heart disease (CHD) and stroke. Participants were 4701 adults aged 18–30 years and free of cardiovascular disease at baseline, followed for clinical events from 1985 and 86 to 2018. A plant-centered diet was represented by higher A Priori Diet Quality Score (APDQS). A blood cholesterol-lowering diet was represented by lower Keys Score. Proportional hazards regression was used to calculate hazard ratios (HR). Higher APDQS showed a nutrient-dense composition that is low in saturated fat but high in fiber, vitamins and minerals. Keys Score and APDQS changes were each inversely associated with concurrent plasma low-density lipoprotein cholesterol (LDL-C) change. Over follow-up, 116 CHD and 80 stroke events occurred. LDL-C predicted CHD, but not stroke. APDQS, but not Keys Score, predicted lower risk of CHD and of stroke. Adjusted HRs (95% CIs) for each 1-SD higher APDQS were 0.73 (0.55–0.96) for CHD and 0.70 (0.50–0.99) for stroke. Neither low dietary fat nor low dietary carbohydrate predicted these events. Our findings support the ongoing shift in diet messages for cardiovascular prevention.     

Fractionating the all-or-nothing definition of goal-directed and habitual decision-making

Goal-directed and habitual decision-making are fundamental processes that support the ongoing adaptive behavior. There is a growing interest in examining their disruption in psychiatric disease, often with a focus on a disease shifting control from one process to the other, usually a shift from goal-directed to habitual control. However, several different experimental procedures can be used to probe whether decision-making is under goal-directed or habitual control, including outcome devaluation and contingency degradation. These different experimental procedures may recruit diverse behavioral and neural processes. Thus, there are potentially many opportunities for these disease phenotypes to manifest as alterations to both goal-directed and habitual controls. In this review, we highlight the examples of behavioral and neural circuit divergence and similarity, and suggest that interpretation based on behavioral processes recruited during testing may leave more room for goal-directed and habitual decision-making to coexist. Furthermore, this may improve our understanding of precisely what the involved neural mechanisms underlying aspects of goal-directed and habitual behavior are, as well as how disease affects behavior and these circuits.     

Perimenopause and depression: strength of association, causal mechanisms and treatment recommendations

Perimenopause represents a significant transition in a woman's life. The evidence to support an association between perimenopause and depression is mixed, yet recent prospective studies have provided stronger evidence to support such an association. Interpretation of study data are complicated by methodological issues, such as a lack of standard definition for perimenopause or depression, reducing comparability. A variety of causal factors, including psychological, genetic and physiological, have been implicated in depression during perimenopause, which lends weight to a multifactorial model. Physicians should consider initiating dialogue about menopause and symptom relief at age 40 and screening perimenopausal women for depressive symptoms. Selective serotonin reuptake inhibitors are a first line of treatment for depression, but hormone therapy could be considered for women experiencing menopausal symptoms unless there are contraindications. Future research should focus on establishing temporality and studying these potential relationships among women of different ethnicities.     

Randomized trial of transcutaneous tibial nerve stimulation to treat urge urinary incontinence in older women

Introduction  

The aim of this study was to examine the efficacy of transcutaneous electrical tibial nerve stimulation (TTNS) to treat urge urinary incontinence (UUI) in older women.