Urinary Bisphenol A Levels in Girls with Idiopathic Central Precocious Puberty

Ob­jec­ti­ve: Bisphenol A (BPA) is an industrial chemical, particularly used to harden plastics. BPA is thought to have negative health effects on both laboratory animals and humans. Consider ing the decline in age of onset of puberty noted in recent years, particularly among girls, the importance of BPA as an estrogenic endocrine disruptor has increased. In this study, we aimed to determine urinary BPA levels in girls with idiopathic central precocious puberty (ICPP).Methods: Non-obese girls newly diagnosed with ICPP (n=28, age 4-8 years) constituted the study group. The control group consisted of 25 healthy age-matched girls with no history of ICPP or any other endocrine disorder. Urinary BPA levels were measured by using high-performance liquid chromatography.Results: In the ICPP group, urinary BPA levels were significantly higher compared to the control group [median 8.34 (0.84-67.35) μg/g creatinine and 1.62 (0.3-25.79) μg/g creatinine, respectively (OR=8.68, 95% CI:2.03-32.72, p=0.001)]. There was no marked correlation between urinary BPA levels and body mass index in either group. In the ICPP group, no significant correlations were found between urinary BPA levels and serum luteinizing hormone, follicle-stimulating hormone and estradiol levels.Conclusions: To our knowledge, this is the first study evaluating the urinary BPA levels in Turkish girls with ICPP. Our results indicate that the estrogenic effects of BPA may be an etiologic factor in ICPP.     

The effects of implantable collamer lens implantation on higher order aberrations

AIM: To evaluate the changes in higher order aberrations (HOAs) after implantable collamer lens (ICL; Staar Surgical, Nidau, Switzerland) implantation. METHODS: Totally 30 eyes of 18 patients with myopia were included in this study with an average age of 25.77y (min: 21, max: 40). Refraction, uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), HOAs (entire, corneal and internal) were evaluated preoperatively and three months postoperatively. Ocular aberrations were measured by using iTrace (Tracey Technology, Houston, Texas, USA). SPSS (IBM Corp. Released 2013. IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY: IBM Corp) was used for the statistical analysis and the interpretation of the data. P values of less than 0.05 were considered statistically significant. RESULTS: The preoperative mean spherical power was -9.01 D (min: -5.00, max: -13.00) and the mean cylindrical error was -2.40 D (min: -0.50, max: -4.75). The postoperative mean residual spherical power was -0.73 D (min: -0.20, max: -1.75) and the mean cylindrical error was -0.89 D (min: -0.18, max: -2.09). Analyses were made on root mean square (RMS) values of total HOAs (tHOAs), spherical aberration, coma and trefoil as entire, corneal and internal components. The differences in entire tHOAs and in internal tHOAs were significant. There was no significant change found in spherical aberrations. The differences in entire coma and in internal coma were significant. There was no significant change found in corneal coma. With respect to trefoil, the only significant difference was in internal trefoil. CONCLUSION: The ICL implantation corrects the refractive error successfully and changes entire and internal HOAs of the eye.     

Early time-locked gamma response and gender specificity

The aim was to investigate whether gender is a causative factor in the gamma status according to which some individuals respond with time-locked, early gamma response, G+, while the others do not show this response, G−. The sample consisted of 42 volunteer participants (between 19 and 37 years of age with at least 9 years of education). There were 22 females and 20 males. Data were collected under the oddball paradigm. Auditory stimulation (10 ms r/f time, 50 ms duration, 65 dB SPL) consisted of target (2000 Hz; p = .20) stimuli that occurred randomly within a series of standard stimuli (1000 Hz; p = .80). Gamma responses were studied in the amplitude frequency characteristics, in the digitally filtered event-related potentials (f-ERPs) and in the distributions which were obtained using the recently developed time–frequency component analysis (TFCA) technique. Participants were classified into G+ and G− groups with a criterion of full agreement between the results of an automated gamma detection technique and expert opinion. The 2 × 2 × 2 ANOVA on f-ERPs and 2 × 2 × 2 multivariate ANOVA on TFCA distributions showed the main effect of gamma status and gender as significant, and the interaction between gamma status and gender as nonsignificant. Accordingly, individual difference in gamma status is a reliable phenomenon, but this does not depend on gender. There are conflicting findings in the literature concerning the effect of gender on ERP components (N100, P300). The present study showed that if the gamma status is not included in research designs, it may produce a confounding effect on ERP parameters.     

Antioxidants but not Doxycycline Treatments Restore Depressed Beta-Adrenergic Responses of the Heart in Diabetic Rats

Reactive oxygen species (ROS) play important roles in the development of diabetic cardiomyopathy. Matrix metalloproteinases (MMPs) can get activated by ROS and contribute to loss of myocardial contractile function in oxidative stress injury. Previously we have shown that either a MMP-2 inhibitor doxycycline or an antioxidant selenium treatment in vivo prevented diabetes-induced cardiac dysfunction significantly. In addition, there is an evidence for impaired cardiac responsiveness to β-adrenoceptor (βAR) stimulation in experimental animals with diabetes. The exact nature of linkage between the functional depression in cardiac responses to catecholamines and the variations in uncoupling of βAR in diabetes has not been clearly defined. Therefore, we aimed to evaluate the effect of in vivo administration of doxycycline on βAR responses of isolated hearts from diabetic rats and compare these data with two well-known antioxidants; sodium selenate and (n−3) fatty acid-treated diabetic rats. We examined the changes in the basal cardiac function in response to the βAR stimulation, adenylate cyclase activity, and βAR affinity to its agonist, isoproterenol. These results showed that antioxidant treatment of diabetic rats could protect the hearts against diabetes-induced depression in βAR responses, significantly while doxycycline did not have any significant beneficial action on these parameters. As a summary, present data, in part, demonstrate that antioxidants and MMP inhibitors could both regulate MMP function but may also utilize different mechanisms of action in cardiomyocytes, particularly related with βAR signaling pathway.     

Lawmakers' use of scientific evidence can be improved

Core to the goal of scientific exploration is the opportunity to guide future decision-making. Yet, elected officials often miss opportunities to use science in their policymaking. This work reports on an experiment with the US Congress—evaluating the effects of a randomized, dual-population (i.e., researchers and congressional offices) outreach model for supporting legislative use of research evidence regarding child and family policy issues. In this experiment, we found that congressional offices randomized to the intervention reported greater value of research for understanding issues than the control group following implementation. More research use was also observed in legislation introduced by the intervention group. Further, we found that researchers randomized to the intervention advanced their own policy knowledge and engagement as well as reported benefits for their research following implementation.

Recent public crises have further illustrated the importance of policymakers using scientific research to craft effective public policies (e.g., opioid epidemic, humanitarian emergencies at the border, COVID-19 pandemic). Yet, despite the ongoing desire among the scientific community and general public to see research being utilized by lawmakers (1), little rigorous study has investigated the effectiveness of approaches to increase policymakers’ use of research evidence (URE; ref. 2). Particularly concerning is that the promising strategies currently available have yet to undergo rigorous experimental evaluation to see if they can change lawmaker behavior. Ultimately, if the scientific community truly wants to see research used, it is time to develop engagement strategies that are themselves evidence-based.Growing scientific study of how to improve the use of scientific evidence has shed light on the “social side” of successful research translation and evidence-based policymaking (2–5). Specifically (4), theoretical work and empirical studies have demonstrated that sustaining researcher-lawmaker relationships may be essential for supporting URE throughout the policymaking process (6, 7). In particular, structures provided by intermediary organizations have the potential to support trusting relationships between the research and policy communities (4, 6). However, work is needed to experimentally test the effectiveness of approaches designed to facilitate these processes.Although researchers’ engagement is critical for bridging research and policy, they face numerous barriers when navigating the policy arena (5, 6, 8, 9). Formal intermediary support for researchers can help improve the frequency and manner of policymakers’ URE (10, 11). This includes understanding restrictions around outreach, overcoming divergent professional norms, and adapting to the dramatically different pace of policy settings. For instance, researchers tend to engage in relatively slow decision-making, while policymakers engage in prompt policy actions in response to opportunities or crises (7, 8, 12, 13). Timeliness of researcher engagement is particularly challenging since public policy goals often shift suddenly in response to socio-political factors (9, 14). Thus, there is a need for engaging researchers in real-time during discrete, time-limited opportunities for policy change (10, 15).Policymakers can decide to use research evidence for varied purposes or intentions. A widely used typology in URE investigations is informed by foundational work of multiple scholars (16, 17). While researchers often deplore political uses of research for persuading others, justifying, or challenging existing policy proposals (i.e., tactical use), research evidence can also be used to guide policy development itself. This includes instances in which research is used to directly inform policy decisions (i.e., instrumental use) as well as instances in which research is indirectly used by changing the way policymakers think about problems or solutions (i.e., conceptual use). While instrumental uses may be relatively observable in specific policy efforts, conceptual use may influence a broad array of decisions in a more indirect manner (16, 17).While some experimental study of evidence use is occurring at the state level, no work has considered how to improve Congressional evidence use (18). In an effort to create evidence-based strategies for increasing policymaker-researcher engagement and supporting URE by lawmakers, we report here on a randomized controlled trial of such a strategy with the US Congress. In this study, we randomized congressional offices and researchers to receive a promising approach for improving URE known as the Research-to-Policy Collaboration (RPC).The RPC is a theory-based and manualized intervention for supporting lawmakers URE (Fig. 1). In particular, this work corresponds with Weiss’ conceptualization of both problem-solving and interactive models of knowledge use (17) by first eliciting policymakers’ needs and then facilitating interactions with researchers. First, a formal legislative needs assessment is used to identify policymakers’ goals, priorities, and need for scientific evidence (e.g., epidemiology and etiology, examples of successful interventions). Then, researchers who have expertise corresponding with those policy domains are coalesced into rapid response networks. These networks are provided with capacity building to increase their readiness to engage with congressional offices, fluency in the policy process, and best practices for translating research. Rapid response teams of researchers are then matched with offices based on office needs assessment results. Next, facilitated meetings occur between the office and researcher teams to further address their needs for scientific evidence. The ultimate goal of the RPC model is to create durable and productive collaborations that move beyond initial requests—with offices calling on researchers for additional questions and needs. The current study examines early indicators of outcomes associated with the model in early stages of this interactive process. Specifically, we examine outcomes associated with an implementation of the RPC pertaining to US federal child and family policymaking, although there is potential for the RPC to be used to support policymaker URE in other disciplines, as well as state or international contexts.Open in a separate windowFig. 1.The RPC Intervention Model. Step 1: Policy Identification involves initial outreach to legislative staff and uses a semistructured needs assessment to inquire about policymakers’ overarching policy goals for the legislative session. Step 2: Rapid Response Network Development involves identifying researchers who have expertise relevant to policymakers’ goals and are willing to contribute to research translation efforts. Their areas of expertise are cataloged in a strategic resource mapping process that builds capacity for matching researchers with policymakers. Step 3: Network Capacity Building occurs through didactic and experiential training that aims to increase policy skills and engagement. This includes training on adapting to legislative norms without violating lobbying regulations, as well as opportunities to respond to lawmakers’ interests identified in Step 1. Step 4: Legislative Needs Assessment identifies short-term priorities and needs in anticipation of matching policymakers with researchers who have corresponding experiences and scholarly interests. This semistructured assessment is action-oriented to identify ways that researchers might support legislative efforts. Step 5: Rapid Response Meetings engage legislative staff and researchers in direct interactions to discuss research, as this is a theorized mechanism for facilitating relationship development. Meetings aim to support the codevelopment of science implications, since research interpretation is a formative and iterative process. Researchers respond to initial legislative requests and plan next steps for ongoing collaboration. Researchers are invited for these meetings based on prior RPC participation, time availability, relevant scholarly interests, and geographic similarities (e.g., researchers having done work in the state the congressional member represents). Step 6: Initial Strategic Planning for rapid responses follows immediately after meetings to summarize goals, determine next steps, prioritize and create a timeline, and identify point person(s) for follow-up. Step 7: Ongoing Collaboration includes rapid responses to legislative requests. As an example, this could include collecting and summarizing research resources, planning briefing events or testimony, or publishing written products for dissemination (e.g., briefs, op-eds).Congressional office engagement is initiated by scheduling a needs assessment conducted by a trained policy associate, which often occurs in-person, but may also be done remotely. Some offices meet multiple times prior to or for the purposes of engaging with researchers, whereas others may meet less often, especially contingent on the clarity in next steps for ongoing collaboration. This interactive process is intended to generate requests for researcher engagement, including translational deliverables such as policy briefs and factsheets, congressional briefings, and testimony, as well as requests to review or provide legislative language for bill drafting (5, 8). Requests, in turn, provide researchers with opportunities to engage in the policy process and create tangible products that align with their professional incentive structures. Throughout the process, researchers are supported with training and technical assistance that facilitates appropriate translation and exchange of research. Training is provided by RPC implementers and policy associates who have experience with legislative engagement, science communications, and the process of using research in public policy. Importantly, no lobbying occurs as part of this process, and researchers are trained in the rules and regulations pertaining to lobbying.To experimentally evaluate this intervention, a dual-population randomized controlled trial was undertaken with congressional offices and researchers (Fig. 2). Congressional offices received either the RPC or a light-touch traditional support condition (i.e., the control condition offered support by providing publicly available, research-based resources). Researchers were randomized to receive the RPC intervention or a traditional static policy engagement training curriculum. Child and family policies were the focus of participants’ engagement; therefore, legislation reviewed in this study pertained to child and family policies.Open in a separate windowFig. 2.Consort diagrams for the RPC Evaluation. (A) Ninety-six congressional offices agreed to participate in the study and were randomized to receive either the RPC or control group condition. (B) Two hundred twenty-six researchers agreed to participate in the study and were randomized to receive either the RPC or control group condition.     

Relationship Between Serum Macrophage Migration Inhibitory Factor Level and Insulin Resistance,High-Sensitivity C-Reactive Protein and Visceral Fat Mass in Prediabetes

Background

Growing evidence suggest that macrophage migration inhibitory factor (MIF) plays a vital role in glucose metabolism. We aimed to ascertain whether MIF levels are altered in subjects with prediabetes and also to determine the relationship between MIF and metabolic parameters as well as visceral fat mass.

Proton-coupled electron transfer and the role of water molecules in proton pumping by cytochrome c oxidase

Molecular oxygen acts as the terminal electron sink in the respiratory chains of aerobic organisms. Cytochrome c oxidase in the inner membrane of mitochondria and the plasma membrane of bacteria catalyzes the reduction of oxygen to water, and couples the free energy of the reaction to proton pumping across the membrane. The proton-pumping activity contributes to the proton electrochemical gradient, which drives the synthesis of ATP. Based on kinetic experiments on the O–O bond splitting transition of the catalytic cycle (A → P_R), it has been proposed that the electron transfer to the binuclear iron–copper center of O₂ reduction initiates the proton pump mechanism. This key electron transfer event is coupled to an internal proton transfer from a conserved glutamic acid to the proton-loading site of the pump. However, the proton may instead be transferred to the binuclear center to complete the oxygen reduction chemistry, which would constitute a short-circuit. Based on atomistic molecular dynamics simulations of cytochrome c oxidase in an explicit membrane–solvent environment, complemented by related free-energy calculations, we propose that this short-circuit is effectively prevented by a redox-state–dependent organization of water molecules within the protein structure that gates the proton transfer pathway.Life on Earth is supported by a constant supply of energy in the form of ATP. Cytochrome c oxidase (CcO) in the respiratory chains of mitochondria and bacteria catalyzes the exergonic reduction of molecular oxygen (O₂) to water and uses the free energy of the reaction to pump protons across the membrane (1–3). The oxygen reduction reaction takes place at a highly conserved active site formed by two metal sites, heme a₃ and Cu_B (Fig. 1 A and B), called the binuclear center (BNC). The electrons donated by the mobile electron carrier cytochrome c reach the BNC via two other conserved metal centers, Cu_A and heme a (Fig. 1A). The protons required for the chemistry of O₂ reduction to water, and for proton pumping, are transported with the assistance of side chains of polar amino acids and conserved water molecules in the protein interior (4–6) (Fig. 1A). Two such proton transfer pathways have been described in the mitochondrial and bacterial A-type oxidases (to distinguish between different types of oxidases, see ref. 7), namely, the D and K channels (8, 9), the names of which are based on the conserved amino acid residues Asp91 and Lys319, respectively (Fig. 1A, amino acid numbering based on the bovine heart CcO). The D channel is responsible for the translocation of all of the pumped protons, and for the transfer of at least two of the four protons required for oxygen reduction chemistry, whereas the K channel supplies one or two protons to the BNC during the reductive phase of the catalytic cycle (8, 9). The D channel terminates at a highly conserved glutamic acid residue, Glu242, from where the protons are either transferred to the BNC for consumption, or to the proton-loading site (PLS) for pumping across the membrane (Fig. 1A). In 2003, Wikström et al. postulated a molecular mechanism in which water molecules in the nonpolar cavity above Glu242 would form proton-transferring chains, the orientation of which depends upon the redox state of the enzyme (10). They proposed that the reduction of the low-spin heme would result in transfer of a proton via a preorganized water chain from Glu242 to the d-propionate (Dprp) of the high-spin heme, whereas in the case when the electron has moved to the BNC, the water chain would reorientate and conduct protons from Glu242 to the BNC (Fig. 1A, and see below). Even though there is little direct experimental support available for such a water-gated mechanism, a recent FTIR study indeed suggests changes in water organization upon changes in the redox state of the enzyme (11). Many of the elementary steps that were postulated in the water-gated mechanism have gained support from experiments in the recent past (12, 13).Open in a separate windowFig. 1.(A) A three-subunit (SU) CcO. SU I (blue), II (red), and III (orange) are displayed as transparent ribbons. The D and K channels of proton transfer are marked with blue arrows. Crystallographic water molecules present in these proton channels are shown in purple. Electron transfer (red arrow) takes place from Cu_A (orange) via heme a (yellow) to the binuclear center comprising heme a₃ (yellow)–Cu_B (orange). Protons are transferred from Glu242 (E242) either to the PLS or to the binuclear center (black arrows). Lipid bilayer (silver lines), water (gray dots), and sodium (light yellow) and chloride (cyan) ions are also displayed. (B) The catalytic cycle of CcO. The states of heme a₃, Cu_B, and the cross-linked tyrosine are displayed. Each light orange rectangle corresponds to a state of the BNC, the name of which is displayed in red (Upper Right). Pumped protons are shown in blue, black H⁺ indicates uptake of a proton for water formation, and e⁻ indicates transfer of an electron from the low-spin heme a. Catalysis of O₂ reduction occurs clockwise.It is generally thought that the proton pump of CcO operates via the same mechanism in each of the 4 one-electron reduction steps of the catalytic cycle (Fig. 1B). However, kinetic data on two different transitions (A → P_R and O_H → E_H) have suggested dissimilarities in some of the elementary steps (12, 13). Fully reduced enzyme reacts with oxygen and forms an oxygenated adduct A in ca. 10 µs, followed by splitting of the O–O bond leading to formation of the P_R intermediate (in ∼25 μs) that is linked to loading of the PLS with a proton (3, 12). O–O bond splitting from state A in the absence of electrons in heme a or Cu_A yields the stable state P_M without proton transfer to the PLS (3, 12). Therefore, it is the electron transfer from heme a into the BNC accompanying O–O bond scission during A → P_R that is linked to the proton transfer to the PLS. The structure of the P_R intermediate is well characterized with ferryl heme a₃, cupric hydroxide, and tyrosinate (3, 14). In P_M the tyrosine is almost certainly in the form of a neutral radical (3, 14), so the reaction P_M → P_R is a proton-coupled electron transfer reaction (PCET) that initiates the reactions of the proton pump (3, 12). Note that in the state P_R the proton at the PLS partially neutralizes the electron in the BNC (3) in accordance with the charge-neutralization principle of the BNC (15). However, an important question arises: how can proton transfer from Glu242 to the BNC be prevented, which would short-circuit one step of proton pumping and form the next stable intermediate F? In the O_H → E_H transition of the catalytic cycle this short-circuit is minimized because reduction of the low-spin heme is thought to raise the pK_a of the PLS sufficiently to lead to its protonation before transfer of the electron to the BNC (3, 10, 13, 16–18), and uncompensated proton transfer to the BNC is endergonic in nature (refs. 13,16,17; cf. ref. 19). In contrast, the likelihood of a proton leak in the A → P_R transition increases manifold because the electron transfer from heme a to the BNC is required for loading of the PLS with a proton (3, 12). This facet is analyzed in the current work, and it is proposed that it is the orientation of the water molecules in the nonpolar cavity above Glu242 that effectively gates the pump and minimizes such a short-circuit.     

Ursodeoxycholic acid and atorvastatin in the treatment of nonalcoholic steatohepatitis.

BACKGROUND/AIMS: Nonalcoholic steatohepatitis (NASH) is a serious disorder with the potential to gradually progress to cirrhosis. It is generally associated with obesity, diabetes and hyperlipidemia. Currently, there is no established therapy for NASH. The aim of the present study was to evaluate the effectiveness of atorvastatin and ursodeoxycholic acid (UDCA) in the treatment of NASH. METHODS: This prospective study included 44 adult patients (24 men, 20 women) with a mean age of 48.90+/-7.69 years and mean body mass index (BMI) of 29.40+/-3.82. Ten patients had a history of diabetes. Serological markers for viral hepatitis were negative in all patients and there was no history of alcohol or drug abuse. Patients who had autoimmune hepatitis were excluded from the study. Liver biopsy was performed before therapy to confirm the diagnosis. Among NASH patients, 17 normolipidemic cases received UDCA 13 to 15 mg/kg/day (group 1), while hyperlipidemic cases (n=27) received atorvastatin 10 mg/day (group 2) for six months. The BMI, serum lipids, liver function tests and liver density, assessed by computerized tomography, were evaluated before and after the treatment period. The BMI, serum aminotransferase levels, histological parameters (steatosis, inflammation, fibrosis scores) and liver densities were not statistically different between the groups at the beginning of therapy. RESULTS: The BMI, serum glucose, and triglyceride levels did not change in either group after the treatment period. In group 1, serum alanine aminotransferase (ALT) and gamma-glutamyl-transferase (GGT) levels reduced significantly, and in group 2, serum cholesterol, aspartate aminotransferase, ALT, alkaline phosphatase and GGT levels reduced significantly. Liver densities increased only in group 2, probably as a result of diminishing fat content of liver. The normalization of transaminases was also more prevalent in group 2. Liver steatosis was closely correlated with liver density, but inflammation and fibrosis were not. CONCLUSIONS: The use of atorvastatin in NASH patients with hyperlipidemia was found to be both effective and safe. The benefit of statin and UDCA therapy in normolipidemic patients with NASH requires confirmation with further placebo-controlled trials.