α-Synuclein (a-Syn), a protein implicated in Parkinson disease, contributes significantly to dopamine metabolism. a-Syn binding inhibits the activity of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis. Phosphorylation of TH stimulates its activity, an effect that is reversed by protein phosphatase 2A (PP2A). In cells, a-Syn overexpression activates PP2A. Here we demonstrate that a-Syn significantly inhibited TH activity in vitro and in vivo and that phosphorylation of a-Syn serine 129 (Ser-129) modulated this effect. In MN9D cells, a-Syn overexpression reduced TH serine 19 phosphorylation (Ser(P)-19). In dopaminergic tissues from mice overexpressing human a-Syn in catecholamine neurons only, TH-Ser-19 and TH-Ser-40 phosphorylation and activity were also reduced, whereas PP2A was more active. Cerebellum, which lacks excess a-Syn, had PP2A activity identical to controls. Conversely, a-Syn knock-out mice had elevated TH-Ser-19 phosphorylation and activity and less active PP2A in dopaminergic tissues. Using an a-Syn Ser-129 dephosphorylation mimic, with serine mutated to alanine, TH was more inhibited, whereas PP2A was more active in vitro and in vivo. Phosphorylation of a-Syn Ser-129 by Polo-like-kinase 2 in vitro reduced the ability of a-Syn to inhibit TH or activate PP2A, identifying a novel regulatory role for Ser-129 on a-Syn. These findings extend our understanding of normal a-Syn biology and have implications for the dopamine dysfunction of Parkinson disease.

Objectives To evaluate whether a novel definition of spirometric respiratory impairment (Global Lung Initiative [GLI]) is strongly associated with respiratory symptoms and, in turn, frequently establishes symptomatic respiratory disease. Design Cross-sectional. Setting Third National Health and Nutrition Examination Survey. Participants Community-dwelling, ages 40-80 (N=7,115). Measurements GLI-defined spirometric respiratory impairment (airflow-obstruction and restrictive-pattern), dyspnea on exertion (DOE), chronic bronchitis (CB), and wheezing. Results Among participants aged 40-80, prevalence rates were 12.7% and 6.2% for airflow-obstruction and restrictive-pattern and 28.6%, 12.6%, and 12.9% for DOE, CB, and wheezing, respectively. Relative to normal spirometry, airflow-obstruction was associated with DOE, CB, and wheezing—adjusted odds ratios (adjORs): 1.69 (1.42, 2.02), 1.92 (1.62, 2.29), and 2.50 (2.08, 3.00), respectively. Similarly, restrictive-pattern was associated with DOE, CB, and wheezing—adjORs: 1.75 (1.36, 2.25), 1.39 (1.08, 1.78) and 1.53 (1.15, 2.04), respectively. Among participants who had airflow-obstruction and restrictive-pattern, however, only a minority had DOE (38.6% and 45.5%), CB (23.3% and 15.9%), and wheezing (24.4% and 19.1%), respectively, yielding a positive predictive value (PPV) of 53% for any respiratory symptom in the setting of any spirometric respiratory impairment. In addition, most participants who had DOE, CB, and wheezing did not have airflow-obstruction or restrictive-pattern (73.0%, 67.8%, and 66.8%, respectively), yielding a PPV of 26% for any spirometric respiratory impairment in the setting of any respiratory symptom. The results differed only modestly when stratified by the age groups of 40-64 and 65-80. Conclusion GLI-defined spirometric respiratory impairment increased the likelihood of respiratory symptoms relative to normal spirometry, but was nonetheless a poor predictor of respiratory symptoms. Similarly, respiratory symptoms were poor predictors of GLI-defined spirometric respiratory impairment. Hence, a comprehensive assessment is needed when evaluating respiratory symptoms, even in the presence of a spirometric respiratory impairment.

Context Healthcare professionals (HCPs) are crucial to physician-assisted death (PAD) provision. Objectives To quantitatively assess the favorability of justifications for or against PAD legalization among HCPs, the effect of the terms “suicide” and “euthanasia” on their views, and their support for three forms of PAD. Methods Our questionnaire presented three cases: physician-assisted suicide, euthanasia for a competent patient, and euthanasia for an incompetent patient with an advance directive for euthanasia. Respondents judged whether each case was ethical and should be legal, and selected their justifications from commonly cited reasons. The sample included physician clinicians, researchers, non-physician clinicians, and other non-clinical staff at a major academic medical center. Results Of 221 HCPs, the majority thought each case was ethical and should be legal. In order of declining favorability, justifications supporting PAD legalization were relief of suffering, right to die, mercy, acceptance of death, non-abandonment, and saving money for the healthcare system; opposing justifications were the slippery slope argument, unnecessary due to palliative care, killing patients is wrong, religious views, and suicide is wrong. Use of suicide and euthanasia terminology did not affect responses. Participants preferred physician-assisted suicide to euthanasia for a competent patient (p<0.0001) and euthanasia for an incompetent patient to euthanasia for a competent patient (p<0.005). Conclusions HCPs endorsed patient-centered justifications over other reasons, including role-specific duties. Suicide and euthanasia language did not bias HCPs against PAD, challenging claims that such value-laden terms hinder dialogue. More research is required to understand the significance of competency in shaping attitudes toward PAD.

The first examples of the use of crotylation as a stereocontrolled complex fragment coupling strategy are described. Asymmetric aldehyde isoprenylation provides access to 2-substituted-1,3-butadienes that may be subjected to highly regio- and stereoselective 1,4 hydrosilylation with trichlorosilane. After complexation with a chiral diamine, the 2-sub-stituted-cis-crotylsilanes may be employed in highly diastereoselective Sc(OTf)3-catalyzed aldehdye crotylation reactions.

α-Synuclein (aSyn), β-Synuclein (bSyn), and γ-Synuclein (gSyn) are members of a conserved family of chaperone-like proteins that are highly expressed in vertebrate neuronal tissues. Of the three synucleins, only aSyn has been strongly implicated in neurodegenerative disorders such as Parkinson's disease, Dementia with Lewy Bodies, and Multiple System Atrophy. In studying normal aSyn function, data indicate that aSyn stimulates the activity of the catalytic subunit of an abundantly expressed dephosphorylating enzyme, PP2Ac in vitro and in vivo. Prior data show that aSyn aggregation in human brain reduces PP2Ac activity in regions with Lewy body pathology, where soluble aSyn has become insoluble. However, because all three synucleins have considerable homology in the amino acid sequences, experiments were designed to test if all can modulate PP2Ac activity. Using recombinant synucleins and recombinant PP2Ac protein, activity was assessed by malachite green colorimetric assay. Data revealed that all three recombinant synucleins stimulated PP2Ac activity in cell-free assays, raising the possibility that the conserved homology between synucleins may endow all three homologs with the ability to bind to and activate the PP2Ac. Co-immunoprecipitation data, however, suggest that PP2Ac modulation likely occurs through endogenous interactions between aSyn and PP2Ac in vivo.

Ethics consultation is a commonly applied mechanism to address clinical ethical dilemmas. However, there is little information on the viewpoints of health care providers towards the relevance of ethics committees and appropriate application of ethics consultation in clinical practice. We sought to use qualitative methodology to evaluate free-text responses to a case-based survey to identify thematically the views of health care professionals towards the role of ethics committees in resolving clinical ethical dilemmas. Using an iterative and reflexive model we identified themes that health care providers support a role for ethics committees and hospitals in resolving clinical ethical dilemmas, that the role should be one of mediation, rather than prescription, but that ultimately legal exposure was dispositive compared to ethical theory. The identified theme of legal fears suggests that the mediation role of ethics committees is viewed by health care professionals primarily as a practical means to avoid more worrisome medico-legal conflict.

Ethics has long been, and continues to be, a central topic among marketing scholars and practitioners. When providing complex services—multiple interactions over time that are predicated on the evolving needs of customers—service providers face ethical dilemmas, which are often resolved by engaging an ethics committee (EC). Despite the prevalence of ECs, research on service providers’ preference to engage with an EC is sparse. This study examines whether the role that health care providers play, as either task manager or relationship manager, makes a difference in their preference for engaging with and utilizing an EC for resolving ethical dilemmas. Results based on 1,440 observations collected from health care service providers show that service providers’ task or relationship management role, as well as prior experience with an ethics consultation, influences their preference both for engaging an EC and for having the EC prescribe a specific outcome to resolve an ethical dilemma. This study extends prior work on conceptual models examining ethical decision-making processes in marketing.

We sought to evaluate whether health care professionals' viewpoints differed on the role of ethics committees and hospitals in the resolution of clinical ethical dilemmas based on practice location. We conducted a survey study from December 21, 2013 to March 15, 2014 of health care professionals at six hospitals (one tertiary care academic medical center, three large community hospitals and two small community hospitals). The survey consisted of eight clinical ethics cases followed by statements on whether there was a role for the ethics committee or hospital in their resolution, what that role might be and case specific queries. Respondents used a 5-point Likert scale to express their degree of agreement with the premises posed. We used the ANOVA test to evaluate whether respondent views significantly varied based on practice location. 240 health care professionals (108-tertiary care center, 92-large community hospitals, 40-small community hospitals) completed the survey (response rate: 63.6 %). Only three individual queries of 32 showed any significant response variations across practice locations. Overall, viewpoints did not vary across practice locations within question categories on whether the ethics committee or hospital had a role in case resolution, what that role might be and case specific queries. In this multicenter survey study, the viewpoints of health care professionals on the role of ethics committees or hospitals in the resolution of clinical ethics cases varied little based on practice location.