Mutations in PTEN-induced putative kinase 1 (PINK1) and parkin cause autosomal-recessive Parkinson’s disease through a common pathway involving mitochondrial quality control. Parkin inactivation leads to accumulation of the parkin interacting substrate (PARIS, ZNF746) that plays an important role in dopamine cell loss through repression of proliferator-activated receptor gamma coactivator-1α (PGC-1α) promoter activity. Here we show that PARIS, links PINK1 and parkin in a common pathway that regulates dopaminergic neuron survival. PINK1 interacts with and phosphorylates serines 322 and 613 of PARIS to control its ubiquitination and clearance by parkin. PINK1 phosphorylation of PARIS alleviates PARIS toxicity as well as repression of PGC-1α promoter activity. Conditional knockdown of PINK1 in adult mouse brains leads to a progressive loss of dopaminergic neurons in the substantia nigra that is dependent on PARIS. Together, these results uncover a function of PINK1 to direct parkin-PARIS regulated PGC-1α expression and dopaminergic neuronal survival.

OBJECTIVES:To characterize vernix caseosa in newborn infants with respect to factors that influence vernix distribution on the skin surface, vernix effects on thermal stability, skin hydration, acid mantle development, and vernix antioxidant properties. STUDY DESIGN:Vernix distribution was determined for 430 infants. Thermal stability was assessed in parallel groups following vernix retention (n ¼ 66) and removal (n ¼ 64). The effects of vernix retention on skin hydration, pH, erythema, and dryness/scaling were determined. Samples were analyzed for vitamin E before and after UV exposure. RESULTS:Vernix distribution depended upon gestational age, delivery mode, gender, race, and meconium exposure. Retention had no effect on axillary temperatures. Skin hydration was significantly higher for vernix-retained skin. Skin pH and erythema were significantly lower with retention. Vitamin E levels were decreased by ultraviolet radiation. CONCLUSIONS:Vernix is a naturally occurring barrier cream with multiple salubrious effects, which support its retention on the skin surface at birth.

Executive SummaryTraditional, mechanistic models of leadership are inadequate for dealing with the serious adaptive challenges facing the modern world. The complex, dynamic systems that result when these adaptive challenges interact requires that we draw upon ecological principles to understand the role that leadership processes can play in creating a sustainable, generative future. Ignoring the systemic nature of leadership processes creates an illusion that traditional positional leaders should be the focus of leadership studies. We propose that a more useful focus is the systemic processes out of which leadership emerges. A theory of leadership derived from principles of ecology calls for a radical shift in our perspectives of leadership. It emphasizes individual responsibility, a long term perspective, developing capacities of individuals within organizations, and harmony with nature, while showing the way toward sustainability for future generations. 63 What new understanding of leadership needs to be developed in order for us to create a sustainable, generative future, a future that is able to support and nourish life? The popular notion of leadership depicts one individual in an appointed, elected, or paid position making the decisions that direct an organization toward success. While highly publicized appointments are made, the recently elected take office, and major corporations hire new CEOs, we see the degradation of our environment, an increasing gap between rich and poor, businesses that go bankrupt, and ethical problems in those who hold public office--all signs of failed leadership. A sustainable world demands new values, attitudes, behaviors, and a greater commitment to cooperative solutions to current challenges. This paper articulates how leadership processes must adapt ' to a changing world and introduces a conceptualization of leadership based upon ecological principles, individual responsibility, and the development of human capacities.We begin by making the case for change in the popular notions of leadership. Then, we propose a theory of leadership based upon ecological principles and describe the nature of systemic leadership processes. We discuss some major issues raised by the theory and end the paper with strategies for change derived from the theory.The Case for Change Leadership based on position and authority is inadequate for the challenges we face today. We need leadership which increases our capacity to learn new ways of understanding, defining, and solving the complex problems we are facing. Ron Heifetz (1994) calls these complex problems adaptive challenges. They demand leadership models that develop the capacity of organizations and people to respond to these challenges. Waiting for great individual leaders to guide and direct organizations as well as guarantee our safety and security is no longer possible. Adaptive Challenges of a Changing WorldOur world is faced with a series of adaptive challenges. These challenges are fundamental global issues with which communities must...

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We prospectively evaluated 59 patients who were deemed candidates for coronary bypass surgery after coronary artery angiography for subclavian artery narrowing, which could compromise the ipsilateral internal thoracic artery graft. Bilateral arm blood pressure (BP) measurements, auscultation for supraclavicular or cervical bruits, and questioning about cerebrovascular ischemic symptoms were compared to brachiocephalic-subclavian arteriography. One neurologic complication occurred during arteriography. An upper extremity BP difference of > or = 15 mm Hg identified all patients with > or = 50% subclavian artery narrowing. We recommend brachiocephalic-subclavian arteriography only in patients with abnormal noninvasive screening for subclavian stenosis, not routinely.

BACKGROUND: HER2-positive metastatic breast cancer (MBC) relapsing after trastuzumab-based therapy may require continued HER2 receptor inhibition to control the disease and preserve the patients' quality-of-life. Efficacy and safety of lapatinib monotherapy was evaluated in Japanese breast cancer patients after trastuzumab-based therapies. METHODS: In studies, EGF100642 and EGF104911 evaluated the efficacy and safety of oral lapatinib given 1500 mg once daily in patients with advanced or MBC. All patients progressed on anthracyclines and taxanes; HER2-positive patients had also progressed on trastuzumab. RESULTS: For HER2-positive tumours (n ¼ 100), objective response rate was 19.0% (95% confidence interval (CI): 11.8 -28.1) and clinical benefit rate (CBR) was 25.0% (95% CI: 16.9 -34.7). One out of 22 HER2-negative tumour was documented as complete response (n ¼ 22). The median time-to-progression (TTP) in the HER2-positive and HER2-negative groups was 13.0 and 8.0 weeks (P ¼ 0.007); median overall survival was 58.3 and 40.0 weeks, respectively. The most frequent adverse event was diarrhoea. TTP and CBR were significantly associated with HER2 expression. Patients with tumours harbouring an H1047R PIK3CA mutation or low expression of PTEN derived clinical benefit from lapatinib. CONCLUSION: Lapatinib monotherapy had shown anti-tumour activity in Japanese patients with HER2-positive MBC that relapsed after trastuzumab-based therapy, including those with brain metastases. Patients benefiting from lapatinib may have biomarker profiles differing from that reported for trastuzumab.

Abstract-Wetland mesocosms were exposed to increasing concentrations of atrazine over time at levels typical of midwestern surface waters following spring runoff (15 to 75 g/L). Atrazine had a half-life of 8 to 14 d in the 230-m-long wetlands. End points measured included nutrient levels; periphyton biomass; periphyton productivity and respiration; growth of selected macrophytes; and survival and growth of Daphnia magna (15, 25 g/L atrazine), Rana pipiens (15, 25 g/L), and Pimephales promelas larvae (25 to 75 g/L) and adults (50, 75 g/L). Interaction between nutrient status or grazing intensity and atrazine effects were measured using periphyton enrichment and grazing exclosure experiments. Only periphyton, Ceratophyllum demersum, Zizania aquatica, and Daphnia were significantly affected by atrazine at any of the concentrations tested. Periphyton net productivity was significantly depressed by incubation in treated water as compared to control water at Ն25 g/L atrazine (9 to 27-d exposures). In response, dissolved nutrient concentrations increased in treated mesocosms after 14 d. Ceratophyllum length/weight ratios increased after 6-d exposures to 50 g/ L atrazine, while Zizania senesced prematurely during treatments of 50 or 75 g/L atrazine (97 d of cumulative exposure). Periphyton developed resistance to atrazine only at concentrations Ն50 g/L. Atrazine effects on periphyton composition varied with the N:P supply ratio. Daphnia survival was significantly depressed at 15 g/L atrazine (48-h exposures).