A place for genetic uncertainty: Parents valuing an unknown in the meaning of disease

Klinefelter, Turner, and fragile X syndromes are conditions defined by a genetic or chromosomal variant. The timing of diagnosis, tests employed, specialists involved, symptoms evident, and prognoses available vary considerably within and across these syndromes, but all three share in common a diagnosis verified through a molecular or cytogenetic test. The genetic or chromosomal variant identified designates a syndrome, even when symptoms associated with the particular syndrome are absent. This article analyzes interviews conducted with parents and grandparents of children with these syndromes from across the US to explore how they interpret a confirmed genetic diagnosis that is associated with a range of possible symptoms that may never be exhibited. Parents’ responses indicate that they see the genetic aspects of the syndrome as stable, permanent and authoritative. But they allow, and even embrace, uncertainty about the condition by focusing on variation between diagnosed siblings, the individuality of their diagnosed child, his or her accomplishments, and other positive aspects that go beyond the genetic diagnosis. Some families counter the genetic diagnosis by arguing that in the absence of symptoms, the syndrome does not exist. They use their own expertise to question the perceived certainty of the genetic diagnosis and to employ the diagnosis strategically. These multiple and often conflicting evaluations of the diagnostic label reveal the rich ways families make meaning of the authority attributed to genetic diagnosis

The WHO UNESCO FIP Pharmacy Education Taskforce: enabling concerted and collective global action

Pharmacy Education is a priority area for the International Pharmaceutical Federation (FIP), the global federation representing pharmacists and pharmaceutical scientists worldwide that is spearheading the Global Pharmacy Education Taskforce. This paper describes the work of the Taskforce that was established in March 2008, explores key issues in pharmacy education development, and describes the Global Pharmacy Action Plan 2008-2010. Given the significance of pharmacy education to the diverse practice of contemporary pharmacists and pharmacy support personnel, there is a need for pharmacy education to attain greater visibility on the global human resources for health agenda. From this perspective, FIP is steering the development of holistic and comprehensive pharmacy education and pharmacy workforce action to support and strengthen regional, national, and local efforts. The role of a global organization such as FIP is to facilitate, catalyze, and share efforts to maximize pharmacy education development and stimulate international research to develop guidance, tools, and better understanding of key issues. To achieve this goal, FIP has (1) established a formal collaborative partnership with the 2 United Nations agencies representing the education and health sectors, United Nations Educational, Scientific and Cultural Organization (UNESCO) and the World Health Organization (WHO); and (2) established the Global Pharmacy Education Taskforce to serve as the coordinating body of these efforts. The initial effort will serve to leverage strategic leadership and maximize the impact of collective actions at global, regional, and national levels. Three project teams have been convened to conduct research, consultations and develop guidance in the domains of vision for pharmacy education, competency, quality assurance, academic workforce, and institutional capacity

Discovery of a gatekeeper residue in the C terminal tail of the extracellular signal-regulated protein kinase 5 (ERK5)

The extracellular signal-regulated protein kinase 5 (ERK5) is a non-redundant mitogen-activated protein kinase (MAPK) that exhibits a unique C terminal extension which comprises distinct structural and functional properties. Here, we sought to elucidate the significance of phosphoacceptor sites in the C terminal transactivation domain of ERK5. We have found that Thr732 acted as a functional gatekeeper residue controlling C terminal-mediated nuclear translocation and transcriptional enhancement. Consistently, using a non-bias quantitative mass spectrometry approach, we demonstrated that phosphorylation at Thr732 conferred selectivity for binding interactions of ERK5 with proteins related to chromatin and RNA biology, whereas a number of metabolic regulators were associated with full-length wild type ERK5. Additionally, our proteomic analysis revealed that phosphorylation of the Ser730-Glu-Thr732-Pro motif could occur independently of dual phosphorylation at Thr218-Glu-Tyr220 in the activation loop. Together these results firmly establish the significance of C terminal phosphorylation in regulating ERK5 function, independently of MEK5. This novel mechanism may be of particular relevance in cancer cells where ERK5 has be found to be hyperphosphoryated on its C terminal tail

HDAC-mediated control of ERK- and PI3K-dependent TGF-β-induced extracellular matrix-regulating genes

Histone deacetylases (HDACs) regulate the acetylation of histones in the control of gene expression. Many non-histone proteins are also targeted for acetylation, including TGF-ß signalling pathway components such as Smad2, Smad3 and Smad7. Our studies in mouse C3H10T1/2 fibroblasts suggested that a number of TGF-ß-induced genes that regulate matrix turnover are selectively regulated by HDACs. Blockade of HDAC activity with trichostatin A (TSA) abrogated the induction of a disintegrin and metalloproteinase 12 (Adam12) and tissue inhibitor of metalloproteinases-1 (Timp-1) genes by TGF-ß, whereas plasminogen activator inhibitor-1 (Pai-1) expression was unaffected. Analysis of the activation of cell signalling pathways demonstrated that TGF-ß induced robust ERK and PI3K activation with delayed kinetics compared to the phosphorylation of Smads. The TGF-ß induction of Adam12 and Timp-1 was dependent on such non-Smad signalling pathways and, importantly, HDAC inhibitors completely blocked their activation without affecting Smad signalling. Analysis of TGF-ß-induced Adam12 and Timp-1 expression and ERK/PI3K signalling in the presence of semi-selective HDAC inhibitors valproic acid, MS-275 and apicidin implicated a role for class I HDACs. Furthermore, depletion of HDAC3 by RNA interference significantly down-regulated TGF-ß-induced Adam12 and Timp-1 expression without modulating Pai-1 expression. Correlating with the effect of HDAC inhibitors, depletion of HDAC3 also blocked the activation of ERK and PI3K by TGF-ß. Collectively, these data confirm that HDACs, and in particular HDAC3, are required for activation of the ERK and PI3K signalling pathways by TGF-ß and for the subsequent gene induction dependent on these signalling pathways

Grounded Theory analysis of commuters discussing a workplace carbon-reduction target: Autonomy, satisfaction, and willingness to change behaviour in drivers, pedestrians, bicyclists, motorcyclists, and bus users

This qualitative analysis compared focus group discussions of a carbon reduction target amongst users of different modes who travel to the same workplace. Grounded Theory analysis showed discussions expanded to wider carbon costs and more issues than those specifically described in the target. Differences in people’s perceptions of carbon emissions varied with travel mode: walkers and bicyclists showed high awareness and concern; car drivers and motorcyclists were more pessimistic and cautious of imposing restrictions, with a particular suspicion of ‘greenwash’ actions that do not provide actual benefits. Changing travel mode for carbon reduction was discussed cautiously by all groups, with concern over the legitimacy of efforts to influence a personal choice, and the need for a ‘balanced’ approach that would not punish personal decisions. Notably, participants discussed their current mode in terms of perceived autonomy, and feared losing this autonomy if they changed mode. This role of autonomy emerged as a central theme in discussions of carbon reduction, providing ideas for future interventions

Pneumonia in adults - Quality standard QS110

IntroductionThis quality standard covers adults (18 years and older) with a suspected or confirmed diagnosis of community acquired pneumonia. For more information see the pneumonia topic overview.Why this quality standard is neededPneumonia is an infection of the lung tissue. When a person has pneumonia the air sacs in their lungs become filled with microorganisms, fluid and inflammatory cells and their lungs are not able to work properly. Diagnosis of pneumonia is based on symptoms and signs of an acute lower respiratory tract infection, and can be confirmed by a chest X-ray showing new shadowing that is not due to any other cause (such as pulmonary oedema or infarction). The NICE guideline on pneumonia classifies pneumonia depending on the source of the infection as community acquired or hospital-acquired, which need different management strategies. Every year between 0.5% and 1% of adults in the UK will have community-acquired pneumonia. It is diagnosed in 5–12% of adults who present to GPs with symptoms of lower respiratory tract infection, and 22–42% of these are admitted to hospital, where the mortality rate is between 5% and 14%. Between 1.2% and 10% of adults admitted to hospital with community acquired pneumonia are managed in an intensive care unit, and for these patients the risk of dying is over 30%. More than half of pneumonia-related deaths occur in people older than 84 years.At any time, 1.5% of hospital patients in England have a hospital-acquired respiratory infection, more than half of which are hospital-acquired pneumonia and are not associated with intubation. Hospital-acquired pneumonia is estimated to increase a hospital stay by about 8 days and has a reported mortality rate ranging from 30–70%. There are variations in clinical management and outcomes across the UK

Effects of controlled diesel exhaust exposure on apoptosis and proliferation markers in bronchial epithelium – an in vivo bronchoscopy study on asthmatics, rhinitics and healthy subjects

BackgroundEpidemiological evidence demonstrates that exposure to traffic-derived pollution worsens respiratory symptoms in asthmatics, but controlled human exposure studies have failed to provide a mechanism for this effect. Here we investigated whether diesel exhaust (DE) would induce apoptosis or proliferation in the bronchial epithelium in vivo and thus contribute to respiratory symptoms.MethodsModerate (n?=?16) and mild (n?=?16) asthmatics, atopic non-asthmatic controls (rhinitics) (n?=?13) and healthy controls (n?=?21) were exposed to filtered air or DE (100 ?g/m 3 ) for 2 h, on two separate occasions. Bronchial biopsies were taken 18 h post-exposure and immunohistochemically analysed for pro-apoptotic and anti-apoptotic proteins (Bad, Bak, p85 PARP, Fas, Bcl-2) and a marker of proliferation (Ki67). Positive staining was assessed within the epithelium using computerized image analysis.ResultsNo evidence of epithelial apoptosis or proliferation was observed in healthy, allergic or asthmatic airways following DE challenge.ConclusionIn the present study, we investigated whether DE exposure would affect markers of proliferation and apoptosis in the bronchial epithelium of asthmatics, rhinitics and healthy controls, providing a mechanistic basis for the reported increased airway sensitivity in asthmatics to air pollutants. In this first in vivo exposure investigation, we found no evidence of diesel exhaust-induced effects on these processes in the subject groups investigated