Functional conservation of Pax6 regulatory elements in humans and mice demonstrated with a novel transgenic reporter mouse

<p>Abstract</p> <p>Background</p> <p>The Pax6 transcription factor is expressed during development in the eyes and in specific CNS regions, where it is essential for normal cell proliferation and differentiation. Mice lacking one or both copies of the <it>Pax6 </it>gene model closely humans with loss-of-function mutations in the <it>PAX6 </it>locus. The sequence of the Pax6/PAX6 protein is identical in mice and humans and previous studies have shown <it>structural </it>conservation of the gene's regulatory regions.</p> <p>Results</p> <p>We generated a transgenic mouse expressing green fluorescent protein (GFP) and neomycin resistance under the control of the entire complement of human <it>PAX6 </it>regulatory elements using a modified yeast artificial chromosome (YAC). Expression of GFP was studied in embryos from 9.5 days on and was confined to cells known to express Pax6. GFP expression was sufficiently strong that expressing cells could be distinguished from non-expressing cells using flow cytometry.</p> <p>Conclusion</p> <p>This work demonstrates the <it>functional </it>conservation of the regulatory elements controlling <it>Pax6/PAX6 </it>expression in mice and humans. The transgene provides an excellent tool for studying the functions of different <it>Pax6/PAX6 </it>regulatory elements in controlling Pax6 expression in animals that are otherwise normal. It will allow the analysis and isolation of cells in which <it>Pax6 </it>is activated, irrespective of the status of the endogenous locus.</p

Comparison of serious inhaler technique errors made by device-naïve patients using three different dry powder inhalers: a randomised, crossover, open-label study

Background: Serious inhaler technique errors can impair drug delivery to the lungs. This randomised, crossover, open-label study evaluated the proportion of patients making predefined serious errors with Pulmojet compared with Diskus and Turbohaler dry powder inhalers. Methods: Patients ≥18 years old with asthma and/or COPD who were current users of an inhaler but naïve to the study devices were assigned to inhaler technique assessment on Pulmojet and either Diskus or Turbohaler in a randomised order. Patients inhaled through empty devices after reading the patient information leaflet. If serious errors potentially affecting dose delivery were recorded, they repeated the inhalations after watching a training video. Inhaler technique was assessed by a trained nurse observer and an electronic inhalation profile recorder. Results: Baseline patient characteristics were similar between randomisation arms for the Pulmojet-Diskus (n = 277) and Pulmojet-Turbohaler (n = 144) comparisons. Non-inferiority in the proportions of patients recording no nurse-observed serious errors was demonstrated for both Pulmojet versus Diskus, and Pulmojet versus Turbohaler; therefore, superiority was tested. Patients were significantly less likely to make ≥1 nurse-observed serious errors using Pulmojet compared with Diskus (odds ratio, 0.31; 95 % CI, 0.19–0.51) or Pulmojet compared with Turbohaler (0.23; 0.12–0.44) after reading the patient information leaflet with additional video instruction, if required. Conclusions These results suggest Pulmojet is easier to learn to use correctly than the Turbohaler or Diskus for current inhaler users switching to a new dry powder inhaler

Outfoxing the fox: effect of prey odor on fox behavior in a pastoral landscape

Invasive mammalian predators have had a devastating effect on native species globally. The European red fox (Vulpes vulpes) is one such species where it has been introduced in Australia. A novel but unexplored tactic to reduce the impact of mammalian predators is the use of unrewarded prey odors to undermine the effectiveness of olfactory hunting behavior. To test the viability of unrewarded prey odors in an applied setting we investigated how foxes responded to the odors of three different prey species. We used the odors of two locally extinct native Australian marsupials; the eastern quoll (a smaller carnivore) and eastern bettong (a fungivore), and the European rabbit, an introduced herbivore. Conducting our research over a period of 3 weeks in a pastoral environment in South-eastern Australia, we used video observations of foxes' behaviors, as they encountered the different odors. We found a reduction in the number of fox visits to bettong odors in the third week. In contrast, we observed a sustained number of visits to rabbit odors. Foxes also spent more time investigating rabbit odors and displayed longer durations of vigilance behavior at quoll odors. Our results support the hypothesis that the exposure of wild foxes to unrewarded odors of novel prey species can reduce their interest in these odors, which might translate to a reduction in predation pressure. Our results also suggest, however, that olfactory pre-exposure may not be as effective at reducing fox interest in a competitor species' odor

Characteristics of patients making serious inhaler errors with a dry powder inhaler and association with asthma-related events in a primary care setting

Acknowledgements The iHARP database was funded by unrestricted grants from Mundipharma International Ltd and Research in Real-Life Ltd; these analyses were funded by an unrestricted grant from Teva Pharmaceuticals. Mundipharma and Teva played no role in study conduct or analysis and did not modify or approve the manuscript. The authors wish to direct a special appreciation to all the participants of the iHARP group who contributed data to this study and to Mundipharma, sponsors of the iHARP group. In addition, we thank Julie von Ziegenweidt for assistance with data extraction and Anna Gilchrist and Valerie L. Ashton, PhD, for editorial assistance. Elizabeth V. Hillyer, DVM, provided editorial and writing support, funded by Research in Real-Life, Ltd.Peer reviewedPublisher PD

Language control and parallel recovery of language in individuals with aphasia

Background: The causal basis of the different patterns of language recovery following stroke in bilingual speakers is not well understood. Our approach distinguishes the representation of language from the mechanisms involved in its control. Previous studies have suggested that difficulties in language control can explain selective aphasia in one language as well as pathological switching between languages. Here we test the hypothesis that difficulties in managing and resolving competition will also be observed in those who are equally impaired in both their languages even in the absence of pathological switching. Aims: To examine difficulties in language control in bilingual individuals with parallel recovery in aphasia and to compare their performance on different types of conflict task. Methods & procedures: Two right-handed, non-native English-speaking participants who showed parallel recovery of two languages after stroke and a group of non-native English-speaking, bilingual controls described a scene in English and in their first language and completed three explicit conflict tasks. Two of these were verbal conflict tasks: a lexical decision task in English, in which individuals distinguished English words from non-words, and a Stroop task, in English and in their first language. The third conflict task was a non-verbal flanker task. Outcomes & Results: Both participants with aphasia were impaired in the picture description task in English and in their first language but showed different patterns of impairment on the conflict tasks. For the participant with left subcortical damage, conflict was abnormally high during the verbal tasks (lexical decision and Stroop) but not during the non-verbal flanker task. In contrast, for the participant with extensive left parietal damage, conflict was less abnormal during the Stroop task than the flanker or lexical decision task. Conclusions: Our data reveal two distinct control impairments associated with parallel recovery. We stress the need to explore the precise nature of control problems and how control is implemented in order to develop fuller causal accounts of language recovery patterns in bilingual aphasia

TNF-block genotypes influence susceptibility to HIV-associated sensory neuropathy in Indonesians and South Africans

HIV-associated sensory neuropathy (HIV-SN) is a disabling complication of HIV disease and antiretroviral therapies (ART). Since stavudine was removed from recommended treatment schedules, the prevalence of HIV-SN has declined and associated risk factors have changed. With stavudine, rs1799964*C (TNF-1031) associated with HIV-SN in Caucasians and Indonesians but not in South Africans. Here, we investigate associations between HIV-SN and rs1799964*C and 12 other polymorphisms spanning TNF and seven neighboring genes (the TNF-block) in Indonesians (n = 202; 34/168 cases) and South Africans (n = 75; 29/75 cases) treated without stavudine. Haplotypes were derived using fastPHASE and haplotype networks built with PopART. There were no associations with rs1799964*C in either population. However, rs9281523*C in intron 10 of BAT1 (alternatively DDX39B) independently associated with HIV-SN in Indonesians after correcting for lower CD4 T-cell counts and \u3e500 copies of HIV RNA/mL (model p = 0.0011, Pseudo R2 = 0.09). rs4947324*T (between NFKBIL1 and LTA) independently associated with reduced risk of HIV-SN and shared haplotype 1 (containing no minor alleles) associated with increased risk of HIV-SN after correcting for greater body weight, a history of tuberculosis and nadir CD4 T-cell counts (model: p = 0.0003, Pseudo R2 = 0.22). These results confirm TNF-block genotypes influence susceptibility of HIV-SN. However, critical genotypes differ between ethnicities and with stavudine use

Improving health care quality for racial/ethnic minorities: a systematic review of the best evidence regarding provider and organization interventions

BACKGROUND: Despite awareness of inequities in health care quality, little is known about strategies that could improve the quality of healthcare for ethnic minority populations. We conducted a systematic literature review and analysis to synthesize the findings of controlled studies evaluating interventions targeted at health care providers to improve health care quality or reduce disparities in care for racial/ethnic minorities. METHODS: We performed electronic and hand searches from 1980 through June 2003 to identify randomized controlled trials or concurrent controlled trials. Reviewers abstracted data from studies to determine study characteristics, results, and quality. We graded the strength of the evidence as excellent, good, fair or poor using predetermined criteria. The main outcome measures were evidence of effectiveness and cost of strategies to improve health care quality or reduce disparities in care for racial/ethnic minorities. RESULTS: Twenty-seven studies met criteria for review. Almost all (n = 26) took place in the primary care setting, and most (n = 19) focused on improving provision of preventive services. Only two studies were designed specifically to meet the needs of racial/ethnic minority patients. All 10 studies that used a provider reminder system for provision of standardized services (mostly preventive) reported favorable outcomes. The following quality improvement strategies demonstrated favorable results but were used in a small number of studies: bypassing the physician to offer preventive services directly to patients (2 of 2 studies favorable), provider education alone (2 of 2 studies favorable), use of a structured questionnaire to assess adolescent health behaviors (1 of 1 study favorable), and use of remote simultaneous translation (1 of 1 study favorable). Interventions employing more than one main strategy were used in 9 studies with inconsistent results. There were limited data on the costs of these strategies, as only one study reported cost data. CONCLUSION: There are several promising strategies that may improve health care quality for racial/ethnic minorities, but a lack of studies specifically targeting disease areas and processes of care for which disparities have been previously documented. Further research and funding is needed to evaluate strategies designed to reduce disparities in health care quality for racial/ethnic minorities