Salen Mn Complexes Mitigate Radiation Injury in Normal Tissues

Salen Mn complexes, including EUK-134, EUK-189 and a newer cyclized analog EUK-207, are synthetic SOD/catalase mimetics that have beneficial effects in many models of oxidative stress. As oxidative stress is implicated in some forms of delayed radiation injury, we are investigating whether these compounds can mitigate injury to normal tissues caused by ionizing radiation. This review describes some of this research, focusing on several tissues of therapeutic interest, namely kidney, lung, skin, and oral mucosa. These studies have demonstrated suppression of delayed radiation injury in animals treated with EUK-189 and/or EUK-207. While an antioxidant mechanism of action is postulated, it is likely that the mechanisms of radiation mitigation by these compounds in vivo are complex and may differ in the various target tissues. Indicators of oxidative stress are increased in lung and skin radiation injury models, and suppressed by salen Mn complexes. The role of oxidative stress in the renal injury model is unclear, though EUK-207 does mitigate. In certain experimental models, salen Mn complexes have shown “mito-protective” properties, that is, attenuating mitochondrial injury. Consistent with this, EUK-134 suppresses effects of ionizing radiation on mitochondrial function in rat astrocyte cultures. In summary, salen Mn complexes could be useful to mitigate delayed radiation injury to normal tissues following radiation therapy, accidental exposure, or radiological terrorism. Optimization of their mode of delivery and other key pharmaceutical properties, and increasing understanding of their mechanism(s) of action as radiation mitigators, are key issues for future study

lipid use in hospitalized adults requiring parenteral nutrition

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Estimation of cosmological parameters using adaptive importance sampling

We present a Bayesian sampling algorithm called adaptive importance sampling or Population Monte Carlo (PMC), whose computational workload is easily parallelizable and thus has the potential to considerably reduce the wall-clock time required for sampling, along with providing other benefits. To assess the performance of the approach for cosmological problems, we use simulated and actual data consisting of CMB anisotropies, supernovae of type Ia, and weak cosmological lensing, and provide a comparison of results to those obtained using state-of-the-art Markov Chain Monte Carlo (MCMC). For both types of data sets, we find comparable parameter estimates for PMC and MCMC, with the advantage of a significantly lower computational time for PMC. In the case of WMAP5 data, for example, the wall-clock time reduces from several days for MCMC to a few hours using PMC on a cluster of processors. Other benefits of the PMC approach, along with potential difficulties in using the approach, are analysed and discussed.Comment: 17 pages, 11 figure

Transient atrioventricular block resulting from left ventricular angiography in infants with ventricular septal defect

Conduction disturbances often occur with manipulation of catheters within the atria or ventricles during cardiac catheterization.1,2 Catheter movement may induce transient right or left bundle branch block, or complete heart block in patients with or without preexistent bundle branch block.3-6 To our knowledge, however, there have been no previous reports of complete heart block resulting from an intramyocardial stain in the region of the atrioventricular (AV) conduction system. This report describes 2 infants who developed transient complete heart block following injection of contrast medium in the left ventricle. In each, complete heart block resulted from the intra-myocardial injection of contrast medium in the region of the AV conduction system.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27865/1/0000278.pd

Contextualized analysis of a needs assessment using the Theoretical Domains Framework: a case example in endocrinology

Background: The Theoretical Domains Framework (TDF) is a set of 14 domains of behavior change that provide a framework for the critical issues and factors influencing optimal knowledge translation. Considering that a previous study has identified optimal knowledge translation techniques for each TDF domain, it was hypothesized that the TDF could be used to contextualize and interpret findings from a behavioral and educational needs assessment. To illustrate this hypothesis, findings and recommendations drawn from a 2012 national behavioral and educational needs assessment conducted with healthcare providers who treat and manage Growth and Growth Hormone Disorders, will be discussed using the TDF. Methods: This needs assessment utilized a mixed-methods research approach that included a combination of: [a] data sources (Endocrinologists (n:120), Pediatric Endocrinologists (n:53), Pediatricians (n:52)), [b] data collection methods (focus groups, interviews, online survey), [c] analysis methodologies (qualitative - analyzed through thematic analysis, quantitative - analyzed using frequencies, cross-tabulations, and gap analysis). Triangulation was used to generate trustworthy findings on the clinical practice gaps of endocrinologists, pediatric endocrinologists, and general pediatricians in their provision of care to adult patients with adult growth hormone deficiency or acromegaly, or children/teenagers with pediatric growth disorders. The identified gaps were then broken into key underlying determinants, categorized according to the TDF domains, and linked to optimal behavioral change techniques. Results: The needs assessment identified 13 gaps, each with one or more underlying determinant(s). Overall, these determinants were mapped to 9 of the 14 TDF domains. The Beliefs about Consequences domain was identified as a contributing determinant to 7 of the 13 challenges. Five of the gaps could be related to the Skills domain, while three were linked to the Knowledge domain. Conclusions: The TDF categorization of the needs assessment findings allowed recommendation of appropriate behavior change techniques for each underlying determinant, and facilitated communication and understanding of the identified issues to a broader audience. This approach provides a means for health education researchers to categorize gaps and challenges identified through educational needs assessments, and facilitates the application of these findings by educators and knowledge translators, by linking the gaps to recommended behavioral change techniques

The Daubert/Kumho Implications of Observer Effects in Forensic Science: Hidden Problems of Expectation and Suggestion

After the Supreme Court's decision in Kumho Tire v. Carmichael and the recent amendment of Federal Rule of Evidence 702, proffers of expert testimony will have to be found reliable for the particular application of the asserted expertise to the "task at hand." That is, expertise which is reliable in some global sense, which might apply to other cases but not to the particular application before the court, does not satisfy the requirements for admission. With that in mind, this article examines the phenomoenon of "observer effects" and the vulnerability of forensic science examinations to such observer effects. Observer effects occur when the results of an examination are distorted by the context and state of the observer, including the observer's expectations and desires. The article reviews the findings and practices of a range of scientific fields concerning such observer effects and their control, with special attention to the relevant research and theory from cognative and social psychology. This literature establishes that in virtually every area of human judgment, such observer effects have a relentless and sometimes dramatic effect on the accuracy of results. The article then examines current forensic science practice in light of that research, concluding that forensic science practice is far behind most scientific fields in controlling for such effects, leaving the reliability and accuracy of many forensic science results in doubt. The article then suggests practical ways in which forensic science practice can be changed to reduce such problems, such as the adoption of blind testing regimes. Finally, the article analyzes the current state of the law under Kumho Tire and Rule 702, concluding that the results of forensic science examinations are in danger of being excluded if their reliability continues to be undermined by the failure to control observer effects.Psycholog

Entrepreneurship and Urban Success: Toward a Policy Consensus

Like all politics, all entrepreneurship is local. Individuals launch firms and, if successful, expand their enterprises to other locations. But new firms must start somewhere, even if their businesses are conducted largely or exclusively on the Internet. Likewise, policymakers at local and state levels increasingly recognize that entrepreneurship is the key to building and sustaining their economies\u27 growth. Although this is a seemingly obvious proposition, it represents something of a departure from past thinking about how local, state, or regional economies grow. Historically, state and local policymakers have put their energies into trying to attract existing firms from somewhere else, either to relocate to a particular area or to build new facilities there. Such smokestack chasing - or, in this cleaner era, simply firm chasing - often has degenerated into what is essentially a zero-sum game for the national economy. When one city or state offers tax breaks or other financial inducements to encourage firms to locate new plants or headquarters, and succeeds, some other city or state loses out in the process. Local, state, and regional economic development centered on entrepreneurship, however, is a fundamentally different phenomenon. The formation and growth of new firms, especially those built around new products or ways of doing things, wherever this occurs, is clearly a positive sum game, not just for the locality, but for the nation as a whole. This essay provides a guide to policymakers and citizens to what is known about the effects of various local and state policies aimed at fostering entrepreneurially driven growth. There is also much we do not know; thus, the essay identifies subjects that require further research

Aortic aneurysms after subclavian angioplasty repair of coarctation of the aorta

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27336/1/0000361.pd

Core components for effective infection prevention and control programmes: new WHO evidence-based recommendations

Abstract Health care-associated infections (HAI) are a major public health problem with a significant impact on morbidity, mortality and quality of life. They represent also an important economic burden to health systems worldwide. However, a large proportion of HAI are preventable through effective infection prevention and control (IPC) measures. Improvements in IPC at the national and facility level are critical for the successful containment of antimicrobial resistance and the prevention of HAI, including outbreaks of highly transmissible diseases through high quality care within the context of universal health coverage. Given the limited availability of IPC evidence-based guidance and standards, the World Health Organization (WHO) decided to prioritize the development of global recommendations on the core components of effective IPC programmes both at the national and acute health care facility level, based on systematic literature reviews and expert consensus. The aim of the guideline development process was to identify the evidence and evaluate its quality, consider patient values and preferences, resource implications, and the feasibility and acceptability of the recommendations. As a result, 11 recommendations and three good practice statements are presented here, including a summary of the supporting evidence, and form the substance of a new WHO IPC guideline

Identification of PKD1L1 Gene Variants in Children with the Biliary Atresia Splenic Malformation Syndrome

Biliary atresia (BA) is the most common cause of end‐stage liver disease in children and the primary indication for pediatric liver transplantation, yet underlying etiologies remain unknown. Approximately 10% of infants affected by BA exhibit various laterality defects (heterotaxy) including splenic abnormalities and complex cardiac malformations — a distinctive subgroup commonly referred to as the biliary atresia splenic malformation (BASM) syndrome. We hypothesized that genetic factors linking laterality features with the etiopathogenesis of BA in BASM patients could be identified through whole exome sequencing (WES) of an affected cohort. DNA specimens from 67 BASM subjects, including 58 patient‐parent trios, from the NIDDK‐supported Childhood Liver Disease Research Network (ChiLDReN) underwent WES. Candidate gene variants derived from a pre‐specified set of 2,016 genes associated with ciliary dysgenesis and/or dysfunction or cholestasis were prioritized according to pathogenicity, population frequency, and mode of inheritance. Five BASM subjects harbored rare and potentially deleterious bi‐allelic variants in polycystin 1‐like 1, PKD1L1, a gene associated with ciliary calcium signaling and embryonic laterality determination in fish, mice and humans. Heterozygous PKD1L1 variants were found in 3 additional subjects. Immunohistochemical analysis of liver from the one BASM subject available revealed decreased PKD1L1 expression in bile duct epithelium when compared to normal livers and livers affected by other non‐cholestatic diseases. Conclusion WES identified bi‐allelic and heterozygous PKD1L1 variants of interest in 8 BASM subjects from the ChiLDReN dataset. The dual roles for PKD1L1 in laterality determination and ciliary function suggest that PKD1L1 is a new, biologically plausible, cholangiocyte‐expressed candidate gene for the BASM syndrome