Importance Of Novel Approaches Research Articles

Editors' note: Child neurology in the 21st century: More than the sum of our RVUs

It is clear that the care of children with neurologic disease is often complex, requiring substantial effort on the part of the provider and multidisciplinary team, and considerable time allocated to training future pediatric neurologists. According to recently published data from the Child Neurology Society (CNS) Task Force, burnout was reported in a significant number of faculty in all but 1 of 25 surveyed programs. Furthermore, the burnout seems to be related—at least in part—to unreachable work Relative Value Units (wRVUs) established by administrative staff. In this review, Dr. Zupanc and colleagues recount their experience with the CNS Task Force survey and report how heavily wRVUs are weighted when it comes to physician compensation and expectations. The authors argue that reliance on wRVUs as the sole measure of academic productivity is inherently flawed. Emphasis was placed on marrying the mission of hospital programs with expectations and compensation of child neurologists. If community outreach, education of future child neurologists, and clinical research are among the core responsibilities of faculty, it is self-evident that sufficient time and resources be dedicated to these pursuits. Dr. Wollack agrees that wRVU targets create hardships for child neurologists, who are often requested to generate far more wRVUs when compared with other pediatric subspecialty providers. Dr. Nash and colleagues underscore the importance of novel approaches to care delivery, such as a dedicated hospitalist model, which may alleviate some of the stresses created by the current wRVU system. As the number of child neurology providers dwindles, it is important now more than ever to rekindle institutional efforts to preserve this medical discipline. It is clear that the care of children with neurologic disease is often complex, requiring substantial effort on the part of the provider and multidisciplinary team, and considerable time allocated to training future pediatric neurologists. According to recently published data from the Child Neurology Society (CNS) Task Force, burnout was reported in a significant number of faculty in all but 1 of 25 surveyed programs. Furthermore, the burnout seems to be related—at least in part—to unreachable work Relative Value Units (wRVUs) established by administrative staff. In this review, Dr. Zupanc and colleagues recount their experience with the CNS Task Force survey and report how heavily wRVUs are weighted when it comes to physician compensation and expectations. The authors argue that reliance on wRVUs as the sole measure of academic productivity is inherently flawed. Emphasis was placed on marrying the mission of hospital programs with expectations and compensation of child neurologists. If community outreach, education of future child neurologists, and clinical research are among the core responsibilities of faculty, it is self-evident that sufficient time and resources be dedicated to these pursuits. Dr. Wollack agrees that wRVU targets create hardships for child neurologists, who are often requested to generate far more wRVUs when compared with other pediatric subspecialty providers. Dr. Nash and colleagues underscore the importance of novel approaches to care delivery, such as a dedicated hospitalist model, which may alleviate some of the stresses created by the current wRVU system. As the number of child neurology providers dwindles, it is important now more than ever to rekindle institutional efforts to preserve this medical discipline.

Approaches to develop a road map for the long-term conservation of an island endemic genus Cylindrocline

Habitat fragmentation and invasive alien species contribute to genetic bottlenecks and the threat of extinction of many endemic species of Mauritius, part of the Madagascan and Indian Ocean biodiversity hotspot. The genus Cylindrocline has two species, C. commersonii (critically endangered) and C. lorencei (extinct in the wild). The last living specimens of C. lorencei disappeared in the wild after the recorded collecting of seeds in 1982 by Conservatoire Botanique National de Brest (CBN Brest). Embryo rescue was used as a method to germinate these seeds and the seedlings raised this way were shared by CBN Brest with Royal Botanic Gardens Kew (RBG Kew) as part of an exchange programme in 2001. Mature plants both at CBN Brest and RBG Kew stopped producing viable seeds and this has made the long-term conservation of C. lorencei even more difficult. Seeds of C. commersonii collected from the wild in 2010 have a very low viability while ex situ grown C. commersonii produce non-viable seeds. Molecular studies conducted in C. lorencei using amplified fragment length polymorphisms (AFLP) showed no genetic variability among remaining individuals. Two samples of C. commersonii showed a very small amount of genetic variability. The variability between the two species was well within the limits commonly found within species or between closely related species and the long-term conservation of the genus requires a radical (to a degree) approach to avoid its extinction. The importance of novel approaches for restoration and long-term conservation are discussed.

The K303R ERα mutation and aromatase inhibitor resistance.

Abstract Abstract #602 Aromatase inhibitors (AIs) are rapidly becoming the first choice for the endocrine treatment of steroid receptor positive breast cancer in postmenopausal women. However, de novo and acquired resistance is a significant problem. We have previously identified, in premalignant and invasive breast cancers, a somatic mutation at nucleotide 908 of ERα, which was significantly associated with postmenopausal status, larger tumor size, and axillary lymph node positivity. This mutation results in a lysine to arginine transition at residue 303 (K303R). We demonstrated that the K303R ERα mutation generated an estrogen hypersensitive phenotype in vitro and in vivo. Thus, we hypothesized that the mutant could provide a continuous mitogenic stimulus to the breast even during phases of low circulating hormone, such as in postmenopausal women, affording a proliferative advantage, especially during treatment with AIs. As preclinical models to directly test whether the mutation confers resistance to AIs, we generated MCF-7 parental and MCF-7-K303R-overexpressing cells stably transfected with the aromatase gene. Cells were stimulated with the aromatase substrate, androstenedione (AD), with or without the AI anastrazole (Ana). We found using MTT assays that Ana decreased AD-stimulated growth of WT vector control cells by 47%, but had no effect on AD-stimulated growth of MCF-7-K303R cells. Furthermore, in soft agar assays, the basal non-stimulated colony number of the mutant cells was increased 10-fold, and the AI was unable to inhibit the formation of mutant colonies. Aromatase activity of both cells was reduced by 95% by Ana, suggesting that this drug resistance cannot be explained by an intrinsic insensitivity of the aromatase enzyme itself to Ana.
 To examine the molecular mechanisms associated with the resistance of the mutant-expressing cells, we examined short-term nongenomic signaling, and found constitutively increased levels of phospho-IGF1R, IRS1 and AKT in the mutant cells. Interestingly, the hypersensitive mutant cells showed increased growth as well as pAkt activation with IGF1 treatment. Blockade of the IGF1R or PI3K/AKT pathways completely reversed the resistant mutant phenotype. To examine for effects on proliferation, immunoblot analyses were performed. K303R cells exhibited decreased levels of the CDK inhibitor p21 with AI treatment. Accordingly, apoptosis was decreased in the mutant cells with an increased ratio of bcl-2/Bax and decreased PARP cleavage.
 We conclude that the mutation indeed confers resistance to an AI. Potential mechanisms of resistance include cellular strategies to evade apoptosis and increase proliferation, possibly through enhanced cross-talk with growth factor pathways and reception of downstream signaling networks, such as AKT. Our results suggest that the mutation might be a new predictive marker of response to AIs in mutation-positive breast tumors, and highlight the importance of novel approaches toward the development of signal transduction inhibitors for treating patients with tumors resistant to hormone therapy. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 602.

Hemodynamic responses in cortex investigated with optical imaging methods. Implications for functional brain mapping

During the last 20 years, optical imaging methods – either alone or in combination with other recording techniques – has proven a fruitful approach to explore both the physiological and the functional aspects of activity-evoked hemodynamic responses in cortex. One of the main advantages of optical imaging consists in its high spatio-temporal resolution (in the order of few microns and milliseconds), allowing not only to unambiguously distinguish between activity patterns relating to the underlying functional architecture and those originating from the activation of medium/large blood vessels, but also to investigate the various activity-evoked hemodynamic processes at very fine detail. Here, we briefly review the principal findings obtained by optical imaging about the spatio-temporal properties of the various hemodynamic responses in cortex, i.e., changes in blood-oxygenation, blood-volume, and, to some extent, blood-flow. We also discuss the implications of those findings for non-invasive high-resolution functional brain imaging, in particular for fMRI. Finally, we underscore the importance of novel approaches for high-resolution blood-flow imaging, in the context of the need to gather information at fine spatial detail about the blood-flow response, necessary to constrain the multiple free parameters of hemodynamic response models.