Differential utilization of ketone bodies by neurons and glioma cell lines: a rationale for ketogenic diet as experimental glioma therapy

Background: Even in the presence of oxygen, malignant cells often highly depend on glycolysis for energy generation, a phenomenon known as the Warburg effect. One strategy targeting this metabolic phenotype is glucose restriction by administration of a high-fat, low-carbohydrate (ketogenic) diet. Under these conditions, ketone bodies are generated serving as an important energy source at least for non-transformed cells. Methods: To investigate whether a ketogenic diet might selectively impair energy metabolism in tumor cells, we characterized in vitro effects of the principle ketone body 3-hydroxybutyrate in rat hippocampal neurons and five glioma cell lines. In vivo, a non-calorie-restricted ketogenic diet was examined in an orthotopic xenograft glioma mouse model. Results: The ketone body metabolizing enzymes 3-hydroxybutyrate dehydrogenase 1 and 2 (BDH1 and 2), 3-oxoacid-CoA transferase 1 (OXCT1) and acetyl-CoA acetyltransferase 1 (ACAT1) were expressed at the mRNA and protein level in all glioma cell lines. However, no activation of the hypoxia-inducible factor-1alpha (HIF-1alpha) pathway was observed in glioma cells, consistent with the absence of substantial 3-hydroxybutyrate metabolism and subsequent accumulation of succinate. Further, 3-hydroxybutyrate rescued hippocampal neurons from glucose withdrawal-induced cell death but did not protect glioma cell lines. In hypoxia, mRNA expression of OXCT1, ACAT1, BDH1 and 2 was downregulated. In vivo, the ketogenic diet led to a robust increase of blood 3-hydroxybutyrate, but did not alter blood glucose levels or improve survival. Conclusion: In summary, glioma cells are incapable of compensating for glucose restriction by metabolizing ketone bodies in vitro, suggesting a potential disadvantage of tumor cells compared to normal cells under a carbohydrate-restricted ketogenic diet. Further investigations are necessary to identify co-treatment modalities, e.g. glycolysis inhibitors or antiangiogenic agents that efficiently target non-oxidative pathways

Art in corporate governance: A Deweyan perspective on board experience

Corporate governance sits at the intersection of many aspects of disciplines from business, management, finance and accounting. The point of departure for the overwhelming portion of studies concerns the ugliness of greed, ambition, misdemeanors and malfeasance of corporations, their directors, and those actors hold own shares in them. This essay takes a rather different starting point. Drawing upon insights from a radically different field, it uses the discussion of aesthetics in Dewey’s treatise on art (1934/1958) to ask what motivates directors to act in ways that constitute the attention and engagement that we associate with the effectiveness of boards. Using Dewey’s thinking about aesthetic experience, this paper compares it with accounts of the experience of corporate boards, both in the literature and in the personal experience of the author. These observations point to need to reflect on motivation when considering both the practice of corporate governance and the policy frameworks in which it operates

Chiropractic physicians: toward a synthesis of electronic medical records and the society, culture, personality model in the new millennium

Abstract Objective: The purpose of this article is to offer aspects of a conceptual model that can be applied as an organizational instrument for aiding preclinical and clinical chiropractic students to develop a thorough understanding of their roles among the next generation of health care providers for the 21st century. Discussion: It is necessary for chiropractic physicians to comprehend the basis of the societyculture-personality model as an organizational device in the health care institution. The structure of the family and the socialization process as conceptual components of the model may allow an enriched understanding of their interrelationships and thereby could expand and provide quality care for patients as a whole. Conclusion: The society-culture-personality model has the potential for synthesizing the features of the socialization process and the family in relation to the institution of health care. This model is particularly appropriate for the needs of the next generation of health care professionals (chiropractic physicians, physicians, dentists, nurses, and osteopathic physicians) who may not have had the chance to be exposed entirely to the behavioral sciences in health care

Prematch Salivary Secretory Immunoglobulin A in Soccer Players From the 2014 World Cup Qualifying Campaign

Purpose: To monitor resting salivary secretory immunoglobulin A (SIgA) levels in international soccer players during the short-term training period that precedes international match play. Methods: In a repeated-measure design, saliva samples were obtained from 13 outfield soccer players who participated in the training camps preceding 7 games (5 home and 2 away) of the 2014 FIFA World Cup qualifying campaign. Samples were obtained daily for 4 d preceding each game (and analyzed for SIgA using the IPRO oral-fluid-collection system) at match day minus 1 (MD-1), minus 2 (MD-2), minus 3 (MD-3), and minus 4 (MD-4). Results: SIgA displayed a progressive decline (P = .01) during the 4-d training period (MD-4, 365 ± 127 μg/mL; MD-3, 348 ± 154 μg/mL; MD-2, 290 ± 138 μg/mL; MD-1, 256 ± 90 μg/mL) such that MD-1 values were significantly lower (P = .01) than both MD-4 and MD-3. The 95% confidence intervals for the differences between MD-1 and MD-4 were -191 to -26 and between MD-1 and MD-3 were -155 to -28. Conclusions: Data demonstrate that a short-term soccer-training camp in preparation for international competition induces detectable perturbations to mucosal immunity. Future studies should monitor SIgA (as a practical and noninvasive measure of immunity) alongside internal and external measures of training load in an attempt to strategically individualize training and nutritional strategies that may support optimal preparation for high-level competition.</p

Ovine model of neuropathic pain for assessing mechanisms of spinal cord stimulation therapy via dorsal horn recordings, von Frey filaments, and gait analysis

Chandan G Reddy,1 John W Miller,1 Kingsley O Abode-Iyamah,1 Sina Safayi,2 Saul Wilson,1 Brian D Dalm,1 Douglas C Fredericks,3 George T Gillies,4 Matthew A Howard III,1 Timothy J Brennan5 1Department of Neurosurgery, University of Iowa Carver College of Medicine, Iowa City, IA, USA; 2Department of Veterinary Clinical Sciences, Iowa State University, Ames, IA, USA; 3Department of Orthopedics and Rehabilitation, University of Iowa Carver College of Medicine, Iowa City, IA, USA; 4Department of Mechanical and Aerospace Engineering, University of Virginia, Charlottesville, VA, USA; 5Department of Anesthesia, University of Iowa Carver College of Medicine, Iowa City, IA, USA Background: It is becoming increasingly important to understand the mechanisms of spinal cord stimulation (SCS) in alleviating neuropathic pain as novel stimulation paradigms arise. Purpose: Additionally, the small anatomic scale of current SCS animal models is a barrier to more translational research. Methods: Using chronic constriction injury (CCI) of the common peroneal nerve (CPN) in sheep (ovine), we have created a chronic model of neuropathic pain that avoids motor deficits present in prior large animal models. This large animal model has allowed us to implant clinical grade SCS hardware, which enables both acute and chronic testing using von Frey filament thresholds and gait analysis. Furthermore, the larger anatomic scale of the sheep allows for simultaneous single-unit recordings from the dorsal horn and SCS with minimal electrical artifact. Results: Detectable tactile hypersensitivity occurred 21 days after nerve injury, with preliminary indications that chronic SCS may reverse it in the painful limb. Gait analysis revealed no hoof drop in the CCI model. Single neurons were identified and discriminated in the dorsal horn, and their activity was modulated via SCS. Unlike previous large animal models that employed a complete transection of the nerve, no motor deficit was observed in the sheep with CCI. Conclusion: To our knowledge, this is the first reported large animal model of chronic neuropathic pain which facilitates the study of both acute and chronic SCS using complementary behavioral and electrophysiologic measures. As demonstrated by our successful establishment of these techniques, an ovine model of neuropathic pain is suitable for testing the mechanisms of SCS. Keywords: neuropathic pain, sheep models, gait analysis, spinal cord stimulation, unit recordings&nbsp