A Dynamic Approach to Stakeholder Theory: A Case Study of Labor - Management Relations at General Motors

The purpose of this thesis is to identify areas for improvement in the current stakeholder management literature. The current stakeholder management theories were analyzed to determine their benefits and detriments. To determine how these theories work in a corporation, General Motors was selected as a single-case study to determine the patterns of stakeholder management over time. These patterns demonstrated the need for dynamic stakeholder management over time, with an emphasis on collaboration and the necessity of recognizing the greater stakeholder network surrounding the corporation. Proper stakeholder management in the early years of General Motors would have prevented its failure, while the organizational culture as a path-dependent variable made it difficult for General Motors to alter long-standing stakeholder relationships

Toxicological evaluation of a novel umami flavour compound: 2-(((3-(2,3-Dimethoxyphenyl)-1H -1,2,4-triazol-5-yl)thio)methyl)pyridine

A toxicological evaluation of a umami flavour compound, 2-(((3-(2, 3-dimethoxyphenyl)-1H -1, 2, 4-triazol-5-yl)thio)methyl)pyridine (S3643, CAS 902136-79-2), was completed for the purpose of assessing its safety for use in food and beverage applications. S3643 undergoes extensive oxidative metabolism in vitro with rat microsomes producing the S3643-sulfoxide and 4′-hydroxy-S3643 as the major metabolites. In incubations with human microsomes, the O -demethyl-S3643 and S3643-sulfoxide were produced as the major metabolites. In pharmacokinetic studies in rats, the S3643-sulfoxide represents the dominant biotransformation product. S3643 was not found to be mutagenic or clastogenic in vitro, and did not induce micronuclei in CHO-WBL cells. In subchronic oral toxicity studies in rats, the no-observed-adverse-effect-level (NOAEL) for S3643 was 100 mg/kg bw/day (highest dose tested) when administered in the diet for 90 consecutive days

Val103Ile polymorphism of the melanocortin-4 receptor gene (MC4R) in cancer cachexia

<p>Abstract</p> <p>Background</p> <p>At present pathogenic mechanisms of cancer cachexia are poorly understood. Previous evidence in animal models implicates the melanocortin-4 receptor gene (<it>MC4R</it>) in the development of cancer cachexia. In humans, <it>MC4R </it>mutations that lead to an impaired receptor function are associated with obesity; in contrast, the most frequent polymorphism (Val103Ile, rs2229616; heterozygote frequency approximately 2%) was shown to be negatively associated with obesity. We tested if cancer patients that are homo-/heterozygous for the Val103Ile polymorphism are more likely to develop cachexia and/or a loss of appetite than non-carriers of the 103Ile-allele.</p> <p>Methods</p> <p>BMI (body mass index in kg/m²) of 509 patients (295 males) with malignant neoplasms was determined; additionally patients were asked about premorbid/pretherapeutical changes of appetite and weight loss. Cachexia was defined as a weight loss of at least 5% prior to initiation of therapy; to fulfil this criterion this weight loss had to occur independently of other plausible reasons; in single cases weight loss was the initial reason for seeing a physician. The average age in years (± SD) was 59.0 ± 14.5 (males: 58.8 ± 14.0, females 59.2 ± 14.0). Blood samples were taken for genotyping of the Val103Ile by PCR- RFLP.</p> <p>Results</p> <p>Most of the patients suffered from lymphoma, leukaemia and gastrointestinal tumours. 107 of the patients (21%) fulfilled our criteria for cancer cachexia. We did not detect association between the Val103Ile polymorphism and cancer cachexia. However, if we exploratively excluded the patients with early leucaemic stages, we detected a trend towards the opposite effect (p < 0.05); heterozygotes for the 103Ile-allele developed cancer cachexia less frequently in comparison to the rest of the study group. Changes of appetite were not associated with the 103Ile-allele carrier status (p > 0.39).</p> <p>Conclusion</p> <p>Heterozygotes for the 103Ile-allele are not more prone to develop cancer cachexia than patients without this allele; possibly, Ile103 carriers might be more resistant to cancer cachexia in patients with solid tumors. Further studies of the melanocortinergic system in cachexia of patients with solid tumors are warranted.</p

Orally Available Selective Melanocortin-4 Receptor Antagonists Stimulate Food Intake and Reduce Cancer-Induced Cachexia in Mice

BACKGROUND: Cachexia is among the most debilitating and life-threatening aspects of cancer. It represents a metabolic syndrome affecting essential functional circuits involved in the regulation of homeostasis, and includes anorexia, fat and muscle tissue wasting. The anorexigenic peptide alpha-MSH is believed to be crucially involved in the normal and pathologic regulation of food intake. It was speculated that blockade of its central physiological target, the melanocortin (MC)-4 receptor, might provide a promising anti-cachexia treatment strategy. This idea is supported by the fact that in animal studies, agouti-related protein (AgRP), the endogenous inverse agonist at the MC-4 receptor, was found to affect two hallmark features of cachexia, i.e. to increase food intake and to reduce energy expenditure. METHODOLOGY/PRINCIPAL FINDINGS: SNT207707 and SNT209858 are two recently discovered, non peptidic, chemically unrelated, orally active MC-4 receptor antagonists penetrating the blood brain barrier. Both compounds were found to distinctly increase food intake in healthy mice. Moreover, in mice subcutaneously implanted with C26 adenocarcinoma cells, repeated oral administration (starting the day after tumor implantation) of each of the two compounds almost completely prevented tumor induced weight loss, and diminished loss of lean body mass and fat mass. CONCLUSIONS/SIGNIFICANCE: In contrast to the previously reported peptidic and small molecule MC-4 antagonists, the compounds described here work by the oral administration route. Orally active compounds might offer a considerable advantage for the treatment of cachexia patients

Effects of dietary Na+ deprivation on epithelial Na+ channel (ENaC), BDNF, and TrkB mRNA expression in the rat tongue

<p>Abstract</p> <p>Background</p> <p>In rodents, dietary Na⁺deprivation reduces gustatory responses of primary taste fibers and central taste neurons to lingual Na⁺stimulation. However, in the rat taste bud cells Na⁺deprivation increases the number of amiloride sensitive epithelial Na⁺channels (ENaC), which are considered as the "receptor" of the Na⁺component of salt taste. To explore the mechanisms, the expression of the three ENaC subunits (α, β and γ) in taste buds were observed from rats fed with diets containing either 0.03% (Na⁺deprivation) or 1% (control) NaCl for 15 days, by using <it>in situ </it>hybridization and real-time quantitative RT-PCR (qRT-PCR). Since BDNF/TrkB signaling is involved in the neural innervation of taste buds, the effects of Na⁺deprivation on BDNF and its receptor TrkB expression in the rat taste buds were also examined.</p> <p>Results</p> <p><it>In situ </it>hybridization analysis showed that all three ENaC subunit mRNAs were found in the rat fungiform taste buds and lingual epithelia, but in the vallate and foliate taste buds, only α ENaC mRNA was easily detected, while β and γ ENaC mRNAs were much less than those in the fungiform taste buds. Between control and low Na⁺fed animals, the numbers of taste bud cells expressing α, β and γ ENaC subunits were not significantly different in the fungiform, vallate and foliate taste buds, respectively. Similarly, qRT-PCR also indicated that Na⁺deprivation had no effect on any ENaC subunit expression in the three types of taste buds. However, Na⁺deprivation reduced BDNF mRNA expression by 50% in the fungiform taste buds, but not in the vallate and foliate taste buds. The expression of TrkB was not different between control and Na⁺deprived rats, irrespective of the taste papillae type.</p> <p>Conclusion</p> <p>The findings demonstrate that dietary Na⁺deprivation does not change ENaC mRNA expression in rat taste buds, but reduces BDNF mRNA expression in the fungiform taste buds. Given the roles of BDNF in survival of cells and target innervation, our results suggest that dietary Na⁺deprivation might lead to a loss of gustatory innervation in the mouse fungiform taste buds.</p

Pathophysiology of melanocortin receptors and their accessory proteins.

The melanocortin receptors (MCRs) and their accessory proteins (MRAPs) are involved in regulation of a diverse range of endocrine pathways. Genetic variants of these components result in phenotypic variation and disease. The MC1R is expressed in skin and variants in the MC1R gene are associated with ginger hair color. The MC2R mediates the action of ACTH in the adrenal gland to stimulate glucocorticoid production and MC2R mutations result in familial glucocorticoid deficiency (FGD). MC3R and MC4R are involved in metabolic regulation and their gene variants are associated with severe pediatric obesity, whereas the function of MC5R remains to be fully elucidated. MRAPs have been shown to modulate the function of MCRs and genetic variants in MRAPs are associated with diseases including FGD type 2 and potentially early onset obesity. This review provides an insight into recent advances in MCRs and MRAPs physiology, focusing on the disorders associated with their dysfunction

Systemic zinc redistribution and dyshomeostasis in cancer cachexia

Cachexia affects up to two thirds of all cancer patients and is a significant cause of morbidity and mortality. It is a complex metabolic syndrome associated with the underlying illness and characterized by loss of skeletal muscle tissue with or without loss of fat mass. Cachexia’s other prominent clinical symptoms include anorexia, systemic inflammation, pediatric growth failure, and hypogonadism. The relationship between the symptoms of cancer cachexia and the underlying illness is unclear, and there is an urgent need for a better understanding of the pathophysiology of this syndrome. Normal Zn metabolism is often disrupted in cancer patients, but the possible effects of systemic Zn dyshomeostasis in cachexia have not been investigated. We propose that the acute phase response can mediate Zn redistribution and accumulation in skeletal muscle tissue and contribute to the activation of the ubiquitin–proteasome pathway that regulates protein catabolism. This chronic redistribution deprives Zn from other tissues and organs and compromises critical physiological functions in the body. The cardinal symptoms of Zn deficiency are anorexia, systemic inflammation, growth failure in children, and hypogonadism. These symptoms also prominently characterize cancer cachexia suggesting that the role of systemic Zn dyshomeostasis in cachexia should be investigated

Pathophysiology and treatment of inflammatory anorexia in chronic disease

Decreased appetite and involuntary weight loss are common occurrences in chronic disease and have a negative impact on both quality of life and eventual mortality. Weight loss in chronic disease comes from both fat and lean mass, and is known as cachexia. Both alterations in appetite and body weight loss occur in a wide variety of diseases, including cancer, heart failure, renal failure, chronic obstructive pulmonary disease and HIV. An increase in circulating inflammatory cytokines has been implicated as a uniting pathogenic mechanism of cachexia and associated anorexia. One of the targets of inflammatory mediators is the central nervous system, and in particular feeding centers in the hypothalamus located in the ventral diencephalon. Current research has begun to elucidate the mechanisms by which inflammation reaches the hypothalamus, and the neural substrates underlying inflammatory anorexia. Research into these neural mechanisms has suggested new therapeutic possibilities, which have produced promising results in preclinical and clinical trials. This review will discuss inflammatory signaling in the hypothalamus that mediates anorexia, and the opportunities for therapeutic intervention that these mechanisms present