Readjusting the glucocorticoid balance: an opportunity for modulators of 11beta-hydroxysteroid dehydrogenase type 1 activity?

Glucocorticoids play a pivotal role in the regulation of most essential physiological processes, including energy metabolism, maintenance of electrolyte balance and blood pressure, immune-modulation and stress responses, cell proliferation and differentiation, as well as regulation of memory and cognitive functions. There are several levels at which glucocorticoid action can be modulated. On a tissue-specific level, glucocorticoid action is tightly controlled by 11beta-hydroxysteroid dehydrogenase (11beta-HSD) enzymes. The conversion of inactive 11-ketoglucocorticoids (cortisone and 11-dehydrocorticosterone) into active 11beta-hydroxyglucocorticoids (cortisol and corticosterone) is catalyzed by 11beta-HSD1, which is expressed in many tissues and plays an important role in metabolically relevant tissues such as the liver, adipose tissue and skeletal muscles. Chronically elevated local glucocorticoid action as a result of increased 11beta-HSD1 activity rather than elevated systemic glucocorticoid levels has been associated with metabolic syndrome, which is characterized by obesity, insulin resistance, type 2 diabetes and cardiovascular complications. Recent studies indicate that compounds inhibiting 11beta-HSD1 activity ameliorate the adverse effects of excessive glucocorticoid concentrations on metabolic processes, providing promising opportunities for the development of therapeutic interventions. This review addresses recent findings relevant for the development and application of therapeutically useful compounds that modulate 11beta-HSD1 function.

Increasing mean arterial blood pressure in sepsis: effects on fluid balance, vasopressor load and renal function.

INTRODUCTION: The objective of this study was to evaluate the effects of two different mean arterial blood pressure (MAP) targets on needs for resuscitation, organ dysfunction, mitochondrial respiration and inflammatory response in a long-term model of fecal peritonitis. METHODS: Twenty-four anesthetized and mechanically ventilated pigs were randomly assigned (n = 8/group) to a septic control group (septic-CG) without resuscitation until death or one of two groups with resuscitation performed after 12 hours of untreated sepsis for 48 hours, targeting MAP 50-60 mmHg (low-MAP) or 75-85 mmHg (high-MAP). RESULTS: MAP at the end of resuscitation was 56 ± 13 mmHg (mean ± SD) and 76 ± 17 mmHg respectively, for low-MAP and high-MAP groups. One animal each in high- and low-MAP groups, and all animals in septic-CG died (median survival time: 21.8 hours, inter-quartile range: 16.3-27.5 hours). Norepinephrine was administered to all animals of the high-MAP group (0.38 (0.21-0.56) mcg/kg/min), and to three animals of the low-MAP group (0.00 (0.00-0.25) mcg/kg/min; P = 0.009). The high-MAP group had a more positive fluid balance (3.3 ± 1.0 mL/kg/h vs. 2.3 ± 0.7 mL/kg/h; P = 0.001). Inflammatory markers, skeletal muscle ATP content and hemodynamics other than MAP did not differ between low- and high-MAP groups. The incidence of acute kidney injury (AKI) after 12 hours of untreated sepsis was, respectively for low- and high-MAP groups, 50% (4/8) and 38% (3/8), and in the end of the study 57% (4/7) and 0% (P = 0.026). In septic-CG, maximal isolated skeletal muscle mitochondrial Complex I, State 3 respiration increased from 1357 ± 149 pmol/s/mg to 1822 ± 385 pmol/s/mg, (P = 0.020). In high- and low-MAP groups, permeabilized skeletal muscle fibers Complex IV-state 3 respiration increased during resuscitation (P = 0.003). CONCLUSIONS: The MAP targets during resuscitation did not alter the inflammatory response, nor affected skeletal muscle ATP content and mitochondrial respiration. While targeting a lower MAP was associated with increased incidence of AKI, targeting a higher MAP resulted in increased net positive fluid balance and vasopressor load during resuscitation. The long-term effects of different MAP targets need to be evaluated in further studies.

Increased mRNA levels for components of the lysosomal, Ca2+-activated, and ATP-ubiquitin-dependent proteolytic pathways in skeletal muscle from head trauma patients.

The cellular mechanisms responsible for enhanced muscle protein breakdown in hospitalized patients, which frequently results in lean body wasting, are unknown. To determine whether the lysosomal, Ca2+-activated, and ubiquitin-proteasome proteolytic pathways are activated, we measured mRNA levels for components of these processes in muscle biopsies from severe head trauma patients. These patients exhibited negative nitrogen balance and increased rates of whole-body protein breakdown (assessed by [13C]leucine infusion) and of myofibrillar protein breakdown (assessed by 3-methylhistidine urinary excretion). Increased muscle mRNA levels for cathepsin D, m-calpain, and critical components of the ubiquitin proteolytic pathway (i.e., ubiquitin, the 14-kDa ubiquitin-conjugating enzyme E2, and proteasome subunits) paralleled these metabolic adaptations. The data clearly support a role for multiple proteolytic processes in increased muscle proteolysis. The ubiquitin proteolytic pathway could be activated by altered glucocorticoid production and/or increased circulating levels of interleukin 1beta and interleukin 6 observed in head trauma patients and account for the breakdown of myofibrillar proteins, as was recently reported in animal studies.

Skeletal muscle and nuclear hormone receptors: Implications for cardiovascular and metabolic disease

Skeletal muscle is a major mass peripheral tissue that accounts for similar to 40% of the total body mass and a major player in energy balance. It accounts for > 30% of energy expenditure, is the primary tissue of insulin stimulated glucose uptake, disposal, and storage. Furthermore, it influences metabolism via modulation of circulating and stored lipid (and cholesterol) flux. Lipid catabolism supplies up to 70% of the energy requirements for resting muscle. However, initial aerobic exercise utilizes stored muscle glycogen but as exercise continues, glucose and stored muscle triglycerides become important energy substrates. Endurance exercise increasingly depends on fatty acid oxidation (and lipid mobilization from other tissues). This underscores the importance of lipid and glucose utilization as an energy source in muscle. Consequently skeletal muscle has a significant role in insulin sensitivity, the blood lipid profile, and obesity. Moreover, caloric excess, obesity and physical inactivity lead to skeletal muscle insulin resistance, a risk factor for the development of type II diabetes. In this context skeletal muscle is an important therapeutic target in the battle against cardiovascular disease, the worlds most serious public health threat. Major risk factors for cardiovascular disease include dyslipidemia, hypertension, obesity, sedentary lifestyle, and diabetes. These risk factors are directly influenced by diet, metabolism and physical activity. Metabolism is largely regulated by nuclear hormone receptors which function as hormone regulated transcription factors that bind DNA and mediate the pathophysiological regulation of gene expression. Metabolism and activity, which directly influence cardiovascular disease risk factors, are primarily driven by skeletal muscle. Recently, many nuclear receptors expressed in skeletal muscle have been shown to improve glucose tolerance, insulin resistance, and dyslipidernia. Skeletal muscle and nuclear receptors are rapidly emerging as critical targets in the battle against cardiovascular disease risk factors. Understanding the function of nuclear receptors in skeletal muscle has enormous pharmacological utility for the treatment of cardiovascular disease. This review focuses on the molecular regulation of metabolism by nuclear receptors in skeletal muscle in the context of dyslipidemia and cardiovascular disease. (c) 2005 Published by Elsevier Ltd.

Orphan nuclear receptors: therapeutic opportunities in skeletal muscle

Orphan nuclear receptors: therapeutic opportunities in skeletal muscle. Am J Physiol Cell Physiol 291: C203-C217, 2006; doi: 10.1152/ajpcell. 00476.2005.-Nuclear hormone receptors (NRs) are ligand-dependent transcription factors that bind DNA and translate physiological signals into gene regulation. The therapeutic utility of NRs is underscored by the diversity of drugs created to manage dysfunctional hormone signaling in the context of reproductive biology, inflammation, dermatology, cancer, and metabolic disease. For example, drugs that target nuclear receptors generate over $10 billion in annual sales. Almost two decades ago, gene products were identified that belonged to the NR superfamily on the basis of DNA and protein sequence identity. However, the endogenous and synthetic small molecules that modulate their action were not known, and they were denoted orphan NRs. Many of the remaining orphan NRs are highly enriched in energy-demanding major mass tissues, including skeletal muscle, brown and white adipose, brain, liver, and kidney. This review focuses on recently adopted and orphan NR function in skeletal muscle, a tissue that accounts for similar to 35% of the total body mass and energy expenditure, and is a major site of fatty acid and glucose utilization. Moreover, this lean tissue is involved in cholesterol efflux and secretes that control energy expenditure and adiposity. Consequently, muscle has a significant role in insulin sensitivity, the blood lipid profile, and energy balance. Accordingly, skeletal muscle plays a considerable role in the progression of dyslipidemia, diabetes, and obesity. These are risk factors for cardiovascular disease, which is the the foremost cause of global mortality (> 16.7 million deaths in 2003). Therefore, it is not surprising that orphan NRs and skeletal muscle are emerging as therapeutic candidates in the battle against dyslipidemia, diabetes, obesity, and cardiovascular disease.

Work/Family Balance: HRM Policy and Practice in Australia

An employee's inability to balance work and family responsibilities has resulted in an increase in stress related illnesses. Historically, research into the nexus between work and family has primarily focused on the work/family conflict relationship, predominately investigating the impact of this conflict on parents, usually mothers. To date research has not sufficiently examined the human resource management practices that enable all parents to achieve a balance between their work and family lives. This paper explores the relationship between contemporary family friendly HRM policies and employed parents perceptions of work/family enhancement, work/family satisfaction, propensity to turnover, and work/family conflict. Self-report questionnaire data from 326 men and women is analysed and discussed to enable organisations to consider the use of family friendly policies and thus create a convergence between the well-being of employees and the effectiveness of the organisation.

Memoirs of a trainer : The search for a balance between quality and best practice

The field of research training (for students and supervisors) is becoming more heavily regulated by the Federal Government. At the same time, quality improvement imperatives are requiring staff across the University to have better access to information and knowledge about a wider range of activities each year. Within the Creative Industries Faculty at the Queensland University of Technology (QUT), the training provided to academic and research staff is organised differently and individually. This session will involve discussion of the dichotomies found in this differentiated approach to staff training, and begin a search for best practice through interaction and input from the audience.

Discourse practice gaps in work life balance : comparative case studies in the Australian construction industry

Perspectives on work-life balance (WLB) reflected in political, media and organisational discourse, would maintain that WLB is on the agenda because of broad social, economic and political factors (Fleetwood 2007). In contrast, critical scholarship which examines work-life balance (WLB) and its associated practices maintains that workplace flexibility is more than a quasi-functionalist response to contemporary problems faced by individuals, families or organisations. For example, the literature identifies where flexible work arrangements have not lived up to expectations of a panacea for work-home conflicts, being characterised as much by employer-driven working conditions that disadvantage workers and constrain balance, as they are by employee friendly practices that enable it (Charlesworth 1997). Further, even where generous organisational work-life balance policies exist, under-utilisation is an issue (Schaefer et al, 2007). Compounding these issues is that many employees perceive their paid work as becoming more intense, pressured and demanding (Townsend et al 2003).

Clypeotheca, a new skeletal structure in scleractinian corals : a potential stress indicator

Physiological responses to environmental stress are increasingly well studied in scleractinian corals. This work reports a new stress-related skeletal structure we term clypeotheca. Clypeotheca was observed in several livecollected common reef-building coral genera and a two to three kya subfossil specimen from Heron Reef, Great Barrier Reef and consists of an epitheca-like skeletal wall that seals over the surface of parts of the corallum in areas of stress or damage. It appears to form from a coordinated process wherein neighboring polyps and adjoining coenosarc seal themselves off from the surrounding environment as they contract and die. Clypeotheca forms from inward skeletal centripetal growth at the edges of corallites and by the merging of flange-like outgrowths that surround individual spines over the surface of the coenosteum. Microstructurally, the merged flanges are similar to upsidedown dissepiments and true epitheca. Clypeotheca is interpreted primarily as a response to stress that may help protect the colony from invasion of unhealthy tissues by parasites or disease by retracting tissues in areas that have become unhealthy for the polyps. Identification of skeletal responses of corals to environmental stress may enable the frequency of certain types of environmental stress to be documented in past environments. Such data may be important for understanding the nature of reef dynamics through intervals of climate change and for monitoring the effects of possible anthropogenic stress in modern coral reef habitats.

What about me? Avoiding fatigue and gaining personal time in the work to leisure transition in work-life balance initiatives

Fatigue and overwork are problems experienced by numerous employees in many industry sectors. Focusing on improving work-life balance can frame the ‘problem’ of long work hours to resolve working time duration issues. Flexible work options through re-organising working time arrangements is key to developing an organisational response for delivering work-life balance and usually involves changing the internal structure of work time. This study examines the effect of compressed long weekly working hours and the consequent ‘long break’ on work-life balance. Using Spillover theory and Border theory, this research considers organisational and personal determinants of overwork and fatigue. It concludes compressed long work hours with a long break provide better work-life balance. Further, a long break allows gaining ‘personal time’ and overcoming fatigue.