The endothelial cell (EC) lining of the pulmonary vasculature forms a semipermeable barrier between the blood and the interstitium of the lung. Disruption of this barrier occurs during inflammatory disease states such as acute lung injury and acute respiratory distress syndrome and results in the movement of fluid and macromolecules into the interstitium and pulmonary air spaces. These processes significantly contribute to the high morbidity and mortality of patients afflicted with acute lung injury. The critical importance of pulmonary vascular barrier function is shown by the balance between competing EC contractile forces, which generate centripetal tension, and adhesive cell-cell and cell-matrix tethering forces, which regulate cell shape. Both competing forces in this model are intimately linked through the endothelial cytoskeleton, a complex network of actin microfilaments, microtubules, and intermediate filaments, which combine to regulate shape change and transduce signals within and between EC. A key EC contractile event in several models of agonist-induced barrier dysfunction is the phosphorylation of regulatory myosin light chains catalyzed by Ca(2+)/calmodulin-dependent myosin light chain kinase and/or through the activity of the Rho/Rho kinase pathway. Intercellular contacts along the endothelial monolayer consist primarily of two types of complexes (adherens junctions and tight junctions), which link to the actin cytoskeleton to provide both mechanical stability and transduction of extracellular signals into the cell. Focal adhesions provide additional adhesive forces in barrier regulation by forming a critical bridge for bidirectional signal transduction between the actin cytoskeleton and the cell-matrix interface. Increasingly, the effects of mechanical forces such as shear stress and ventilator-induced stretch on EC barrier function are being recognized. The critical role of the endothelial cytoskeleton in integrating these multiple aspects of pulmonary vascular permeability provides a fertile area for the development of clinically important barrier-modulating therapies.

Organisms respond to elevated temperatures and to chemical and physiological stresses by an increase in the synthesis of heat shock proteins. The regulation of heat shock gene expression in eukaryotes is mediated by the conserved heat shock transcription factor (HSF). HSF is present in a latent state under normal conditions; it is activated upon heat stress by induction of trimerization and high-affinity binding to DNA and by exposure of domains for transcriptional activity. Analysis of HSF cDNA clones from many species has defined structural and regulatory regions responsible for the inducible activities. The heat stress signal is thought to be transduced to HSF by changes in the physical environment, in the activity of HSF-modifying enzymes, or by changes in the intracellular level of heat shock proteins.

Since its introduction almost 20 years ago, the tail suspension test has become one of the most widely used models for assessing antidepressant-like activity in mice. The test is based on the fact that animals subjected to the short-term, inescapable stress of being suspended by their tail, will develop an immobile posture. Various antidepressant medications reverse the immobility and promote the occurrence of escape-related behaviour. This review focuses on the utility this test as part of a research program aimed at understanding the mechanism of action of antidepressants. We discuss the inherent difficulties in modeling depression in rodents. We describe how the tail suspension differs from the closely related forced swim test. Further, we address some key issues associated with using the TST as a model of antidepressant action. We discuss issues regarding whether it satisfies criteria to be a valid model for assessing depression-related behavioural traits. We elaborate on the tests' ease of use, strain differences observed in the test and gender effects in the test. We focus on the utility of the test for genetic analysis. Furthermore, we discuss the concept of whether immobility maybe a behavioural trait relevant to depression. All of the available pharmacological data using the test in genetically modified mice is collated. Special attention is given to selective breeding programs such as the Rouen 'depressed' mice which have been bred for high and low immobility in the tail suspension test. We provide an extensive pooling of the pharmacological studies published to date using the test. Finally, we provide novel pharmacological validation of an automated system (Bioseb) for assessing immobility. Taken together, we conclude that the tail suspension test is a useful test for assessing the behavioural effects of antidepressant compounds and other pharmacological and genetic manipulations relevant to depression.

Although the fact that genetic predisposition and environmental exposures interact to shape development and function of the human brain and, ultimately, the risk of psychiatric disorders has drawn wide interest, the corresponding molecular mechanisms have not yet been elucidated. We found that a functional polymorphism altering chromatin interaction between the transcription start site and long-range enhancers in the FK506 binding protein 5 (FKBP5) gene, an important regulator of the stress hormone system, increased the risk of developing stress-related psychiatric disorders in adulthood by allele-specific, childhood trauma-dependent DNA demethylation in functional glucocorticoid response elements of FKBP5. This demethylation was linked to increased stress-dependent gene transcription followed by a long-term dysregulation of the stress hormone system and a global effect on the function of immune cells and brain areas associated with stress regulation. This identification of molecular mechanisms of genotype-directed long-term environmental reactivity will be useful for designing more effective treatment strategies for stress-related disorders.

MicroRNAs (miRNAs) are a class of regulatory RNAs of approximately 21 nucleotides that posttranscriptionally regulate gene expression by directing mRNA cleavage or translational inhibition. Increasing evidence points to a potential role of miRNAs in diverse physiological processes. miR398 targets two closely related Cu/Zn superoxide dismutases (cytosolic CSD1 and chloroplastic CSD2) that can detoxify superoxide radicals. CSD1 and CSD2 transcripts are induced in response to oxidative stress, but the regulatory mechanism of the induction is unknown. Here, we show that miR398 expression is downregulated transcriptionally by oxidative stresses, and this downregulation is important for posttranscriptional CSD1 and CSD2 mRNA accumulation and oxidative stress tolerance. We also provide evidence for an important role of miR398 in specifying the spatial and temporal expression patterns of CSD1 and CSD2 mRNAs. Our results suggest that CSD1 and CSD2 expression is fine-tuned by miR398-directed mRNA cleavage. Additionally, we show that transgenic Arabidopsis thaliana plants overexpressing a miR398-resistant form of CSD2 accumulate more CSD2 mRNA than plants overexpressing a regular CSD2 and are consequently much more tolerant to high light, heavy metals, and other oxidative stresses. Thus, relieving miR398-guided suppression of CSD2 in transgenic plants is an effective new approach to improving plant productivity under oxidative stress conditions.

Metabolism generates oxygen radicals, which contribute to oncogenic mutations. Activated oncogenes and loss of tumor suppressors in turn alter metabolism and induce aerobic glycolysis. Aerobic glycolysis or the Warburg effect links the high rate of glucose fermentation to cancer. Together with glutamine, glucose via glycolysis provides the carbon skeletons, NADPH, and ATP to build new cancer cells, which persist in hypoxia that in turn rewires metabolic pathways for cell growth and survival. Excessive caloric intake is associated with an increased risk for cancers, while caloric restriction is protective, perhaps through clearance of mitochondria or mitophagy, thereby reducing oxidative stress. Hence, the links between metabolism and cancer are multifaceted, spanning from the low incidence of cancer in large mammals with low specific metabolic rates to altered cancer cell metabolism resulting from mutated enzymes or cancer genes.

The AMP-activated protein kinase (AMPK) is an important regulator of cellular metabolism in response to metabolic stress and to other regulatory signals. AMPK activity is absolutely dependent upon phosphorylation of AMPKalphaThr-172 in its activation loop by one or more AMPK kinases (AMPKKs). The tumor suppressor kinase, LKB1, is a major AMPKK present in a variety of tissues and cells, but several lines of evidence point to the existence of other AMPKKs. We have employed three cell lines deficient in LKB1 to study AMPK regulation and phosphorylation, HeLa, A549, and murine embryo fibroblasts derived from LKB(-/-) mice. In HeLa and A549 cells, mannitol, 2-deoxyglucose, and ionomycin, but not 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR), treatment activates AMPK by alphaThr-172 phosphorylation. These responses, as well as the downstream effects of AMPK on the phosphorylation of acetyl-CoA carboxylase, are largely inhibited by the Ca(2+)/ calmodulin-dependent protein kinase kinase (CaMKK) inhibitor, STO-609. AMPKK activity in HeLa cell lysates measured in vitro is totally inhibited by STO-609 with an IC50 comparable with that of the known CaMKK isoforms, CaMKKalpha and CaMKKbeta. Furthermore, 2-deoxyglucose- and ionomycin-stimulated AMPK activity, alphaThr-172 phosphorylation, and acetyl-CoA carboxylase phosphorylation are substantially reduced in HeLa cells transfected with small interfering RNAs specific for CaMKKalpha and CaMKKbeta. Lastly, the activation of AMPK in response to ionomycin and 2-deoxyglucose is not impaired in LKB1(-/-) murine embryo fibroblasts. These data indicate that the CaMKKs function in intact cells as AMPKKs, predicting wider roles for these kinases in regulating AMPK activity in vivo.

Alternative splicing can enhance transcriptome plasticity and proteome diversity. In plants, alternative splicing can be manifested at different developmental stages, and is frequently associated with specific tissue types or environmental conditions such as abiotic stress. We mapped the Arabidopsis transcriptome at single-base resolution using the Illumina platform for ultrahigh-throughput RNA sequencing (RNA-seq). Deep transcriptome sequencing confirmed a majority of annotated introns and identified thousands of novel alternatively spliced mRNA isoforms. Our analysis suggests that at least approximately 42% of intron-containing genes in Arabidopsis are alternatively spliced; this is significantly higher than previous estimates based on cDNA/expressed sequence tag sequencing. Random validation confirmed that novel splice isoforms empirically predicted by RNA-seq can be detected in vivo. Novel introns detected by RNA-seq were substantially enriched in nonconsensus terminal dinucleotide splice signals. Alternative isoforms with premature termination codons (PTCs) comprised the majority of alternatively spliced transcripts. Using an example of an essential circadian clock gene, we show that intron retention can generate relatively abundant PTC(+) isoforms and that this specific event is highly conserved among diverse plant species. Alternatively spliced PTC(+) isoforms can be potentially targeted for degradation by the nonsense mediated mRNA decay (NMD) surveillance machinery or regulate the level of functional transcripts by the mechanism of regulated unproductive splicing and translation (RUST). We demonstrate that the relative ratios of the PTC(+) and reference isoforms for several key regulatory genes can be considerably shifted under abiotic stress treatments. Taken together, our results suggest that like in animals, NMD and RUST may be widespread in plants and may play important roles in regulating gene expression.

Adverse early life events can induce long-lasting changes in physiology and behavior. We found that early-life stress (ELS) in mice caused enduring hypersecretion of corticosterone and alterations in passive stress coping and memory. This phenotype was accompanied by a persistent increase in arginine vasopressin (AVP) expression in neurons of the hypothalamic paraventricular nucleus and was reversed by an AVP receptor antagonist. Altered Avp expression was associated with sustained DNA hypomethylation of an important regulatory region that resisted age-related drifts in methylation and centered on those CpG residues that serve as DNA-binding sites for the methyl CpG-binding protein 2 (MeCP2). We found that neuronal activity controlled the ability of MeCP2 to regulate activity-dependent transcription of the Avp gene and induced epigenetic marking. Thus, ELS can dynamically control DNA methylation in postmitotic neurons to generate stable changes in Avp expression that trigger neuroendocrine and behavioral alterations that are frequent features in depression.

This paper evaluates the validity, reliability and utility of the chronic mild stress (CMS) model of depression. In the CMS model, rats or mice are exposed sequentially, over a period of weeks, to a variety of mild stressors, and the measure most commonly used to track the effects is a decrease in consumption of a palatable sweet solution. The model has good predictive validity (behavioural changes are reversed by chronic treatment with a wide variety of antidepressants), face validity (almost all demonstrable symptoms of depression have been demonstrated), and construct validity (CMS causes a generalized decrease in responsiveness to rewards, comparable to anhedonia, the core symptom of the melancholic subtype of major depressive disorder). Overall, the CMS procedure appears to be at least as valid as any other animal model of depression. The procedure does, however, have two major drawbacks. One is the practical difficulty of carrying out CMS experiments, which are labour intensive, demanding of space, and of long duration. The other is that, while the procedure operates reliably in many laboratories, it can be difficult to establish, for reasons which remain unclear. However, once established, the CMS model can be used to study problems that are extremely difficult to address by other means.

Activation of PERK following the accumulation of unfolded proteins in the endoplasmic reticulum (ER) promotes translation inhibition and cell cycle arrest. PERK function is essential for cell survival following exposure of cells to ER stress, but the mechanisms whereby PERK signaling promotes cell survival are not thoroughly understood. We have identified the Nrf2 transcription factor as a novel PERK substrate. In unstressed cells, Nrf2 is maintained in the cytoplasm via association with Keap1. PERK-dependent phosphorylation triggers dissociation of Nrf2/Keap1 complexes and inhibits reassociation of Nrf2/Keap1 complexes in vitro. Activation of PERK via agents that trigger the unfolded protein response is both necessary and sufficient for dissociation of cytoplasmic Nrf2/Keap1 and subsequent Nrf2 nuclear import. Finally, we demonstrate that cells harboring a targeted deletion of Nrf2 exhibit increased cell death relative to wild-type counterparts following exposure to ER stress. Our data demonstrate that Nrf2 is a critical effector of PERK-mediated cell survival.

To determine whether a cumulative sleep debt (in a range commonly experienced) would result in cumulative changes in measures of waking neurobehavioral alertness, 16 healthy young adults had their sleep restricted 33% below habitual sleep duration, to an average 4.98 hours per night [standard deviation (SD) = 0.57] for seven consecutive nights. Subjects slept in the laboratory, and sleep and waking were monitored by staff and actigraphy. Three times each day (1000, 1600, and 2200 hours) subjects were assessed for subjective sleepiness (SSS) and mood (POMS) and were evaluated on a brief performance battery that included psychomotor vigilance (PVT), probed memory (PRM), and serial-addition testing, Once each day they completed a series of visual analog scales (VAS) and reported sleepiness and somatic and cognitive/emotional problems. Sleep restriction resulted in statistically robust cumulative effects on waking functions. SSS ratings, subscale scores for fatigue, confusion, tension, and total mood disturbance from the POMS and VAS ratings of mental exhaustion and stress were evaluated across days of restricted sleep (p = 0.009 to p = 0.0001). PVT performance parameters, including the frequency and duration of lapses, were also significantly increased by restriction (p = 0.018 to p = 0.0001). Significant time-of-day effects were evident in SSS and PVT data, but time-of-day did not interact with the effects of sleep restriction across days. The temporal profiles of cumulative changes in neurobehavioral measures of alertness as a function of sleep restriction were generally consistent. Subjective changes tended to precede performance changes by 1 day, but overall changes in both classes of measure were greatest during the first 2 days (P1, P2) and last 2 days (P6, P7) of sleep restriction. Data from subsets of subjects also showed: 1) that significant decreases in the MSLT occurred during sleep restriction, 2) that the elevated sleepiness and performance deficits continued beyond day 7 of restriction, and 3) that recovery from these deficits appeared to require two full nights of sleep. The cumulative increase in performance lapses across days of sleep restriction correlated closely with MSLT results (r = -0.95) from an earlier comparable experiment by Carskadon and Dement (1). These findings suggest that cumulative nocturnal sleep debt had a dynamic and escalating analog in cumulative daytime sleepiness and that asymptotic or steady-state sleepiness was not achieved in response to sleep restriction.

We have developed a general profile for the proteins of the TetR family of repressors. The stretch that best defines the profile of this family is made up of 47 amino acid residues that correspond to the helix-turn-helix DNA binding motif and adjacent regions in the three-dimensional structures of TetR, QacR, CprB, and EthR, four family members for which the function and three-dimensional structure are known. We have detected a set of 2,353 nonredundant proteins belonging to this family by screening genome and protein databases with the TetR profile. Proteins of the TetR family have been found in 115 genera of gram-positive, alpha-, beta-, and gamma-proteobacteria, cyanobacteria, and archaea. The set of genes they regulate is known for 85 out of the 2,353 members of the family. These proteins are involved in the transcriptional control of multidrug efflux pumps, pathways for the biosynthesis of antibiotics, response to osmotic stress and toxic chemicals, control of catabolic pathways, differentiation processes, and pathogenicity. The regulatory network in which the family member is involved can be simple, as in TetR (i.e., TetR bound to the target operator represses tetA transcription and is released in the presence of tetracycline), or more complex, involving a series of regulatory cascades in which either the expression of the TetR family member is modulated by another regulator or the TetR family member triggers a cell response to react to environmental insults. Based on what has been learned from the cocrystals of TetR and QacR with their target operators and from their three-dimensional structures in the absence and in the presence of ligands, and based on multialignment analyses of the conserved stretch of 47 amino acids in the 2,353 TetR family members, two groups of residues have been identified. One group includes highly conserved positions involved in the proper orientation of the helix-turn-helix motif and hence seems to play a structural role. The other set of less conserved residues are involved in establishing contacts with the phosphate backbone and target bases in the operator. Information related to the TetR family of regulators has been updated in a database that can be accessed at www.bactregulators.org.

BACKGROUND

High blood glucose concentration may increase risk of death and poor outcome after acute myocardial infarction. We did a systematic review and meta-analysis to assess the risk of in-hospital mortality or congestive heart failure after myocardial infarction in patients with and without diabetes who had stress hyperglycaemia on admission.

METHODS

We did two searches of MEDLINE for English-language articles published from 1966 to October, 1998, a computerised search of Science Citation Index from 1980 to September, 1998, and manual searches of bibliographies. Two searchers identified all cohort studies or clinical trials reporting in-hospital mortality or rates of congestive heart failure after myocardial infarction in relation to glucose concentration on admission. We compared the relative risks of in-hospital mortality and congestive heart failure in hyperglycaemic and normoglycaemic patients with and without diabetes.

RESULTS

14 articles describing 15 studies were identified. Patients without diabetes who had glucose concentrations more than or equal to range 6.1-8.0 mmol/L had a 3.9-fold (95% CI 2.9-5.4) higher risk of death than patients without diabetes who had lower glucose concentrations. Glucose concentrations higher than values in the range of 8.0-10.0 mmol/L on admission were associated with increased risk of congestive heart failure or cardiogenic shock in patients without diabetes. In patients with diabetes who had glucose concentrations more than or equal to range 10.0-11.0 mmol/L the risk of death was moderately increased (relative risk 1.7 [1.2-2.4]).

CONCLUSIONS

Stress hyperglycaemia with myocardial infarction is associated with an increased risk of in-hospital mortality in patients with and without diabetes; the risk of congestive heart failure or cardiogenic shock is also increased in patients without diabetes.

The c-Jun amino-terminal kinase (JNK) group of MAP kinases has been identified in mammals and insects. JNK is activated by exposure of cells to cytokines or environmental stress, indicating that this signaling pathway may contribute to inflammatory responses. Genetic and biochemical studies demonstrate that this signaling pathway also regulates cellular proliferation, apoptosis, and tissue morphogenesis. A functional role for JNK is therefore established in both the cellular response to stress and in many normal physiological processes.

A single entity, the AMP-activated protein kinase (AMPK), phosphorylates and regulates in vivo hydroxymethylglutaryl-CoA reductase and acetyl-CoA carboxylase (key regulatory enzymes of sterol synthesis and fatty acid synthesis, respectively), and probably many additional targets. The kinase is activated by high AMP and low ATP via a complex mechanism, which involves allosteric regulation, promotion of phosphorylation by an upstream protein kinase (AMPK kinase), and inhibition of dephosphorylation. This protein-kinase cascade represents a sensitive system, which is activated by cellular stresses that deplete ATP, and thus acts like a cellular fuel gauge. Our central hypothesis is that, when it detects a 'low-fuel' situation, it protects the cell by switching off ATP-consuming pathways (e.g. fatty acid synthesis and sterol synthesis) and switching on alternative pathways for ATP generation (e.g. fatty acid oxidation). Native AMP-activated protein kinase is a heterotrimer consisting of a catalytic alpha subunit, and beta and gamma subunits, which are also essential for activity. All three subunits have homologues in budding yeast, which are components of the SNF1 protein-kinase complex. SNF1 is activated by glucose starvation (which in yeast leads to ATP depletion) and genetic studies have shown that it is involved in derepression of glucose-repressed genes. This raises the intriguing possibility that AMPK may regulate gene expression in mammals. AMPK/SNF1 homologues are found in higher plants, and this protein-kinase cascade appears to be an ancient system which evolved to protect cells against the effects of nutritional or environmental stress.

Drug addiction is a chronically relapsing disorder characterized by compulsion to seek and take drugs and has been linked to dysregulation of brain regions that mediate reward and stress. Activation of brain stress systems is hypothesized to be key to the negative emotional state produced by dependence that drives drug seeking through negative reinforcement mechanisms. This review explores the role of brain stress systems (corticotropin-releasing factor, norepinephrine, orexin [hypocretin], vasopressin, dynorphin) and brain antistress systems (neuropeptide Y, nociceptin [orphanin FQ]) in drug dependence, with emphasis on the neuropharmacological function of extrahypothalamic systems in the extended amygdala. The brain stress and antistress systems may play a key role in the transition to and maintenance of drug dependence once initiated. Understanding the role of brain stress and antistress systems in addiction provides novel targets for treatment and prevention of addiction and insights into the organization and function of basic brain emotional circuitry.

Telomere maintenance is thought to play a role in signaling cellular senescence; however, a link with organismal aging processes has not been established. The telomerase null mouse provides an opportunity to understand the effects associated with critical telomere shortening at the organismal level. We studied a variety of physiological processes in an aging cohort of mTR-/- mice. Loss of telomere function did not elicit a full spectrum of classical pathophysiological symptoms of aging. However, age-dependent telomere shortening and accompanying genetic instability were associated with shortened life span as well as a reduced capacity to respond to stresses such as wound healing and hematopoietic ablation. In addition, we found an increased incidence of spontaneous malignancies. These findings demonstrate a critical role for telomere length in the overall fitness, reserve, and well being of the aging organism.

Overcoming metabolic stress is a critical step for solid tumour growth. However, the underlying mechanisms of cell death and survival under metabolic stress are not well understood. A key signalling pathway involved in metabolic adaptation is the liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway. Energy stress conditions that decrease intracellular ATP levels below a certain level promote AMPK activation by LKB1. Previous studies showed that LKB1-deficient or AMPK-deficient cells are resistant to oncogenic transformation and tumorigenesis, possibly because of the function of AMPK in metabolic adaptation. However, the mechanisms by which AMPK promotes metabolic adaptation in tumour cells are not fully understood. Here we show that AMPK activation, during energy stress, prolongs cell survival by redox regulation. Under these conditions, NADPH generation by the pentose phosphate pathway is impaired, but AMPK induces alternative routes to maintain NADPH and inhibit cell death. The inhibition of the acetyl-CoA carboxylases ACC1 and ACC2 by AMPK maintains NADPH levels by decreasing NADPH consumption in fatty-acid synthesis and increasing NADPH generation by means of fatty-acid oxidation. Knockdown of either ACC1 or ACC2 compensates for AMPK activation and facilitates anchorage-independent growth and solid tumour formation in vivo, whereas the activation of ACC1 or ACC2 attenuates these processes. Thus AMPK, in addition to its function in ATP homeostasis, has a key function in NADPH maintenance, which is critical for cancer cell survival under energy stress conditions, such as glucose limitations, anchorage-independent growth and solid tumour formation in vivo.

Chemotherapy and radiation therapy for cancer often have severe side effects that limit their efficacy. Because these effects are in part determined by p53-mediated apoptosis, temporary suppression of p53 has been suggested as a therapeutic strategy to prevent damage of normal tissues during treatment of p53-deficient tumors. To test this possibility, a small molecule was isolated for its ability to reversibly block p53-dependent transcriptional activation and apoptosis. This compound, pifithrin-alpha, protected mice from the lethal genotoxic stress associated with anticancer treatment without promoting the formation of tumors. Thus, inhibitors of p53 may be useful drugs for reducing the side effects of cancer therapy and other types of stress associated with p53 induction.

The induction of programmed cell death, or apoptosis, involves activation of a signalling system, many elements of which remain unknown. The sphingomyelin pathway, initiated by hydrolysis of the phospholipid sphingomyelin in the cell membrane to generate the second messenger ceramide, is thought to mediate apoptosis in response to tumour-necrosis factor (TNF)-alpha, to Fas ligand and to X-rays. It is not known whether it plays a role in the stimulation of other forms of stress-induced apoptosis. Given that environmental stresses also stimulate a stress-activated protein kinase (SAPK/JNK), the sphingomyelin and SAPK/JNK signalling systems may be coordinated in induction of apoptosis. Here we report that ceramide initiates apoptosis through the SAPK cascade and provide evidence for a signalling mechanism that integrates cytokine- and stress-activated apoptosis.

Metabolic syndrome is defined by a constellation of interconnected physiological, biochemical, clinical, and metabolic factors that directly increases the risk of cardiovascular disease, type 2 diabetes mellitus, and all cause mortality. Insulin resistance, visceral adiposity, atherogenic dyslipidemia, endothelial dysfunction, genetic susceptibility, elevated blood pressure, hypercoagulable state, and chronic stress are the several factors which constitute the syndrome. Chronic inflammation is known to be associated with visceral obesity and insulin resistance which is characterized by production of abnormal adipocytokines such as tumor necrosis factor α , interleukin-1 (IL-1), IL-6, leptin, and adiponectin. The interaction between components of the clinical phenotype of the syndrome with its biological phenotype (insulin resistance, dyslipidemia, etc.) contributes to the development of a proinflammatory state and further a chronic, subclinical vascular inflammation which modulates and results in atherosclerotic processes. Lifestyle modification remains the initial intervention of choice for such population. Modern lifestyle modification therapy combines specific recommendations on diet and exercise with behavioural strategies. Pharmacological treatment should be considered for those whose risk factors are not adequately reduced with lifestyle changes. This review provides summary of literature related to the syndrome's definition, epidemiology, underlying pathogenesis, and treatment approaches of each of the risk factors comprising metabolic syndrome.

All homeotherms use thermogenesis to maintain their core body temperature, ensuring that cellular functions and physiological processes can continue in cold environments. In the prevailing model of thermogenesis, when the hypothalamus senses cold temperatures it triggers sympathetic discharge, resulting in the release of noradrenaline in brown adipose tissue and white adipose tissue. Acting via the β(3)-adrenergic receptors, noradrenaline induces lipolysis in white adipocytes, whereas it stimulates the expression of thermogenic genes, such as PPAR-γ coactivator 1a (Ppargc1a), uncoupling protein 1 (Ucp1) and acyl-CoA synthetase long-chain family member 1 (Acsl1), in brown adipocytes. However, the precise nature of all the cell types involved in this efferent loop is not well established. Here we report in mice an unexpected requirement for the interleukin-4 (IL-4)-stimulated program of alternative macrophage activation in adaptive thermogenesis. Exposure to cold temperature rapidly promoted alternative activation of adipose tissue macrophages, which secrete catecholamines to induce thermogenic gene expression in brown adipose tissue and lipolysis in white adipose tissue. Absence of alternatively activated macrophages impaired metabolic adaptations to cold, whereas administration of IL-4 increased thermogenic gene expression, fatty acid mobilization and energy expenditure, all in a macrophage-dependent manner. Thus, we have discovered a role for alternatively activated macrophages in the orchestration of an important mammalian stress response, the response to cold.

Although oxidants clearly possess the capacity to behave in a random and destructive fashion, growing evidence suggests that in many instances the production of reactive oxygen species is tightly regulated and their downstream targets exquisitely specific. This past year, several notable advances have been made in defining the specific redox-dependent targets of intracellular oxidants, as well as the myriad pathways that appear to employ oxidants as effector molecules. These new studies have significantly altered our understanding of how reactive oxygen species participate in diverse processes from tumourigenesis to ageing.