Evidence has accumulated over the past several years demonstrating that lung injury following inhalation of irritants like ozone is due, not only to direct effects of the chemical, but also indirectly to the actions of inflammatory mediators released by infiltrating macrophages. Among the mediators involved in the cytotoxic process, reactive nitrogen species (RNS) are of particular interest because of their well-documented cytotoxic potential. Findings that macrophage suppression blocks RNS production and ozone-induced toxicity provide strong support for a role of these cells and inflammatory mediators in lung injury. Recent investigations have focused on understanding pathways by which macrophages become activated to release RNS. One protein that has attracted considerable attention is caveolin-1, a membrane scaffolding molecule that functions to negatively regulate cell signaling. The fact that expression of caveolin-1 is down-regulated in macrophages after ozone inhalation suggests a mechanism controlling the release of cytotoxic mediators by these inflammatory cells.
macrophages; ozone; nitric oxide; caveolin; TNFα
Spinal motoneurons (MNs) amplify synaptic inputs by producing strong dendritic persistent inward currents (PICs), which allow the MN to generate the firing rates and forces necessary for normal behaviors. However, PICs prolong MN depolarization after the initial excitation is removed, tend to “wind-up” with repeated activation and are regulated by a diffuse neuromodulatory system that affects all motor pools. We have shown that PICs are very sensitive to reciprocal inhibition from Ia afferents of antagonist muscles and as a result PIC amplification is related to limb configuration. Because reciprocal inhibition is tightly focused, shared only between strict anatomical antagonists, this system opposes the diffuse effects of the descending neuromodulation that facilitates PICs. Because inhibition appears necessary for PIC control, we hypothesize that Ia inhibition interacts with Ia excitation in a “push–pull” fashion, in which a baseline of simultaneous excitation and inhibition allows depolarization to occur via both excitation and disinhibition (and vice versa for hyperpolarization). Push–pull control appears to mitigate the undesirable affects associated with the PIC while still taking full advantage of PIC amplification.
PIC; neuromodulation; push–pull; motoneuron
Mammalian reproduction requires that nursing mothers transfer large amounts of calcium to their offspring through milk. As a result, lactation is associated with dramatic alterations in bone and mineral metabolism, including reversible bone loss. One theme that has emerged from recent studies examining these adaptations is that the lactating breast actively participates in regulating bone and mineral metabolism. This review will detail our current knowledge of interactions between the breast, skeleton and hypothalamus during lactation and will consider implications that this reproductive physiology has for the pathophysiology of osteoporosis and breast cancer.
Osteoporosis; Bone Metastases; Lactation; Estrogen Deficiency; Calcium-Sensing Receptor; Parathyroid Hormone-Related Protein
Addiction to opiates and illicit use of psychostimulants is a chronic, relapsing brain disease that, if left untreated, can cause major medical, social and economic problems. This article reviews recent progress in studies of association of gene variants with vulnerability to develop opiate and cocaine addictions, focusing primarily on genes of the opioid and monoaminergic systems. In addition, we provide the first evidence of a cis-acting polymorphism and a functional haplotype in the PDYN gene, of significantly higher DNA methylation rate of the OPRM1 gene in the lymphocytes of heroin addicts, and significant differences in genotype frequencies of three single nucleotide polymorphisms of the P-glycoprotein gene (ABCB1) between “higher” and “lower” methadone doses in methadone-maintained patients. In genome-wide and multi-gene association studies, we have found association of a number of new genes and new variants of known genes with heroin addiction. Finally, we have described the development and application of a novel technique: molecular haplotyping for studies in genetics of drug addiction.
opiate and cocaine addiction; genetics of drug addiction; epigenetics; pharmacogenetics; allele-specific gene expression; molecular haplotyping
Hyperglycemia is a common occurrence in hospitalized patients, and several studies have shown a strong association between hyperglycemia and the risk of complications, prolonged hospitalization, and death for patients with and without diabetes. Past studies have shown that glucose management in the intensive care setting improves clinical outcomes by reducing the risk of multiorgan failure, systemic infection, and mortality, and that the importance of hyperglycemia also applies to noncritically ill patients. Based on several past observational and interventional studies, aggressive control of blood glucose had been recommended for most adult patients with critical illness. Recent randomized controlled trials, however, have shown that aggressive glycemic control compared to conventional control with higher blood glucose targets is associated with an increased risk of hypoglycemia and may not result in the improvement in clinical outcomes. This review aims to give an overview of the evidence for tight glycemic control (blood glucose targets <140 mg/dL), the evidence against tight glycemic control, and the updated recommendations for the inpatient management of diabetes in the critical care setting and in the general wards.
inpatient hyperglycemia; guidelines; intensive care unit; general wards; hypoglycemia
Stroke induces a complex web of pathophysiology that may evolve over hours to days and weeks after onset. It is now recognized that inflammation is an important phenomenon that can dramatically influence outcomes after stroke. In this minireview, we explore the hypothesis that inflammatory signals after stroke are biphasic in nature. The high-mobility group box 1 (HMGB1) protein is discussed as an example of this idea. HMGB1 is normally present in the nucleus. Under ischemic conditions, it is released extracellularly from many types of cells. During the acute phase poststroke, HMGB1 promotes necrosis and influx of damaging inflammatory cells. However, during the delayed phase poststroke, HMGB1 can mediate beneficial plasticity and recovery in many cells of the neurovascular unit. These emerging findings support the hypothesis that inflammation after stroke can be both detrimental and beneficial, depending on the cellular situations involved.
stroke; inflammation; stroke recovery; HMGB1
Adults with better jobs enjoy better health: job title was, in fact, the social gradient metric first used to study the relationship between social class and chronic disease etiology, a core finding now replicated in most developed countries. What has been less well proved is whether this correlation is causal, and if so, through what mechanisms. During the past decade, much research has been directed at these issues.Best evidence in2009 suggests that occupation does affect health. Most recent research on the relationship has been directed at disentangling the pathways through which lower-status work leads to adverse health outcomes. This review focuses on six areas of recent progress: (1) the role of status in a hierarchical occupational system; (2) the roles of psychosocial job stressors; (3) effects of workplace physical and chemical hazard exposures; (4) evidence that work organization matters as a contextual factor; (5) implications for the gradient of new forms of nonstandard or “precarious” employment such as contract and shift work; and (6) emerging evidence that women may be impacted differently by adverse working conditions, and possibly more strongly, than men.
occupational health; psycho-social stressors; work organization; women in the workplace; nonstandard work
Werner syndrome (WS) is a premature aging disorder caused by mutations in a RecQ-like DNA helicase. Mice lacking the helicase domain of the WRN homologue exhibit many phenotypic features of WS. Importantly, mutant WrnΔhel/Δhel mice show abnormal increases in visceral fat deposition and fasting blood triglyceride levels followed by insulin resistance and high blood glucose levels. These mice also exhibit increased heart and liver tissue reactive oxygen species concomitantly with oxidative DNA damage, indicating a pro-oxidant status. We treated mice with either ascorbate or catechin hydrate for 9 months. Vitamin C supplementation reduced oxidative stress in liver and heart tissues and reversed hypertriglyceridemia, hyperglycemia, and insulin resistance and reduced fat weight in mutant WrnΔhel/Δhel mice. Although the free scavenger catechin hydrate also reduced oxidative DNA damage in heart and liver tissues, it did not reverse any of the metabolic phenotype aspects in treated mutant mice. Finally, vitamin C and catechin hydrate did not affect the metabolic status of wild-type mice. These results indicate that vitamin C supplementation could be beneficial for WS patients.
PMID: 20536831 CAMSID: cams3016
Werner syndrome; metabolic syndrome; vitamin C; catechin; Wrn mutant mice
Perception of sound is a fundamental role of the auditory system. Traveling with the force of their mechanical energy, sound waves are captured by the ear and activate the sensory pathway of this complex organ. The hair cells, specialized sensory cells within the inner ear, function to transmit the mechanical energy into electrical nerve stimuli that reach the brain. A large number of proteins are responsible for the overarching tasks required to maintain the complex mechanism of sound sensation. Many hearing disorders are due to single gene defects, inherited in a Mendelian fashion, enabling clinical diagnostics. However, at the same time, hearing impairment is genetically heterogeneous, with both common and rare forms occurring due to mutations in over 100 genes. The crosstalk between human and mouse genetics has enabled comprehensive studies on gene identification and protein function, taking advantage of the tools animal models have to offer. The aim of the following review is to provide background and examples of human deafness genes and the discovery of their function in the auditory system.
deafness; Usher syndrome; myosin VIIA; cadherin 23; stereocilin; microRNA-96
Infertility is defined as the inability of a couple to conceive despite trying for a year, and it affects approximately 15% of the reproductive-age population. It is considered a genetically lethal factor, as the family lineage stops at that individual with no progeny produced. A genetic defect associated with an infertile individual cannot be transmitted to the offspring, ensuring the maintenance of reproductive fitness of the species. However, with the advent of assisted reproductive techniques (ART), we are now able to overcome sterility and bypass nature’s protective mechanisms that developed through evolution to prevent fertilization by defective or deficient sperm.
mendelian genetics; male infertility; asthenozoospermia; oligospermia
Hepcidin (HAMP) negatively regulates iron absorption, degrading the iron exporter ferroportin at the level of enterocytes and macrophages. We showed that mice with β-thalassemia intermedia (th3/+) have increased anemia and iron overload. However, their hepcidin expression is relatively low compared to their iron burden. We also showed that the iron metabolism gene Hfe is down-regulated in concert with hepcidin in th3/+ mice. These observations suggest that low hepcidin levels are responsible for abnormal iron absorption in thalassemic mice and that down-regulation of Hfe might be involved in the pathway that controls hepcidin synthesis in β-thalassemia. Therefore, these studies suggest that increasing hepcidin and/or Hfe expression could be a strategy to reduces iron overload in these animals. The goal of this paper is to review recent findings that correlate hepcidin, Hfe, and iron metabolism in β-thalassemia and to discuss potential novel therapeutic approaches based on these recent discoveries.
β-thalassemia; iron overload; hepcidin; Hfe; lentiviral vectors
Rapidly accumulating evidence indicates that clinically used general anesthesia causes massive, widespread neuroapoptotic degeneration in the developing mammalian brain. Susceptibility to anesthesia-induced neurotoxicity has been documented in rats, mice, guinea pigs, primates, and in this study, piglets; in short, anesthesia-induced developmental neuroapoptosis is not species-dependent. Our findings with piglets, like those in other immature mammals, demonstrate that relatively short exposure to anesthesia is just as detrimental to species with long periods of synaptogenesis as it is to those with short periods of synaptogenesis. However, the highly reproducible findings in different species also indicate that the timing of exposure to anesthesia is critically important; that is, brain regions that are at the peak of synaptogenesis are most vulnerable even when the exposure to anesthesia is relatively brief. Because the peak of synaptogenesis is characterized by intense, highly programmed neuronal communication that is vital for the survival and proper function of immature neurons, we conclude that anesthesia causes severe disturbances in the fine equilibrium between excitatory and inhibitory neurotransmission in the developing mammalian brain, ultimately leading to neuronal redundancy and death.
piglets; isoflurane; midazolam; nitrous oxide; fentanyl; synaptogenesis
A hallmark of cardiac metabolism before birth is the predominance of carbohydrate use for energy provision. After birth, energy substrate metabolism rapidly switches to the oxidation of fatty acids. This switch accompanies the expression of “adult” isoforms of metabolic enzymes and other proteins. However, in a variety of pathophysiologic conditions, including hypoxia, ischemia, hypertrophy, atrophy, diabetes, and hypothyroidism, the postnatal heart returns to the “fetal” gene program. These adaptive mechanisms are also a feature of the failing heart muscle, where at a certain point this fetal-like reprogramming no longer suffices to support cardiac structure and function. We advance the hypothesis that in the postnatal heart, metabolic remodeling triggers the process through glycosylation of transcription factors, potentially protecting the stressed heart from irreversible functional impairment and programmed cell death. In other words, we propose a metabolic link to gene expression in the heart.
fetal heart; hypertrophy; atrophy; hibernating myocardium; heart failure; glucose; metabolism
β-thalassemia is a disease associated with decreased β-globin production leading to anemia, ineffective erythropoiesis, and iron overload. New mechanisms associated with modulation of erythropoiesis and iron metabolism have recently been discovered in thalassemic mice, improving our understanding of the pathophysiology of this disease. These discoveries have the potential to be translated into clinically-relevant therapeutic options to reduce ineffective erythropoiesis and iron overload. A new generation of therapies based on limiting ineffective erythropoiesis, iron absorption, and the correction of iron maldistribution could be on the way, possibly complementing and improving the current standard of patient care.
β-thalassemia; ineffective erythropoiesis; Jak2; iron overload; hepcidin; transferrin
Acute myocardial infarction is still one of the leading causes of death in the industrial nations. Even after successful revascularization, myocardial ischemia results in a loss of cardiomyocytes and scar formation. Embryonic EPCs (eEPCs), retroinfused into the ischemic region of the pig heart, provided rapid paracrine benefit to acute and chronic ischemia in a PI-3K/Akt-dependent manner. In a model of acute myocardial ischemia, infarct size and loss of regional myocardial function decreased after eEPC application, unless cell pre-treatment with thymosin β4 shRNA was performed. Thymosin β4 peptide retroinfusion mimicked the eEPC-derived improvement of infarct size and myocardial function. In chronic ischemia (rabbit model), eEPCs retroinfused into the ischemic hindlimb enhanced capillary density, collateral growth, and perfusion. Therapeutic neovascularization was absent when thymosin β4 shRNA was introduced into eEPCs before application. In conclusion, eEPCs are capable of acute and chronic ischemia protection in a thymosin β4 dependent manner.
thymosin β4; progenitor cells; ischemia/reperfusion; infarct size; angiogenesis
Neonatal spinalized (NST) rats can achieve autonomous weight supported locomotion never seen after adult injury. Mechanisms that support function in NST rats include increased importance of cortical trunk control, and altered biomechanical control strategies for stance and locomotion. Hindlimbs are isolated from perturbations in quiet stance and act in opposition to forelimbs in locomotion in NST rats. Control of roll and yaw of the hindlimbs is crucial in their locomotion. The biomechanics of the hind limbs of NST rats are also likely crucial. We present new data showing the whole leg musculature scales proportional to normal rat musculature in NST rats, regardless of function. This scaling is a prerequisite for the NST rats to most effectively use pattern generation mechanisms and motor patterns that are similar to those present in intact rats. Pattern generation may be built into the lumbar spinal cord by evolution and matched to the limb biomechanics, so preserved muscle scaling may be essential to the NST function observed.
The critical discovery in the past two decades of the Transient Receptor Potential (TRP) superfamily of ion channels has revealed the potential mechanisms by which cells sense diverse stimuli beyond the prototypical “five senses”, identifying ion channels that are gated by heat, cold, mechanical loading, osmolarity, and other physical and chemical stimuli. Transient receptor potential vanilloid 4 (TRPV4) is a Ca2+-permeable non-selective cation channel that appears to play a mechano- or osmosensory roles in several musculoskeletal tissues. In articular cartilage, TRPV4 exhibits osmotic sensitivity, controlling cellular volume recovery and other physiologic responses to osmotic stress. TRPV4 is expressed in both osteoblasts and osteoclasts, and the absence of TRPV4 prevents disuse-induced bone loss. TRPV4 activation promotes chondrogenesis by inducing SOX9 transcription, whereas a TRPV4 gain-of-function mutation leads to a developmental skeletal dysplasia, suggesting a critical role for TRPV4 in skeletal development. These studies provide mounting evidence for a regulatory role for the sensory channel TRPV4 in control of musculoskeletal tissues.
osteoarthritis; osteoporosis; stretch-activated ion channel; mechanotransduction; mechanical signal transduction; remodeling
Recent studies of the spinal motor system of zebrafish, along with work in other species, are leading to some principles that appear to underlie the organization and recruitment of motor networks in cord: (1) broad neuronal classes defined by a set of transcription factors, key morphological features, and transmitter phenotypes arise in an orderly way from different dorso-ventral zones in spinal cord; (2) motor behaviors and both motoneurons and interneurons differentiate in order from gross, often faster, movements and the neurons driving them to progressively slower movements and their underlying neurons; (3) recruitment order of motoneurons and interneurons is based upon time of differentiation; (4) different locomotor speeds involve some shifts in the set of active interneurons. Here we review these principles and some of their implications for other parts of the brain, other vertebrates, and limbed locomotion.
motoneurons; spinal interneurons; transcription factors; locomotion; motor pattern
The established role for Phosphatidylinositol (3,4,5) triphosphate (PI(3,4,5)P3) signalling pathways is to regulate cell metabolism. More recently it has emerged that PI(3,4,5)P3 signalling via mTOR and Foxo transcription factors also controls lymphocyte trafficking by determining the repertoire of adhesion and chemokine receptors expressed by T lymphocytes. In quiescent T cells, non-phosphorylated active Foxos maintain expression of KLF2, a transcription factor that regulates expression of the chemokine receptors CCR7 and S1P1and the adhesion receptor CD62L that together control T cell transmigration into secondary lymphoid tissues. PI(3,4,5)P3 mediated activation of Protein Kinase B phosphorylates and inactivates Foxos thereby terminating expression of KLF2 and its target genes. The correct localization of lymphocytes is essential for effective immune responses and the ability of PI3K and mTOR to regulate expression of chemokine receptor and adhesion molecules puts these signaling molecules at the core of the molecular mechanisms that control lymphocyte trafficking.
Phosphatidylinositol (3,4,5) triphosphate; KLF2; CCR7; S1P1; CD62L; lymphocytes
Cellular ferritin is central for iron balance during transfusions therapies; serum ferritin is a small fraction of body ferritin, albeit a convenient reporter. Iron overload induces extra ferritin protein synthesis but the protein is overfilled with the extra iron that damages ferritin, with conversion to toxic hemosiderin. Three new approaches that manipulate ferritin to address excess iron, hemosiderin, and associated oxidative damage in Cooley’s Anemia and other iron overload conditions, are faster removal of ferritin iron with chelators guided to ferritin gated pores by peptides; more ferritin protein synthesis using ferritin mRNA activators, by metal complexes that target mRNA 3D structures; and determining if endocytotic absorption of iron from legumes, which is mostly ferritin, is regulated during iron overload to prevent excess iron entry while providing protein. More of a focus on ferritin features, including protein cage structure, iron mineral, regulatable mRNA, and specific gut absorption properties, will achieve the three novel experimental goals for managing iron homeostasis with transfusion therapies.
iron; ferritin; chelator
Nuclear receptors (NRs) control cell fate and regulate tissue function. Some of the NRs are expressed in a circadian and tissue specific manner. Clock genes are part of the circadian network and fine tune gene expression in adipose and skeletal tissues. Pparg, a master transcription factor that determines adipogenesis exhibits a circadian expression pattern in white adipose tissue and liver. In this paper we found that message and protein for a peripheral clock gene, nocturnin, is markedly up-regulated with Pparg activation in adipocytes and bone marrow stromal cells. Nocturnin is also expressed in relatively high amounts in other tissues which may have physiologic relevance for bone, including the brain and hypothalamus. Importantly, we found polymorphic strain differences in bone marrow nocturnin expression that relate to phenotypic determinants of skeletal acquisition. Defining the function of nocturnin in peripheral tissues should provide new insights into lineage allocation and the intimate relationship between nuclear receptors and physiologic timekeeping.
Cardiovascular disease is a leading cause of mortality worldwide. While the etiology for the majority of cardiovascular disease is presumed to be a combination of genetic and environmental factors, developments in our understanding of the basic biology of cardiac disorders have been greatly advanced through discoveries made studying heart diseases that exhibit Mendelian forms of inheritance. Most of these diseases primarily affect children and young adults and include cardiomyopathies, arrhythmias, aortic aneurysms and congenital heart defects. The discovery of the genetic etiologies for these diseases have had significant impact on our understanding of more complex forms of cardiovascular disease and in some cases led to novel diagnostic and treatment modalities. In this review, we will summarize these seminal genetic discoveries, highlighting a few that have resulted in significant impact on human disease, and discuss the potential utility of studying Mendelian-inherited heart disease with the development of new genetic technologies and our increased understanding of the human genome.
This paper provides an overview of racial variations in health and shows that differences in socioeconomic status (SES) across racial groups are a major contributor to racial disparities in health. However, race reflects multiple dimensions of social inequality and individual and household indicators of SES capture relevant but limited aspects of this phenomenon. Research is needed that will comprehensively characterize the critical pathogenic features of social environments and identify how they combine with each other to affect health over the life course. Migration history and status are also important predictors of health and research is needed that will enhance understanding of the complex ways in which race, SES, and immigrant status combine to affect health. Fully capturing the role of race in health also requires rigorous examination of the conditions under which medical care and genetic factors can contribute to racial and SES differences in health. The paper identifies research priorities in all of these areas.
B cells represent an important link between the adaptive and innate immune systems, as they express both antigen-specific B cell receptors (BCRs) as well as various toll-like receptors (TLRs). Several checkpoints in B cell development ensure that self-specific cells are eliminated from the mature B cell repertoire to avoid harmful autoreactive responses. These checkpoints are controlled by BCR-mediated events, but are also influenced by TLR-dependent signals from the innate immune system. Additionally, B cell-intrinsic and extrinsic TLR signaling are critical for inflammatory events required for the clearance of microbial infections. Factors secreted by TLR-activated macrophages or dendritic cells directly influence the fate of protective and autoreactive B cells. Additionally, naïve and memory B cells respond differentially to TLR ligands, as do different B cell subsets. We review here recent literature describing intrinsic and extrinsic effects of TLR stimulation on the fate of B cells, with particular attention to autoimmune diseases.
B cells; Toll-like receptors; TLRs; autoimmunity; autoreactive; tolerance; innate; SLE; Lupus; BAFF; IFN-I