Showing papers in "The Scientific World Journal in 2007"

Opioid-induced glial activation: mechanisms of activation and implications for opioid analgesia, dependence, and reward.

Abstract: This review will introduce the concept of toll-like receptor (TLR)–mediated glial activation as central to all of the following: neuropathic pain, compromised acute opioid analgesia, and unwanted opioid side effects (tolerance, dependence, and reward). Attenuation of glial activation has previously been demonstrated both to alleviate exaggerated pain states induced by experimental pain models and to reduce the development of opioid tolerance. Here we demonstrate that selective acute antagonism of TLR4 results in reversal of neuropathic pain as well as potentiation of opioid analgesia. Attenuating central nervous system glial activation was also found to reduce the development of opioid dependence, and opioid reward at a behavioral (conditioned place preference) and neurochemical (nucleus accumbens microdialysis of morphine-induced elevations in dopamine) level of analysis. Moreover, a novel antagonism of TLR4 by (

The physiology of obese-hyperglycemic mice [ob/ob mice].

Abstract: This review summarizes key aspects of what has been learned about the physiology of leptin deficiency as it can be observed in obese-hyperglycemic ob/ob mice. These mice lack functional leptin. They are grossly overweight and hyperphagic, particularly at young ages, and develop severe insulin resistance. They have been used as a model for obesity and as a rich source of pancreatic islets with high insulin release capacity. The leptin deficiency manifests also with regard to immune function, the cardiovascular system including angiogenesis, supportive tissue function, malignancies, and reproductive function. ob/ob Mice are well suited for studies on the interaction between leptin and insulin, and for studies on initial aspects of metabolic disturbances leading to type-2 diabetes.

Collagen structure of tendon relates to function.

Abstract: A tendon is a tough band of fibrous connective tissue that connects muscle to bone, designed to transmit forces and withstand tension during muscle contraction. Tendon may be surrounded by different structures: 1) fibrous sheaths or retinaculae; 2) reflection pulleys; 3) synovial sheaths; 4) peritendon sheaths; 5) tendon bursae. Tendons contain a) few cells, mostly represented by tenoblasts along with endothelial cells and some chondrocytes; b) proteoglycans (PGs), mainly decorin and hyaluronan, and c) collagen, mostly type I. Tendon is a good example of a high ordered extracellular matrix in which collagen molecules assemble into filamentous collagen fibrils (formed by microfibrils) which aggregate to form collagen fibers, the main structural components. It represents a multihierarchical structure as it contains collagen molecules arranged in fibrils then grouped in fibril bundles, fascicles and fiber bundles that are almost parallel to the long axis of the tendon, named as primary, secondary and tertiary bundles. Collagen fibrils in tendons show prevalently large diameter, a D-period of about 67 nm and appear built of collagen molecules lying at a slight angle (< 5 degrees). Under polarized light microscopy the collagen fiber bundles appear crimped with alternative dark and light transverse bands. In recent studies tendon crimps observed via SEM and TEM show that the single collagen fibrils suddenly changing their direction contain knots. These knots of collagen fibrils inside each tendon crimp have been termed "fibrillar crimps", and even if they show different aspects they all may fulfil the same functional role. As integral component of musculoskeletal system, the tendon acts to transmit muscle forces to the skeletal system. There is no complete understanding of the mechanisms in transmitting/absorbing tensional forces within the tendon; however it seems likely that a flattening of tendon crimps may occur at a first stage of tendon stretching. Increasing stretching, other transmission mechanisms such as an interfibrillar coupling via PGs linkages and a molecular gliding within the fibrils structure may be involved.

Origin, fate, and function of epicardium-derived cells (EPDCs) in normal and abnormal cardiac development.

Abstract: During heart development, cells of the primary and secondary heart field give rise to the myocardial component of the heart. The neural crest and epicardium provide the heart with a considerable amount of nonmyocardial cells that are indispensable for correct heart development. During the past 2 decades, the importance of epicardium-derived cells (EPDCs) in heart formation became increasingly clear. The epicardium is embryologically formed by the outgrowth of proepicardial cells over the naked heart tube. Following epithelial-mesenchymal transformation, EPDCs form the subepicardial mesenchyme and subsequently migrate into the myocardium, and differentiate into smooth muscle cells and fibroblasts. They contribute to the media of the coronary arteries, to the atrioventricular valves, and the fibrous heart skeleton. Furthermore, they are important for the myocardial architecture of the ventricular walls and for the induction of Purkinje fiber formation. Whereas the exact signaling cascades in EPDC migration and function still need to be elucidated, recent research has revealed several factors that are involved in EPDC migration and specialization, and in the cross-talk between EPDCs and other cells during heart development. Among these factors are the Ets transcription factors Ets-1 and Ets-2. New data obtained with lentiviral antisense constructs targeting Ets-1 and Ets-2 specifically in the epicardium indicate that both factors are independently involved in the migratory behavior of EPDCs. Ets-2 seems to be especially important for the migration of EPDCs into the myocardial wall, and to subendocardial positions in the atrioventricular cushions and the trabeculae. With respect to the clinical importance of correct EPDC development, the relation with coronary arteriogenesis has been noted well before. In this review, we also propose a role for EPDCs in cardiac looping, and emphasize their contribution to the development of the valves and myocardial architecture. Lastly, we focus on the congenital heart anomalies that might be caused primarily by an epicardial developmental defect.

Construction of efficacious gait and upper limb functional interventions based on brain plasticity evidence and model-based measures for stroke patients.

Abstract: For neurorehabilitation to advance from art to science, it must become evidence-based. Historically, there has been a dearth of evidence from which to construct rehabilitation interventions that are properly framed, accurately targeted, and credibly measured. In many instances, evidence of treatment response has not been sufficiently robust to demonstrate a change in function that is clinically, statistically, and economically important. Research evidence of activity-dependent central nervous system (CNS) plasticity and the requisite motor learning principles can be used to construct an efficacious motor recovery intervention. Brain plasticity after stroke refers to the regeneration of brain neuronal structures and/or reorganization of the function of neurons. Not only can CNS structure and function change in response to injury, but also, the changes may be modified by "activity". For gait training or upper limb functional training for stroke survivors, the "activity" is motor behavior, including coordination and strengthening exercise and functional training that comprise motor learning. Critical principles of motor learning required for CNS activity-dependent plasticity include: close-to-normal movements, muscle activation driving practice of movement; focused attention, repetition of desired movements, and training specificity. The ultimate goal of rehabilitation is to restore function so that a satisfying quality of life can be experienced. Accurate measurement of dysfunction and its underlying impairments are critical to the development of accurately targeted interventions that are sufficiently robust to produce gains, not only in function, but also in quality of life. The Classification of Functioning, Disability, and Health Model (ICF) model of disablement, put forth by the World Health Organization, can provide not only some guidance in measurement level selection, but also can serve as a guide to incorporate function and quality of life enhancement as the ultimate goals of rehabilitation interventions. Based on the evidence and principles of activity-dependent plasticity and motor learning, we developed gait training and upper limb functional training protocols. Guided by the ICF model, we selected and developed measures with characteristics rendering them most likely to capture change in the targeted aspects of intervention, as well as measures having membership not only in the impairment, but also in the functional or life role participation levels contained in the ICF model. We measured response to innovative gait training using a knee flexion coordination measure, coefficient of coordination consistency (ACC) of relative hip/knee (H/K) movement across multiple steps (H/K ACC), and milestones of participation in life role activities. We measured response to upper limb functional training according to measures designed to quantify functional gains in response to treatment targeted at wrist/hand or shoulder elbow training (Arm Motor Ability Test for wrist/hand (AMAT W/H) or shoulder/elbow (AMAT S/E)). We found that there was a statistically significant advantage for adding FES-IM gait training to an otherwise comparable and comprehensive gait training, according to the following measures: H/K ACC, the measure of consistently executed hip/knee coordination during walking; a specific measure of isolated joint knee flexion coordination; and a measure of multiple coordinated gait components. Further, enhanced gains in gait component coordination were robust enough to result in achievement of milestones in participation in life role activities. In the upper limb functional training study, we found that robotics + motor learning (ROB ML; shoulder/elbow robotics practice plus motor learning) produced a statistically significant gain in AMAT S/E; whereas functional electrical stimulation + motor learning (FES ML) did not. We found that FES ML (wrist/hand FES plus motor learning) produced a statistically significant gain in AMAT W/H; whereas ROB ML did not. These results together, support the phenomenon of training specificity in that the most practiced joint movements improved in comparison to joint movements that were practiced at a lesser intensity and frequency. Both ROB ML and FES ML protocols addressed an array of impairments thought to underlie dysfunction. If we are willing to adhere to the ICF model, we accept the challenge that the goal of rehabilitation is life role participation, with functional improvement as in important intermediary step. The ICF model suggests that we intervene at multiple lower levels (e.g., pathology and impairment) in order to improve the higher levels of function and life role participation. The ICF model also suggests that we measure at each level. Not only can we then understand response to treatment at each level, but also, we can begin to understand relationships between levels (e.g., impairment and function). With the ICF model proffering the challenge of restoring life role participation, it then becomes important to design and test interventions that result in impairment gains sufficiently robust to be reflected in functional activities and further, in life role participation. Fortunately, CNS plasticity and associated motor learning principles can serve well as the basis for generating such interventions. These principles were useful in generating both efficacious gait training and efficacious upper limb functional training interventions. These principles led to the use of therapeutic agents (FES and robotics) so that close-to-normal movements could be practiced. These principles supported the use of specific therapeutic agents (BWSTT, FES, and robotics) so that sufficient movement repetition could be provided. These principles also supported incorporation of functional task practice and the demand of attention to task practice within the intervention. The ICF model provided the challenge to restore function and life role participation. The means to that end was provided by principles of CNS plasticity and motor learning.

Cardiovascular Development and the Colonizing Cardiac Neural Crest Lineage

Abstract: Although it is well established that transgenic manipulation of mammalian neural crest-related gene expression and microsurgical removal of premigratory chicken and Xenopus embryonic cardiac neural crest progenitors results in a wide spectrum of both structural and functional congenital heart defects, the actual functional mechanism of the cardiac neural crest cells within the heart is poorly understood. Neural crest cell migration and appropriate colonization of the pharyngeal arches and outflow tract septum is thought to be highly dependent on genes that regulate cell-autonomous polarized movement (i.e., gap junctions, cadherins, and noncanonical Wnt1 pathway regulators). Once the migratory cardiac neural crest subpopulation finally reaches the heart, they have traditionally been thought to participate in septation of the common outflow tract into separate aortic and pulmonary arteries. However, several studies have suggested these colonizing neural crest cells may also play additional unexpected roles during cardiovascular development and may even contribute to a crest-derived stem cell population. Studies in both mice and chick suggest they can also enter the heart from the venous inflow as well as the usual arterial outflow region, and may contribute to the adult semilunar and atrioventricular valves as well as part of the cardiac conduction system. Furthermore, although they are not usually thought to give rise to the cardiomyocyte lineage, neural crest cells in the zebrafish (Danio rerio) can contribute to the myocardium and may have different functions in a species-dependent context. Intriguingly, both ablation of chick and Xenopus premigratory neural crest cells, and a transgenic deletion of mouse neural crest cell migration or disruption of the normal mammalian neural crest gene expression profiles, disrupts ventral myocardial function and/or cardiomyocyte proliferation. Combined, this suggests that either the cardiac neural crest secrete factor/s that regulate myocardial proliferation, can signal to the epicardium to subsequently secrete a growth factor/s, or may even contribute directly to the heart. Although there are species differences between mouse, chick, and Xenopus during cardiac neural crest cell morphogenesis, recent data suggest mouse and chick are more similar to each other than to the zebrafish neural crest cell lineage. Several groups have used the genetically defined Pax3 (splotch) mutant mice model to address the role of the cardiac neural crest lineage. Here we review the current literature, the neural crest-related role of the Pax3 transcription factor, and discuss potential function/s of cardiac neural crest-derived cells during cardiovascular developmental remodeling.

Prostanoid Receptors in the Human Vascular Wall

Abstract: The mechanisms involved in vascular homeostasis and disease are mostly dependent on the interactions between blood, vascular smooth muscle, and endothelial cells. There is an accumulation of evidence for the involvement of prostanoids, the arachidonic acid metabolites derived from the cyclooxygenase enzymatic pathway, in physiological and/or pathophysiological conditions. In humans, the prostanoids activate different receptors. The classical prostanoid receptors (DP, EP1-4, FP, IP, and TP) are localized at the cell plasma or nuclear membrane. In addition, CRTH2 and the nuclear PPAR receptors are two other targets for prostanoids, namely, prostacyclin (PGI2) or the natural derivatives of prostaglandin D2. While there is little information on the role of CRTH2, there are many reports on PPAR activation and the consecutive expression of genes involved in the human vascular system. The role of the classical prostanoid receptors stimulated by PGI2 and thromboxane in the control of the vascular tone has been largely documented, whereas the other receptor subtypes have been overlooked. There is now increasing evidence that suggests a role of PGE2 and the EP receptor subtypes in the control of the human vascular tone and remodeling of the vascular wall. These receptors are also present on leukocytes and platelets, and they are implicated in most of the inflammatory processes within the vascular wall. Consequently, the EP receptor subtypes or isoforms would provide a novel and specific cardiovascular therapeutic approach in the near future.

Linking increasing drought stress to Scots pine mortality and bark beetle infestations.

Abstract: In the dry Swiss Rhone Valley, Scots pine forests have experienced increased mortality in recent years. It has commonly been assumed that drought events and bark beetles fostered the decline, however, whether bark beetle outbreaks increased in recent years and whether they can be linked to drought stress or increasing temperature has never been studied. In our study, we correlated time series of drought indices from long-term climate stations, 11-year mortality trends from a long-term research plot, and mortality probabilities modeled from tree rings (as an indicator of tree vitality) with documented occurrences of various bark beetle species and a buprestid beetle, using regional Forest Service reports from 1902 to 2003 and advisory cases of the Swiss Forest Protection Service (SFPS) from 1984 to 2005. We compared the historical findings with measured beetle emergence from a 4-year tree felling and breeding chamber experiment. The documented beetle-related pine mortality cases increased dramatically in the 1990s, both in the forest reports and the advisory cases. The incidents of beetle-related pine mortality correlated positively with spring and summer temperature, and with the tree-ring based mortality index, but not with the drought index. The number of advisory cases, on the other hand, correlated slightly with summer drought index and temperature, but very highly with tree-ring-based mortality index. The tree-ring-based mortality index and observed tree mortality increased in years following drought. This was confirmed by the beetle emergences from felled trees. Following dry summers, more than twice as many trees were colonized by beetles than following wet summers. We conclude that increased temperatures in the Swiss Rhone Valley have likely weakened Scots pines and favored phloeophagous beetle population growth. Beetles contributed to the increased pine mortality following summer drought. Among the factors not addressed in this study, changed forest use may have also contributed to increased beetle populations and Scots pine mortality, whereas air pollution seems to be of lesser importance.

Mechanisms of action of probiotics in intestinal diseases.

Abstract: Intestinal microbiota is a positive health asset that exerts a conditioning effect on intestinal homeostasis. Resident bacteria deliver regulatory signals to the epithelium and instruct mucosal immune responses. Recent research has revealed a potential therapeutic role for the manipulation of the microbiota and exploitation of host-microbial signalling pathways in the maintenance of human health and treatment of various mucosal disorders. A variety of pharmabiotic strategies, such as the use of specific members of the microbiota, their surface components, or metabolites, as well as genetically modified commensal bacteria, are being investigated for their ability to enhance the beneficial components of the microbiota. It is clear that engagement with host cells is central to pharmabiotic action, and several strain-specific mechanisms of action have been elucidated. However, the molecular details underpinning these mechanisms remain almost entirely unknown. Understanding how pharmabiotics exert their beneficial effects is critical for the establishment of definitive selection criteria for certain pharmabiotic strategies for specific clinical conditions. Scientifically accredited evidence of efficacy and studies to elucidate the molecular mechanisms of host-microbiota interactions are needed to lend credence to the use of pharmabiotic strategies in clinical medicine.

Prostaglandin Receptor Signaling in Disease

Abstract: Prostanoids, consisting of the prostaglandins (PGs) and the thromboxanes (TXs), are a group of lipid mediators formed in response to various stimuli. They include PGD2, PGE2, PGF2α, PGI2, and TXA2. They are released outside of the cells immediately after synthesis, and exert their actions by binding to a G-protein coupled rhodopsin-type receptor on the surface of target cells. There are eight types of the prostanoid receptors conserved in mammals from mouse to human. They are the PGD receptor (DP), four subtypes of the PGE receptor (EP1, EP2, EP3, and EP4), the PGF receptor (FP), PGI receptor (IP), and TXA receptor (TP). Recently, mice deficient in each of these prostanoid receptors were generated and subjected to various experimental models of disease. These studies have revealed the roles of PG receptor signaling in various pathological conditions, and suggest that selective manipulation of the prostanoid receptors may be beneficial in treatment of the pathological conditions. Here we review these recent findings of roles of prostanoid receptor signaling and their therapeutic implications.

Circadian rhythms, the mesolimbic dopaminergic circuit, and drug addiction.

Abstract: Drug addiction is a devastating disease that affects millions of individuals worldwide. Through better understanding of the genetic variations that create a vulnerability for addiction and the molecular mechanisms that underlie the progression of addiction, better treatment options can be created for those that suffer from this condition. Recent studies point to a link between abnormal or disrupted circadian rhythms and the development of addiction. In addition, studies suggest a role for specific genes that make up the molecular clock in the regulation of drug sensitivity, sensitization, and reward. The influence of circadian genes and rhythms on drug-induced behaviors may be mediated through the mesolimbic dopaminergic system. This system has long been implicated in the development of addiction, and recent evidence supports a regulatory role for the brain's central pacemaker and circadian gene expression in the regulation of dopaminergic transmission. This review highlights the association between circadian genes and drug addiction, and the possible role of the mesolimbic dopaminergic system in this association.

Adenosine Receptor Heteromers and their Integrative Role in Striatal Function

Abstract: By analyzing the functional role of adenosine receptor heteromers, we review a series of new concepts that should modify our classical views of neurotransmission in the central nervous system (CNS). Neurotransmitter receptors cannot be considered as single functional units anymore. Heteromerization of neurotransmitter receptors confers functional entities that possess different biochemical characteristics with respect to the individual components of the heteromer. Some of these characteristics can be used as a "biochemical fingerprint" to identify neurotransmitter receptor heteromers in the CNS. This is exemplified by changes in binding characteristics that are dependent on coactivation of the receptor units of different adenosine receptor heteromers. Neurotransmitter receptor heteromers can act as "processors" of computations that modulate cell signaling, sometimes critically involved in the control of pre- and postsynaptic neurotransmission. For instance, the adenosine A1-A2A receptor heteromer acts as a concentration-dependent switch that controls striatal glutamatergic neurotransmission. Neurotransmitter receptor heteromers play a particularly important integrative role in the "local module" (the minimal portion of one or more neurons and/or one or more glial cells that operates as an independent integrative unit), where they act as processors mediating computations that convey information from diverse volume-transmitted signals. For instance, the adenosine A2A-dopamine D2 receptor heteromers work as integrators of two different neurotransmitters in the striatal spine module.

F-waves--physiology and clinical uses.

Abstract: F-waves are low amplitude responses produced by antidromic activation of motoneurons. They may not appear after each stimulus and are inherently variable in latency, amplitude, and configuration. Meaningful analysis of F-waves requires an appreciation of these characteristics of F-waves as well as an understanding of their physiology. These features of F-waves as well as their physiology are reviewed. This is important since F-waves are one of the most frequently used studies in clinical neurophysiology and much of the controversies surrounding the use of F-waves relates to a failure to adequately consider the requirements of F-wave analysis. These requirements include the number of F-waves that need to be recorded, the parameters that should be evaluated, and the muscle from which the F-waves are recorded. If analyzed correctly, current reports would indicate that F-waves are the most sensitive and reliable nerve conduction study for evaluating polyneuropathies, can be abnormal in focal proximal nerve dysfunction, can be at least as sensitive as needle electromyography for defining lumbosacral radiculopathies, and can provide a meaningful physiological window into disorders of the central nervous system. Reports supporting these statements and their clinical relevance are discussed.

Basic Concepts in G-Protein-Coupled Receptor Homo- and Heterodimerization

Abstract: Until recently, heptahelical G-protein-coupled receptors (GPCRs) were considered to be expressed as monomers on the cell surface of neuronal and non-neuronal cells. It is now becoming evident that this view must be overtly changed since these receptors can form homodimers, heterodimers, and higher-order oligomers on the plasma membrane. Here we discuss some of the basics and some new concepts of receptor homo- and heteromerization. Dimers-oligomers modify pharmacology, trafficking, and signaling of receptors. First of all, GPCR dimers must be considered as the main molecules that are targeted by neurotransmitters or by drugs. Thus, binding data must be fitted to dimer-based models. In these models, it is considered that the conformational changes transmitted within the dimer molecule lead to cooperativity. Cooperativity must be taken into account in the binding of agonists-antagonists-drugs and also in the binding of the so-called allosteric modulators. Cooperativity results from the intramolecular cross-talk in the homodimer. As an intramolecular cross-talk in the heterodimer, the binding of one neurotransmitter to one receptor often affects the binding of the second neurotransmitter to the partner receptor. Coactivation of the two receptors in a heterodimer can change completely the signaling pathway triggered by the neurotransmitter as well as the trafficking of the receptors. Heterodimer-specific drugs or dual drugs able to activate the two receptors in the heterodimer simultaneously emerge as novel and promising drugs for a variety of central nervous system (CNS) therapeutic applications.

PDZ and LIM Domain-Encoding Genes: Molecular Interactions and their Role in Development

Abstract: PDZ/LIM genes encode a group of proteins that play very important, but diverse, biological roles They have been implicated in numerous vital processes, eg, cytoskeleton organization, neuronal signaling, cell lineage specification, organ development, and oncogenesis In mammals, there are ten genes that encode for both a PDZ domain, and one or several LIM domains: four genes of the ALP subfamily (ALP, Elfin, Mystique, and RIL), three of the Enigma subfamily (Enigma, Enigma Homolog, and ZASP), the two LIM kinases (LIMK1 and LIMK2), and the LIM only protein 7 (LMO7) Functionally, all PDZ and LIM domain proteins share an important trait, ie, they can associate with and/or influence the actin cytoskeleton We review here the PDZ and LIM domain-encoding genes and their different gene structures, their binding partners, and their role in development and disease Emphasis is laid on the important questions: why the combination of a PDZ domain with one or more LIM domains is found in such a diverse group of proteins, and what role the PDZ/LIM module could have in signaling complex assembly and localization Furthermore, the current knowledge on splice form specific expression and the function of these alternative transcripts during vertebrate development will be discussed, since another source of complexity for the PDZ and LIM domain-encoding proteins is introduced by alternative splicing, which often creates different domain combinations

Neurophysiological endophenotypes, CNS disinhibition, and risk for alcohol dependence and related disorders.

Abstract: Biological endophenotypes are more proximal to gene function than psychiatric diagnosis, providing a powerful strategy in searching for genes in psychiatric disorders. These intermediate phenotypes identify both affected and unaffected members of an affected family, including offspring at risk, providing a more direct connection with underlying biological vulnerability. The Collaborative Study on the Genetics of Alcoholism (COGA) has employed heritable neurophysiological features (i.e., brain oscillations) as endophenotypes, making it possible to identify susceptibility genes that may be difficult to detect with diagnosis alone. We found significant linkage and association between brain oscillations and genes involved with inhibitory neural networks (e.g., GABRA2, CHRM2), including frontal networks that are deficient in individuals with alcohol dependence, impulsivity, and related disinhibitory disorders. We reported significant linkage and linkage disequilibrium for the beta frequency of the EEG and GABRA2, a GABAA receptor gene on chromosome 4, which we found is also associated with diagnosis of alcohol dependence and related disorders. More recently, we found significant linkage and association with GABRA2 and interhemispheric theta coherence. We also reported significant linkage and linkage disequilibrium between the theta and delta event-related oscillations underlying P3 to target stimuli and CHRM2, a cholinergic muscarinic receptor gene on chromosome 7, which we found is also associated with diagnosis of alcohol dependence and related disorders. Thus, the identification of genes important for the expression of the endophenotypes (brain oscillations) helps when identifying genes that increase the susceptibility for risk of alcohol dependence and related disorders. These findings underscore the utility of quantitative neurophysiological endophenotypes in the study of the genetics of complex disorders. We will present our recent genetic findings related to brain oscillations and Central Nervous System (CNS) disinhibition.

Traumatic brain injury and delayed sequelae: a review--traumatic brain injury and mild traumatic brain injury (concussion) are precursors to later-onset brain disorders, including early-onset dementia.

Abstract: Brain injuries are too common. Most people are unaware of the incidence of and horrendous consequences of traumatic brain injury (TBI) and mild traumatic brain injury (MTBI). Research and the advent of sophisticated imaging have led to progression in the understanding of brain pathophysiology following TBI. Seminal evidence from animal and human experiments demonstrate links between TBI and the subsequent onset of premature, psychiatric syndromes and neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Objectives of this summary are, therefore, to instill appreciation regarding the importance of brain injury prevention, diagnosis, and treatment, and to increase awareness regarding the long-term delayed consequences following TBI.

Impact of prenatal stress on neuroendocrine programming.

Abstract: Since life emerged on the Earth, the development of efficient strategies to cope with sudden and/or permanent changes of the environment has been virtually the unique goal pursued by every organism in order to ensure its survival and thus perpetuate the species. In this view, evolution has selected tightly regulated processes aimed at maintaining stability among internal parameters despite external changes, a process termed homeostasis. Such an internal equilibrium relies quite heavily on three interrelated physiological systems: the nervous, immune, and endocrine systems, which function as a permanently activated watching network, communicating by the mean of specialized molecules: neurotransmitters, cytokines, and hormones or neurohormones. Potential threats to homeostasis might occur as early as during in utero life, potentially leaving a lasting mark on the developing organism. Indeed, environmental factors exert early-life influences on the structural and functional development of individuals, giving rise to changes that can persist throughout life. This organizational phenomenon, encompassing prenatal environmental events, altered fetal growth, and development of long-term pathophysiology, has been named early-life programming. Over the past decade, increased scientific activities have been devoted to deciphering the obvious link between states of maternal stress and the behavioral, cognitive, emotional, and physiological reactivity of the progeny. This growing interest has been driven by the discovery of a tight relationship between prenatal stress and development of short- and long-term health disorders. Among factors susceptible of contributing to such a deleterious programming, nutrients and hormones, especially steroid hormones, are considered as powerful mediators of the fetal organization since they readily cross the placental barrier. In particular, variations in circulating maternal glucocorticoids are known to impact this programming strongly, notably when hormonal surges occur during sensitive periods of development, so-called developmental windows of vulnerability. Stressful events occurring during the perinatal period may impinge on various aspects of the neuroendocrine programming, subsequently amending the offspring's growth, metabolism, sexual maturation, stress responses, and immune system. Such prenatal stress-induced modifications of the phenotypic plasticity of the progeny might ultimately result in the development of long-term diseases, from metabolic syndromes to psychiatric disorders. Yet, we would like to consider the outcome of this neuroendocrine programming from an evolutionary perspective. Early stressful events during gestation might indeed shape internal parameters of the developing organisms in order to adapt the progeny to its everyday environment and thus contribute to an increased reproductive success, or fitness, of the species. Moreover, parental care, adoption, or enriched environments after birth have been shown to reverse negative long-term consequences of a disturbed gestational environment. In this view, considering the higher potential for neonatal plasticity within the brain in human beings as compared to other species, long-term consequences of prenatal stress might not be as inexorable as suggested in animal-based studies published to date.

Impacts of air pollution and climate change on forest ecosystems--emerging research needs.

Abstract: Outcomes from the 22nd meeting for Specialists in Air Pollution Effects on Forest Ecosystems "Forests under Anthropogenic Pressure--Effects of Air Pollution, Climate Change and Urban Development", September 10-16, 2006, Riverside, CA, are summarized. Tropospheric or ground-level ozone (O3) is still the phytotoxic air pollutant of major interest. Challenging issues are how to make O3 standards or critical levels more biologically based and at the same time practical for wide use; quantification of plant detoxification processes in flux modeling; inclusion of multiple environmental stresses in critical load determinations; new concept development for nitrogen saturation; interactions between air pollution, climate, and forest pests; effects of forest fire on air quality; the capacity of forests to sequester carbon under changing climatic conditions and coexposure to elevated levels of air pollutants; enhanced linkage between molecular biology, biochemistry, physiology, and morphological traits.

Regulation of immune cells by eicosanoid receptors.

Abstract: Eicosanoids are potent, bioactive, lipid mediators that regulate important components of the immune response, including defense against infection, ischemia, and injury, as well as instigating and perpetuating autoimmune and inflammatory conditions. Although these lipids have numerous effects on diverse cell types and organs, a greater understanding of their specific effects on key players of the immune system has been gained in recent years through the characterization of individual eicosanoid receptors, the identification and development of specific receptor agonists and inhibitors, and the generation of mice genetically deficient in various eicosanoid receptors. In this review, we will focus on the receptors for prostaglandin D2, DP1 and DP2/CRTH2; the receptors for leukotriene B4, BLT1 and BLT2; and the receptors for the cysteinyl leukotrienes, CysLT1 and CysLT2, by examining their specific effects on leukocyte subpopulations, and how they may act in concert towards the development of immune and inflammatory responses.

Environmental behavior, sources, and effects of chlorinated polycyclic aromatic hydrocarbons.

Abstract: The environmental sources and behaviors of chlorinated 2- to 5-ring polycyclic aromatic hydrocarbons (ClPAHs). ClPAHs are ubiquitous contaminants found in urban air, vehicle exhaust gas, snow, tap water, and sediments. The concentrations of ClPAHs in each of these environments are generally higher than those of dioxins but markedly lower than the concentrations of the parent compounds, PAHs. Environmental data and emission sources analysis for ClPAHs reveal that the dominant process of generation is by reaction of PAHs with chlorine in pyrosynthesis. This secondary reaction process also occurs in aquatic environments. Certain ClPAHs show greater toxicity, such as mutagenicity and aryl hydrocarbon receptor activity, than their corresponding parent PAHs. Investigation of the sources and environmental behavior of ClPAHs is of great importance in the assessment of human health risks.

Class B gene expression and the modified ABC model in nongrass monocots.

Abstract: The discovery of the MADS-box genes and the study of model plants such as Arabidopsis thaliana and Antirrhinum majus have greatly improved our understanding of the molecular mechanisms driving the diversity in floral development. The class B genes, which belong to the MADS-box gene family, are important regulators of the development of petals and stamens in flowering plants. Many nongrass monocot flowers have two whorls of petaloid organs, which are called tepals. To explain this floral morphology, the modified ABC model was proposed. This model was exemplified by the tulip, in which expansion and restriction of class B gene expression is linked to the transition of floral morphologies in whorl 1. The expression patterns of class B genes from many monocot species nicely fit this model; however, those from some species, such as asparagus, do not. In this review, we summarize the relationship between class B gene expression and floral morphology in nongrass monocots, such as Liliales (Liliaceae) and Asparagales species, and discuss the applicability of the modified ABC model to monocot flowers.

Tackling adolescent substance abuse in Hong Kong: where we should and should not go.

Abstract: In the 2007 Policy Address, the Chief Executive of the Hong Kong Special Administrative Region, P.R.C. expressed the Administration’s concern about adolescent substance abuse and proposed to form a high-level interdepartmental task force to tackle the problem in a holistic manner. In this paper, the author presents his observations about adolescent substance abuse in Hong Kong, and outlines the risk factors and related strategies based on the ecological perspective that the Government should consider in order to tackle the problem of adolescent substance abuse in Hong Kong. Furthermore, the directions where the Government should and should not go are discussed.

Effects of glucocorticoids on apoptosis and clearance of apoptotic cells.

Abstract: The glucocorticoid (GC) drugs are one of the most commonly prescribed and effective anti-inflammatory agents used for the treatment of many inflammatory disorders through their ability to attenuate phlogistic responses. The glucocorticoid receptor (GCR) primarily mediates GC actions via activation or repression of gene expression. GCs directly induce the expression of proteins displaying anti-inflammatory activities. However, the likely predominant effect of GCs is the repression of multiple inflammatory genes that invariably are overexpressed during nonresolving chronic inflammation. Although most GC actions are mediated through regulation of transcription, rapid nongenomic actions have also been reported. In addition, GCs modulate inflammatory cell survival, inducing apoptosis in immature thymocytes and eosinophils, while delaying constitutive neutrophil apoptosis. Importantly, GCs promote noninflammatory phagocytosis of apoptotic cell targets, a process important for the successful resolution of inflammation. Here, the effects and mechanisms of action of GC on inflammatory cell apoptosis and phagocytosis will be discussed.

Drugs of abuse can entrain circadian rhythms.

Abstract: Circadian rhythms prepare organisms for predictable events during the Earth's 24-h day. These rhythms are entrained by a variety of stimuli. Light is the most ubiquitous and best known zeitgeber, but a number of others have been identified, including food, social cues, locomotor activity, and, most recently drugs of abuse. Given the diversity of zeitgebers, it is probably not surprising that genes capable of clock functions are located throughout almost all organs and tissues. Recent evidence suggests that drugs of abuse can directly entrain some circadian rhythms. We have report here that entrainment by drugs of abuse is independent of the suprachiasmatic nucleus and the light/dark cycle, is not dependent on direct locomotor stimulation, and is shared by a variety of classes of drugs of abuse. We suggest that drug-entrained rhythms reflect variations in underlying neurophysiological states. This could be the basis for known daily variations in drug metabolism, tolerance, and sensitivity to drug reward. These rhythms could also take the form of daily periods of increased motivation to seek and take drugs, and thus contribute to abuse, addiction and relapse.

Laparoscopic Radical Nephrectomy: The New Gold Standard Surgical Treatment for Localized Renal Cell Carcinoma

Abstract: We will try to demonstrate that laparoscopic radical nephrectomy could be the new gold standard treatment for renal cell carcinoma with the aid of the current reports exploring the advantages and disadvantages of laparoscopic radical nephrectomy over open surgery. Reported perioperative outcomes like operating time, blood loss, postoperative analgesia requirement, and length of hospital stay and duration of convalescence had been found to be in favor of laparoscopic radical nephrectomy. Some technical issues like approach of laparoscopic technique (Transperitoneal versus retroperitoneal laparoscopic nephrectomy), removal of dissected specimen and need for lymph node dissection had been also discussed in detail in this review. Besides, oncological safety of laparoscopic radical nephrectomy had been explored. The overall five-year disease free survival rates of laparoscopic radical nephrectomy in recent series were found to be over 90%. All of the series including the present one at least confirmed the oncological efficacy of LRN as compared with open surgical approach. The contemporary review of the literature documents clearly demonstrated the perioperative benefits of laparoscopy compared to the open approach. Nevertheless, the development, however, more safe and reliable technique in laparoscopy is necessary for tumor extraction. Recent studies confirmed the long-term similar cancer control results of laparoscopic radical nephrectomy with open surgery. Despite some technical modifications by the different groups, it can be stated that laparoscopic radical nephrectomy is the new gold standard treatment modality for patients with localized renal cell carcinoma.

GITR-GITRL system, a novel player in shock and inflammation.

Abstract: Glucocorticoid-induced TNFR-Related (GITR) protein is a member of the tumor necrosis factor receptor superfamily that modulates acquired and natural immune response. It is expressed in several cells and tissues, including T cells, natural killer cells, and, at lower levels, in cells of innate immunity. GITR is activated by its ligand, GITRL, mainly expressed on antigen presenting and endothelial cells. Recent evidence suggests that the GITR/GITRL system participates in the development of inflammatory responses, including shock, either due to early response of neutrophils and macrophages, or together with autoimmune/allergic pathogenesis. The pro-inflammatory role of the GITR/GITRL system is due to: 1) modulation of the extravasation process, 2) activation of innate immunity cells, 3) activation of effector T cells also favored by partial inhibition of suppressor T cells and modulation of dendritic function. This review summarizes the in vivo role of the GITR/GITRL system in inflammation and shock, explaining the mechanisms responsible for their effects, considering the interplay among the different cells of the immune system and transduction pathways activated by GITR and GITRL triggering. The hidden aspects about GITR/GITRL function, crucial for treatment planning of inflammatory diseases and shock by modulation of this system is stressed.

Cysteinyl-leukotriene receptors and cellular signals

Abstract: Cysteinyl-leukotrienes (cysteinyl-LTs) exert a range of proinflammatory effects, such as constriction of airways and vascular smooth muscle, increase of endothelial cell permeability leading to plasma exudation and edema, and enhanced mucus secretion. They have proved to be important mediators in asthma, allergic rhinitis, and other inflammatory conditions, including cardiovascular diseases, cancer, atopic dermatitis, and urticaria. The classification into subtypes of the cysteinyl-LT receptors (CysLTRs) was based initially on binding and functional data, obtained using the natural agonists and a wide range of antagonists. CysLTRs have proved remarkably resistant to cloning. However, in 1999 and 2000, the CysLT1R and CysLT2R were successfully cloned and both shown to be members of the G-protein coupled receptors (GPCRs) superfamily. Molecular cloning has confirmed most of the previous pharmacological characterization and identified distinct expression patterns only partially overlapping. Recombinant CysLTRs couple to the Gq/11 pathway that modulates inositol phospholipids hydrolysis and calcium mobilization, whereas in native systems, they often activate a pertussis toxin-insensitive Gi/o-protein, or are coupled promiscuously to both G-proteins. Interestingly, recent data provide evidence for the existence of an additional receptor subtype that seems to respond to both cysteinyl-LTs and uracil nucleosides, and of an intracellular pool of CysLTRs that may have roles different from those of plasma membrane receptors. Finally, a cross-talk between the cysteinyl-LT and the purine systems is being delineated. This review will summarize recent data derived from studies on the molecular and cellular pharmacology of CysLTRs.

An emerging role for the delta opioid receptor in the regulation of mu opioid receptor function.

Abstract: Morphine and related opiates are commonly used in the clinical management of various types of pain. However, the antinociceptive properties of morphine are often overshadowed by the development of tolerance and dependence following its chronic use. The mechanisms underlying opiate tolerance are not fully understood, but appear to involve numerous and complex physiological adaptations. Recently, a role for the heterodimerization of mu and delta opioid receptors in the development of morphine tolerance has been proposed. This novel mechanism could help us to understand several observations, such as the critical role of delta opioid receptor regulation, the impact of delta opioid receptor binding site occupancy, and the participation of beta-arrestin2, in the development of morphine tolerance.

MicroRNA profiling: from dark matter to white matter, or identifying new players in neurobiology.

Abstract: Contemporary biology has been revolutionized by a recently discovered class of small regulatory RNA molecules, microRNAs (miRNAs). Missed by researchers for decades due to their tiny size, usually mapping to non-protein-coding regions of genomes, miRNAs and miRNA-mediated regulatory networks have been the "dark matter" of molecular biology. Deciphering miRNA pathways and functions in the CNS of complex organisms is tightly linked to understanding miRNA expression patterns. To facilitate these emerging studies, I here review the basic principles of medium- and high-throughput technologies available for miRNA expression profiling.