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Byline: Sadananda. Naik, R. Murali Krishna Keraunoparalysis is a catastrophic but fortunately totally reversible neuroparalysis of the limbs occurring due to a lightning strike. One such case with transient right [...]

There is a growing appreciation for the role that acute kidney injury (AKI) plays in the propagation of critical illness. In children, AKI is not only an independent predictor of morbidity and mortality, but is also associated with especially negative outcomes when concurrent with acute lung injury (ALI). Experimental data provide evidence that kidney-lung crosstalk occurs and can be bidirectionally deleterious, although details of the precise molecular mechanisms involved in the AKI-ALI interaction remain incomplete. Clinically, ALI, and the subsequent clinical interventions used to stabilize gas exchange, carry consequences for the homeostasis of kidney function. Meanwhile, AKI negatively affects lung physiology significantly by altering the homeostasis of fluid balance, acid-base balance, and vascular tone. Experimental AKI research supports an 'endocrine' role for the kidney, triggering a cascade of extra-renal inflammatory responses affecting lung homeostasis. In this review, we will discuss the pathophysiologyof kidney-lung crosstalk, the multiple pathways by which AKI affects kidney-lung homeostasis, and discuss how these phenomena may be unique in critically ill children. Understanding how AKI may affect a 'balance of communication' that exists between the kidneys and the lungs is requisite when managing critically ill children, in whom imbalance is the norm. Keywords kidney-lung crosstalk * AKI * ALI * Fluid overload * Renal angina, Introduction Organ cross-talk is of particular importance to practitioners in the intensive care unit (ICU); many disease processes that affect ICU patients carry the potential to affect a number of [...]

The first adipokine, leptin, discovered almost 20 years ago, is secreted into circulation mainly from adipose tissue and acts both centrally and peripherally. Leptin regulates energy metabolism, reproductive function, bone metabolism, and immune response. However in some physiological or pathological situations such as enhancement of undesired immune responses in autoimmune diseases, tumorigenesis, elevated blood pressure, and certain cardiovascular pathologies, leptin activity may be harmful. In this review we screen different approaches to blocking leptin action, in vitro and in vivo. The recent development of superactive leptin muteins exhibiting antagonistic properties, and other leptin-action-blocking peptides, proteins, monoclonal antibodies, and nanobodies, opens new perspectives for their use in research, and eventually, therapy for cachexia, autoimmune disease, cancer, and other pathologies. Key words: leptin, antagonist, inflammatory disease, anti-autoimmune diseases, cancer, uremic cachexia, blood pressure, metabolic syndrome, T2DM model. La leptine, premiere adipokine decouverte il y a presque 20 ans, est principalement secretee dans la circulation par le tissu adipeux et elle agit de facon centrale et peripherique. La leptine regule le metabolisme energetique, la fonction reproductrice, le metabolisme osseux et la reponse immunitaire. Toutefois, dans certaines situations physiologiques ou pathologiques comme l'accroissement de reponses immunes indesirables dans les maladies auto-immunes, la tumorigenese, l'hypertension et certaines pathologies cardiovasculaires, l'activite de la leptine peut etre nefaste. Dans cet article de revue, nous passons au crible differentes approches de blocage de l'action de la leptine in vitro et in vivo. Le developpement recent de muteines de leptine tres actives montrant des proprietes antogonistes, ainsi que d'autres peptides, anticorps et nanocorps monoclonaux bloquant l'action de la leptine, ouvre ainsi de nouvelles perspectives a leur utilisation en recherche et, eventuellement, dans la therapie de la cachexie, des maladies auto-immunes, du cancer et autres pathologies. [Traduit par la Redaction] Mots-cles: leptine, antagoniste, maladie inflammatoire, maladies auto-immunes, cancer, cachexie uremique, pression sanguine, syndrome metabolique, modele de DT2., Introduction Although leptin (LEP) and leptin receptor (LEPR) were cloned almost 20 years ago (Zhang et al. 1994; Tartaglia et al. 1995) and LEP's 3D structure was resolved a few [...]

Hydrogen sulfide ([H.sub.2]S) is synthesized from L-cysteine by cystathionine β-synthase (CBS) or cystathionine γ-lyase (CSE), and is enzymatically metabolized in mitochondria by sulfide:quinone oxidoreductase (SQR). Recent studies have indicated that [H.sub.2]S is synthesized by CSE in perivascular adipose tissue (PVAT), and is responsible for the anticontractile effect of PVAT on adjacent vessels. The lipophilic statin atorvastatin increases PVAT-derived [H.sub.2]S by suppressing its mitochondrial oxidation; the effect that results from statin-induced depletion of ubiquinone. Experimental obesity induced by a highly palatable diet has a time-dependent effect on [H.sub.2]S in PVAT. Adipose tissue hypoxia suppresses [H.sub.2]S oxidation and increases its level in short-term obesity not associated with insulin resistance. In contrast, in long-term obesity, insulin resistance and (or) hyperinsulinemia result in the down-regulation of CSE and [H.sub.2]S deficiency, which is corrected by treatment with the insulin sensitizer rosiglitazone. In addition, cannabinoid CB1 receptor agonist administered for 2 weeks increases [H.sub.2]S by impairing mitochondria biogenesis. This indicates that the rate of mitochondrial [H.sub.2]S oxidation plays an important role in the regulation of [H.sub.2]S level in PVAT. Up-regulation of [H.sub.2]S signaling in short-term obesity and (or) by elevated endocannabinoids may be a compensatory mechanism that maintains vascular tone, despite endothelial dysfunction. Key words: hydrogen sulfide, perivascular adipose tissue, obesity, metabolic syndrome, arterial hypertension, vascular tone, insulin sensitivity, hypoxia, endocannabinoids. Le sulfure d'hydrogene ([H.sub.2]S) est synthetise a partir de la L-cysteine par la cystathionine β-synthase (CBS) ou la cystathionine γ-lyase (CSE), et il est metabolise de facon enzymatique dans la mitochondrie par la sulfide:quinone oxydoreductase (SQR). Des etudes recentes indiquent que le [H.sub.2]S est synthetise par la CSE dans le tissu adipeux perivasculaire (TAPV) et qu'il est responsable de l'effet anti-constricteur du TAPV sur les vaisseaux adjacents. L'atorvastatine, une statine lipophile, accroit le niveau de [H.sub.2]S derive du TAPV en supprimant son oxydation mitochondriale, consequence de la depletion en ubiquinone induite par la statine. L'obesite experimentale induite par une diete hautement palatable exerce un effet sur le [H.sub.2]S dans le TAPV en fonction du temps. L'hypoxie du tissu adipeux supprime l'oxydation du [H.sub.2]S et ses niveaux sont accrus dans l'obesite al court terme non associee a la resistance a l'insuline. Au contraire, dans l'obesite a long terme, la resistance a l'insuline et (ou) l'hyperinsulinemie resultent en une regulation a la baisse de la CSE et en une deficience en [H.sub.2]S, ce qui peut etre corrige par un traitement avec un sensibilisateur a l'insuline, le rosiglitazone. En outre, un agoniste du recepteur des cannabinoides CB1 administre pendant 2 semaines augmente le [H.sub.2]S en alterant la biogenese mitochondriale. Ces donnees indiquent que le taux d'oxydation mitochondriale de [H.sub.2]S joue un role important dans la regulation du niveau de [H.sub.2]S dans le TAPV. La regulation a la hausse de la signalisation du [H.sub.2]S dans l'obesite a court terme et (ou) lors de l'elevation des niveaux d'endocannabinoides peut constituer un mecanisme compensatoire qui maintien le tonus vasculaire malgre la dysfonction endotheliale. [Traduit par la Redaction] Mots-cles: sulfure d'hydrogene, tissu adipeux perivasculaire, obesite, syndrome metabolique, hypertension arterielle, tonus vasculaire, hypoxie, endocannabinoides., Introduction Perivascular adipose tissue (PVAT) surrounds most of the large (conduit) and medium-size (resistance) arteries and also some veins. PVAT is not a passive component of the vascular wall, or [...]

Fragile X syndrome (FXS), the most common cause of inherited mental retardation and autism, is caused by transcriptional silencing of FMR1, which encodes the translational repressor fragile X mental retardation [...]

During the inflammatory response that drives atherogenesis, macrophages accumulate progressively in the expanding arterial wall (1), (2). The observation that circulating monocytes give rise to lesional macrophages (3-9) has reinforced [...]

MicroRNAs (miRNAs) are highly conserved, small, noncoding RNAs that regulate gene expression at the posttranscriptional level. Their actions affect numerous important biological processes, including adipocyte differentiation and function, sugar and lipid metabolism, and insulin production and secretion. Recent reports suggest miRNAs may also be involved in the pathogenic processes of obesity, diabetes, and insulin resistance. In this review, we summarize research progresses on adipocyte miRNAs and their physiological and pathological implications. Key words: miRNAs, adipose tissue, adipogenesis, obesity, diabetes, insulin resistance. Les microARN (miARN) sont de petits ARN non codants hautement conserves qui regulent l'expression genique au niveau post-transcriptionnel. Leurs actions ont un impact sur plusieurs processus biologiques importants, notamment la differenciation et la fonction des adipocytes, le metabolisme des glucides et des lipides, la production et la secretion d'insuline. Des rapports recents suggerent que les miARN peuvent aussi etre impliques dans les processus pathogenes de l'obesite, du diabete et de la resistance a l'insuline. Dans cet article de synthese, nous resumons les progres realises en recherche sur les miARN des adipocytes et leurs implications physiologiques et pathologiques. [Traduit par la Redaction] Mots-cles: miARN, tissu adipeux, adipogenese, obesite, diabete, resistance a l'insuline., Introduction Epidemic obesity, a serious public health problem, prevails worldwide. Obesity is characterized by increased fat mass resulting from accelerated adipogenesis, a process to generate functional mature adipocytes (Vazquez-Vela et [...]

To analyze the interconnection between erythropoiesis and iron metabolism, one of the issues raised in this study was to know iron bioavailability under physiopathological conditions. Our aim was to understand the functional axis responsecomposed of erythropoietin (Epo)--hepcidin--ferroportin (FPN), when 2 dysfunctional states coexist, using an animal model of iron overload followed by hypoxia. FPN and prohepcidin were assessed by immunohistochemistry using rabbit anti-mouse FPN polyclonal and prohepcidin monoclonal antibodies. Goat- labeled polymer - horseradish peroxidase anti-rabbit EnVision + System (DAB) was used as the secondary antibody. Epo levels were measured by ELISA. Tissue iron was studied by Prussian blue iron staining. Erythropoietic response was assessed using conventional hematological tests. Iron overload increased prohepcidin that remained high in hypoxia, coexisting with high levels of Epo in hypoxia, with or without iron overload. In hypoxia, FPN was clearly evident in reticuloendothelial macrophages, more than in hypoxia with iron overload. Interestingly, duodenal FPN was clearly identified on the basolateral membrane in hypoxia, with or without iron overload. Our data indicate that 2 signals could induce the cell--specific response as follows: (i) iron signal, induced prohepcidin, which reduced reticuloendothelial FPN and reduced iron availability; and (ii) hypoxia signal, stimulated Epo, which affected iron absorption by stabilizing duodenal FPN and allowed iron supply to erythropoiesis independently of store size. Key words: ferroportin, prohepcidin, erythropoietin, iron, hypoxia. Resume : Afin d'analyser la relation qui existe entre l'erythropoiese et le metabolisme du fer, une des questions soulevees dans cette etude consiste a connaitre la biodisponibilite du fer en conditions physiopathologiques. Notre but etait de comprendre l'axe fonctionnel de reponse compose de l'erythropoietine (Epo)--hepcidine--ferroportine (FPN) lorsque deux etats dysfonctionnels coexistent, a l'aide d'un modele animal de surcharge en fer suivie d'une hypoxie. La FPN et la prohepcidine ont ete estimees par immunohistochimie a l'aide d'une anticorps polyclonal anti-FPN de souris produit chez le lapin et d'un anticorps monoclonal anti--prohepcidine. Le systeme Envision+ constitue de polymere marque a la peroxydase de raifort anti-lapin produit chez la chevre a ete utilise comme anticorps secondaire. Les niveaux d'Epo ont ete mesures par ELISA. Le fer tissulaire a ete etudie par coloration au Bleu de Prusse. L'erythropoiese a ete evaluee par des tests hematologiques conventionnels. La surcharge en fer accroissait la prohepcidine qui demeurait elevee en hypoxie, coexistant avec de hauts niveaux d'Epo en hypoxie, avec ou sans surcharge. En hypoxie, la FPN etait clairement evidente dans les macrophages reticulo-endotheliaux, davantage que lors de l'hypoxie avec surcharge en fer. Fait interessant, la FPN duodenale etait clairement detectable dans les membranes basolaterales en hypoxie, avec ou sans surcharge en fer. Nos donnees indiquent que deux signaux pourraient induire une reponse specifique au type de cellules : (i) le signal du fer, qui a induit la prohepcidine, laquelle reduit la FPN reticulo-endotheliale et consequemment la disponibilite en fer ; (ii) le signal hypoxique qui a stimule l'Epo, affectant l'absorption du fer en stabilisant la FPN duodenale, permettant un apport en fer pour l'erythropoiese, independamment de la taille des reserves. [Traduit par la Redaction] Mots-cles: ferroportine, prohepcidine, erythropoietine, fer, hypoxie., Introduction Iron is an essential nutrient for the growth and development of all living organisms, particularly for mammalian erythropoiesis (Fleming 2008). It is well known that body iron homeostasis is [...]

BACKGROUND AND OBJECTIVES: The pathogenesis of the metabolic syndrome (MetS) is not well understood. This review is based on the hypothesis that both traditional and emerging risk factors act through adiponectin. SUBJECTS AND METHODS: We conducted a search of the literature using prominent electronic databases and search terms that included in combination: adiponectin, diet, dietary patterns, exercise, metabolic rate, MetS and testosterone. Articles were restricted to studies conducted on adult humans, reported in English and within the time period 2000-2012. RESULTS AND CONCLUSIONS: Both traditional and emerging risk factors associated with the MetS show some evidence of exerting their influence through adiponectin. High-quality randomized controlled trials that alter adiponectin levels are required to further corroborate this hypothesis. European Journal of Clinical Nutrition (2013) 67, 485-491; doi:10.1038/ejcn.2013.1; published online 30 January 2013 Keywords: metabolic syndrome; adiponectin; diet; vitamin D; basal metabolic rate; mitochondria, INTRODUCTION The metabolic syndrome (MetS) represents a clustering of risk factors for cardiovascular disease and type 2 diabetes mellitus (T2DM), which include: hypertension, low high-density lipoprotein-cholesterol (HDL-C), high triglycerides (TG), [...]

Background: The dopamine (DA) [D.sub.2] receptors exist in 2 states: a high-affinity state ([D.sub.2.sup.high]) that is linked to second messenger systems, responsible for functional effects, exhibits high affinity for agonists (e.g., DA), and a low-affinity state that is functionally inert exhibits lower affinity for agonists. The DA [D.sub.3] receptor subtype exhibits high agonist affinity, whereas the existence of the multiple affinity states is controversial. Preclinical studies in animal models of psychosis have shown a selective increase of [D.sub.2.sup.high] as the common factor in psychosis, and the [D.sub.3] receptor has been suggested to be involved in the pathophysiology of schizophrenia. Methods: We studied [D.sub.2.sup.high] and [D.sub.3] in people at clinical high risk (CHR) for schizophrenia and in antipsychotic-naive patients with schizophrenia using the novel positron emission tomography radiotracer, [[sup.11]C]-(+)-PHNO. The binding potential nondisplaceable ([BP.sub.ND]) was examined in the regions of interest (ROI; caudate, putamen, ventral striatum, globus pallidus, substantia nigra and thalamus) using an ROI and a voxel-wise approach while participants performed a cognitive task. Results: We recruited 12 CHR individuals and 13 antipsychotic-naive patients with schizophreniaspectrum disorder, whom we compared with 12 age- and sex-matched healthy controls. The [BP.sub.ND] between patients and controls did not differ in any of the ROIs, consistent with the voxel-wise analysis. Correlations between the [BP.sub.ND] in [D.sub.3]- rich regions and psychopathology warrant further investigation. Limitations: In the absence of resting-state (baseline) [BP.sub.ND] data, or following a depletion paradigm (i.e., α-methyl partyrosine), it is not possible to ascertain whether the lack of difference among the groups is owing to different levels of baseline DA or to release during the cognitive task. Conclusion: To our knowledge, the present study represents the first effort to measure the [D.sub.2] and [D.sub.3] receptors under a cognitive challenge in individuals putative/prodromal for schizophrenia using [[sup.11]C]-(+)-PHNO., Introduction It is well established that the [D.sub.2/3] dopamine (DA) receptor subtypes are the targets of most antipsychotic drugs, though the exact role of these receptors in the pathophysiology of [...]

Recent research indicates an association between brain dysfunction and the pathogenesis of metabolic syndrome. To investigate this, we created a Medline search (up to December 2011) of articles in PubMed. The results indicated that refined carbohydrates, saturated and total fat, high levels of ω-6 fatty acids, and low levels of ω-3 fatty acids and other long chain polyunsaturated fatty acids (PUFA), all in conjunction with sedentary behaviour and mental stress can predispose to inflammation. Increased sympathetic activity, with increased secretion of catecholamine, cortisol, and serotonin can cause oxidative stress, which may damage the arcuate nucleus as well as the hypothalamus and macrophages, and the liver may release pro-inflammatory cytokines. These, in conjunction with an underlying deficiency in long chain PUFA, may damage the arcuate nucleus as well as neuropeptide-Y and pro-opiomelanocortin neurons and insulin receptors in the brain, especially during fetal life, infancy, and childhood, resulting in their dysfunction. Of the fatty acids in the brain, 30%-50% are long chain PUFA, which are incorporated in the cell membrane phospholipids. Hence, m-3 fatty acids, which are also known to enhance parasympathetic activity and increase the secretion of anti-inflammatory cytokines interleukin (IL)-4 and IL-10 as well as acetylcholine in the hippocampus, may be protective. Therefore, treatment with ω-3 fatty acids may be applied for the prevention of metabolic syndrome. Key words: hypothalamus, glucose intolerance, insulin resistance, brain disease, diet, nutrition, ω-3 fatty acids, brain development, brain-heart connection, Mediterranean diet. La recherche recente indique qu'il existe une association entre la dysfonction cerebrale et la pathogenese du syndrome metabolique. Pour etudier ce, nous avons cree un recherche sur Medline jusqu'a decembre 2011 les articles publies sur PubMed. Les resultats ont montre que les sucres raffines, les gras satures et totaux, les acides gras ω-6 eleves et ω-3 faibles ainsi que les autres acides gras polyinsatures (AGP) a longue chaine, combines a la sedentarite et au stress peuvent predisposer a l'inflammation. Une activite sympathique accrue et une augmentation de la secretion de catecholamines, de cortisol et de serotonine peuvent causer un stress oxydant qui pourrait endommager le noyau arque de l'hypothalamus et les macrophages, ainsi qu' une liberation de cytokines pro-inflammatoires. Tout ceci combine a une deficience sous-jacente en AGP a longue chaine peut endommager le noyau arque, les neurones a neuropeptide Y et a pro-opio-melanocortine et les recepteurs d'insuline du cerveau, notamment durant la vie faetale, la petite enfance et l'enfance, resultant en leur dysfonction. Trente a cinquante pourcent des acides gras du cerveau sont des AGP a longue chaine qui sont incorpores dans les phospholipides des membranes cellulaires. Donc, les acides gras ω-3, qui sont aussi connus pour augmenter l'activite parasympathique et accroitre la secretion de cytokines anti-inflammatoires IL-4 et IL-10 de meme que d'acetylcholine dans l'hippocampe, pourraient etre protecteurs. En consequence, un traitement aux acides gras ω-3 pourrait etre utilise pour prevenir le syndrome metabolique. Mots-cles : hypothalamus, intolerance au glucose, resistance a l'insuline, maladie cerebrale, diete, nutrition, acides gras ω-3, developpement du cerveau, connexion cerveau-caeur, diete mediterraneenne. [Traduit par la Redaction], Introduction Nutritional deficiencies and overnutrition in the form of central obesity and overweight coexist in most of the developing countries (WHO Study Group 1990; Barker et al. 1993; Singh et [...]

Massive transfusion of blood can lead to clinical complications, including multiorgan dysfunction and even death. Such severe clinical outcomes have been associated with longer red blood cell (rbc) storage times. Collectively referred to as the rbc storage lesion, rbc storage results in multiple biochemical changes that impact intracellular processes as well as membrane and cytoskeletal properties, resulting in cellular injury in vitro. However, how the rbc storage lesion triggers pathophysiology in vivo remains poorly defined. In this study, we developed a guinea pig transfusion model with blood stored under standard blood banking conditions for 2 (new), 21 (intermediate), or 28 days (old blood). Transfusion with old but not new blood led to intravascular hemolysis, acute hypertension, vascular injury, and kidney dysfunction associated with pathophysiology driven by hemoglobin (Hb). These adverse effects were dramatically attenuated when the high-affinity Hb scavenger haptoglobin (Hp) was administered at the time of transfusion with old blood. Pathologies observed after transfusion with old blood, together with the favorable response to Hp supplementation, allowed us to define the in vivo consequences of the rbc storage lesion as storage-related posttransfusion hemolysis producing Hb-driven pathophysiology. Hb sequestration by Hp might therefore be a therapeutic modality for enhancing transfusion safety in severely ill or massively transfused patients., Introduction Donor-derived red blood cell (rbc) products are routinely stored for up to 42 days before transfusion. Retrospective and prospective analyses of patients undergoing multiple blood transfusions have correlated poor [...]

Ischemic kidney injury often occurs in the context of multiple organ failure and sepsis. Here, we review the major components of this dynamic process, which involves hemodynamic alterations, inflammation, and [...]

Atherosclerotic plaques tend to form in the major arteries at certain predictable locations. As these arteries vary in atherosusceptibility, interarterial differences in endothelial cell biology are of considerable interest. To explore the origin of differences observed between typical atheroprone and atheroresistant arteries, we used DNA microarrays to compare gene expression profiles of harvested porcine coronary (CECs) and iliac artery endothelial cells (IECs) grown in static culture out to passage 4. Fewer differences were observed between the transcriptional profiles of CECs and IECs in culture compared with in vivo, suggesting that most differences observed in vivo were due to distinct environmental cues in the two arteries. One-class significance of microarrays revealed that most in vivo interarterial differences disappeared in culture, as fold differences after passaging were not significant for 85% of genes identified as differentially expressed in vivo at 5% false discovery rate. However, the three homeobox genes, HOXA9, HOXA10, and HOXD3, remained underexpressed in coronary endothelium for all passages by at least nine-, eight-, and twofold, respectively. Continued differential expression, despite removal from the in vivo environment, suggests that primarily heritable or epigenetic mechanism(s) influences transcription of these three genes. Quantitative real-time polymerase chain reaction confirmed expression ratios for seven genes associated with atherogenesis and over- or underexpressed by threefold in CECs relative to IECs. The present study provides evidence that both local environment and vascular bed origin modulate gene expression in arterial endothelium. The transcriptional differences observed here may provide new insights into pathways responsible for coronary artery susceptibility. vascular endothelium; atherosclerosis; pathophysiology; genomics; epigenetics doi: 10.1152/ajpheart.00002.2010.

Much of our knowledge of human uterine physiology and pathology has been extrapolated from the study of diverse animal models, as there is no ideal system for studying human uterine biology in vitro. Although it remains debatable whether mouse models are the most suitable system for investigating human uterine function(s), gene-manipulated mice are considered by many the most useful tool for mechanistic analysis, and numerous studies have identified many similarities in female reproduction between the two species. This Review brings together information from studies using animal models, in particular mouse models, that shed light on normal and pathologic aspects of uterine biology and pregnancy complications., The uterus: a privileged place for new life Early in the history of medicine, the uterus was considered a root of women's mental health. Hippocrates conceived the term 'hysteria' (from [...]

Ang II plays an important role in the pathophysiology of cardiovascular disease. Angiotensin-converting enzyme (ACE) inhibitors lower Ang II levels by inhibiting conversion of Ang I to Ang II, but Ang II levels have been shown to return to normal with chronic ACE inhibitor treatment. In this issue of the JCI, Wei et al. show that ACE inhibition induces an increase in chymase activity in cardiac interstitial fluid, providing an alternate pathway for Ang II generation., Despite ongoing advances in modern medicine, cardiovascular disease (CVD) remains a major cause of death. Ang II has been implicated in the pathophysiology of atherosclerosis and heart failure (HF) due [...]

Neuronal nitric oxide synthase is critically involved in the pathogenesis of acute lung injury resulting from combined burn and smoke inhalation injury. We hypothesized that 7-nitroindazole, a selective neuronal nitric oxide synthase inhibitor, blocks central molecular mechanisms involved in the pathophysiology of this double-hit insult. Twenty-five adult ewes were surgically prepared and randomly allocated to 1) an uninjured, untreated sham group (n = 7), 2) an injured control group with no treatment (n = 7), 3) an injury group treated with 7-nitroindazole from 1-h postinjury to the remainder of the 24-h study period (n = 7), or 4) a sham-operated group subjected only to 7-nitroindazole to judge the effects in health. The combination injury was associated with twofold increased activity of neuronal nitric oxide synthase and oxidative/nitrosative stress, as indicated by significant increases in plasma nitrate/nitrite concentrations, 3-nitrotyrosine (an indicator of peroxynitrite formation), and malondialdehyde lung tissue content. The presence of systemic inflammation was evidenced by twofold, sixfold, and threefold increases in poly(ADP-ribose) polymerase, IL-8, and myeloperoxidase lung tissue concentrations, respectively (each P < 0.05 vs. sham). These molecular changes were linked to tissue damage, airway obstruction, and pulmonary shunting with deteriorated gas exchange. 7-Nitroindazole blocked, or at least attenuated, all these pathological changes. Our findings suggest 1) that nitric oxide formation derived from increased neuronal nitric oxide synthase activity represents a pivotal reactive agent in the pathophysiology of combined burn and smoke inhalation injury and 2) that selective neuronal nitric oxide synthase inhibition represents a goal-directed approach to attenuate the degree of injury. pathogenesis; acute lung injury doi:10.1152/ajplung.00147.2009.

Few infectious diseases are entirely human-specific: Most human pathogens also circulate in animals or else originated in nonhuman hosts. Influenza, plague, and trypanosomiasis are classic examples of zoonotic infections that transmit from animals to humans. The multihost ecology of zoonoses leads to complex dynamics, and analytical tools, such as mathematical modeling, are vital to the development of effective control policies and research agendas. Much attention has focused on modeling pathogens with simpler life cycles and immediate global urgency, such as influenza and severe acute respiratory syndrome. Meanwhile, vector-transmitted, chronic, and protozoan infections have been neglected, as have crucial processes such as cross-species transmission. Progress in understanding and combating zoonoses requires a new generation of models that addresses a broader set of pathogen Life histories and integrates across host species and scientific disciplines. doi: 10.1126/science.1177345

Pulmonary arterial hypertension (PAH) is a chronic lung disease that leads to right ventricular (RV) hypertrophy (RVH), remodeling, and failure. We tested treatment with bone marrow-derived mesenchymal stem cells (MSCs) obtained from donor rats with monocrotaline (MCT)-induced PAH to recipient rats with MCT-induced PAH on pulmonary artery pressure, lung pathology, and RV function. This model was chosen to mimic autologous MSC therapy. On day 1, PAH was induced by MCT (60 mg/kg) in 20 female Wistar rats. On day 14, rats were treated with [10.sup.6] MSCs intravenously (MCT + MSC) or with saline (MCT60). MSCs were obtained from donor rats with PAH at 28 days after MCT. A control group received saline on days 1 and 14. On day 28, the RV function of recipient rats was assessed, followed by isolation of the lungs and heart. RVH was quantified by the weight ratio of the RV/(left ventricle + interventricular septum). MCT induced an increase of RV peak pressure (from 27 [+ or -] 5 to 42 [+ or -] 17 mmHg) and RVH (from 0.25 [+ or -] 0.04 to 0.47 [+ or -] 0.12), depressed the RV ejection fraction (from 56 [+ or -] 11 to 43 [+ or -] 6%), and increased lung weight (from 0.96 [+ or -] 0.15 to 1.66 [+ or -] 0.32 g), including thickening of the arteriolar walls and alveolar septa. MSC treatment attenuated PAH (31 [+ or -] 4 mmHg) and RVH (0.32 [+ or -] 0.07), normalized the RV ejection fraction (52 [+ or -] 5%), reduced lung weight (1.16 [+ or -] 0.24 g), and inhibited the thickening of the arterioles and alveolar septa. We conclude that the application of MSCs from donor rats with PAH reduces RV pressure overload, RV dysfunction, and lung pathology in recipient rats with PAH. These results suggest that autologous MSC therapy may alleviate cardiac and pulmonary symptoms in PAH patients. pulmonary arterial hypertension; heart failure; hypertrophy; remodeling; monocrotaline doi: 10.1152/ajpheart.00590.2009.

To improve contractile function, the myocardium undergoes hypertrophic growth without myocyte proliferation in response to both pathologic and physiologic stimulation. Various membrane-bound receptors and intermediate signal transduction pathways regulate the induction of cardiac hypertrophy, but the cardioprotective regulatory pathways or effectors that antagonize cardiac hypertrophy remain poorly understood. Here we identify the small GTPase Cdc42 as a signaling intermediate that restrained the cardiac growth response to physiologic and pathologic stimuli. Cdc42 was specifically activated in the heart after pressure overload and in cultured cardiomyocytes by multiple agonists. Mice with a heart-specific deletion of Cdc42 developed greater cardiac hypertrophy at 2 and 8 weeks of stimulation and transitioned more quickly into heart failure than did wild-type controls. These mice also displayed greater cardiac hypertrophy in response to neuroendocrine agonist infusion for 2 weeks and, more remarkably, enhanced exercise-induced hypertrophy and sudden death. These pathologies were associated with an inability to activate JNK following stimulation through a MEKK1/MKK4/MKK7 pathway, resulting in greater cardiac nuclear factor of activated T cells (NFAT) activity. Restoration of cardiac JNK signaling with an Mkk7 heart-specific transgene reversed the enhanced growth effect. These results identify what we believe to be a novel antihypertrophic and protective cardiac signaling pathway, whereby Cdc42-dependent JNK activation antagonizes calcineurin-NFAT activity to reduce hypertrophy and prevent transition to heart failure., Introduction The adult heart hypertrophies in response to environmental stress as a means of augmenting pump function and reducing wall stress (1). The heart undergoes pathologic cardiac hypertrophy in response [...]

Modulation of voltage-gated potassium (Kv) channels by the KCNE family of single transmembrane proteins has physiological and pathophysiological importance. All five KCNE proteins (KCNE1-KCNE5) have been demonstrated to modulate heterologously expressed KCNQ1 (Kv7.1) with diverse effects, making this channel a valuable experimental platform for elucidating structure-function relationships and mechanistic differences among members of this intriguing group of accessory subunits. Here, we specifically investigated the determinants of KCNQ1 inhibition by KCNE4, the least well-studied KCNE protein. In CHO-K1 cells, KCNQ1, but not KCNQ4, is strongly inhibited by coexpression with KCNE4. By studying KCNQ1-KCNQ4 chimeras, we identified two adjacent residues (K326 and T327) within the extracellular end of the KCNQ1 S6 segment that determine inhibition of KCNQ1 by KCNE4. This dipeptide motif is distinct from neighboring S6 sequences that enable modulation by KCNE1 and KCNE3. Conversely, S6 mutations (S338C and F340C) that alter KCNE1 and KCNE3 effects on KCNQ1 do not abrogate KCNE4 inhibition. Further, KCNQ1-KCNQ4 chimeras that exhibited resistance to the inhibitory effects of KCNE4 still interact biochemically with this protein, implying that accessory subunit binding alone is not sufficient for channel modulation. These observations indicate that the diverse functional effects observed for KCNE proteins depend, in part, on structures intrinsic to the pore-forming subunit, and that distinct S6 subdomains determine KCNQ1 responses to KCNE1, KCNE3, and KCNE4.

Background: Neuregulin1 (NRG1) influences the development of white matter connectivity and is implicated in genetic susceptibility to schizophrenia. The cingulum bundle is a white matter structure implicated in schizophrenia. Its anterior component is especially implicated, as it provides reciprocal connections between brain regions with prominent involvement in the disorder. Abnormalities in the structural integrity of the anterior cingulum in patients with schizophrenia have been reported previously. The present study investigated the potential contribution of NRG1 variation to anterior cingulum abnormalities in participants with schizophrenia. Methods: We studied 31 men with schizophrenia and 36 healthy men using diffusion tensor imaging to investigate the association between fractional anisotropy in the anterior cingulum and a single-nucleotide polymorphism (SNP8NRG221533: rs35753505) of NRG1. Results: Consistent with previous reports, fractional anisotropy was significantly reduced in the anterior cingulum in the schizophrenia group. Moreover, the results revealed a significant group (schizophrenia, control) by genotype (C/C, T carriers, including CT and TT) interaction between genetic variation in NRG1 and diagnosis of schizophrenia, such that the patients with the T allele for SNP8NRG221533 had significantly decreased anterior cingulum fractional anisotropy compared with patients homozygous for the C allele and healthy controls who were T carriers. Limitations: Limitations of our study included the small sample size of the TT subgroup and our use of only fractional anisotropy as an index of myelin integrity. In addition, the use of diffusion tensor imaging acquisition methods limited our ability to study other brain regions that may be involved in schizophrenia. Conclusion: Our results suggest that NRG1 variation may play a role in the pathophysiology of anterior cingulum abnormalities in patients with schizophrenia. Contexte: La neuroreguline-1 (NRG1) influe sur le developpement de la connectivite de la substance blanche et participe a la predisposition genetique a la schizophrenie. Le faisceau cingulaire est une structure de la substance blanche qui intervient dans la schizophrenie. Sa partie anterieure est particulierement en cause, puisqu&apos;elle assure les connexions reciproques entre les principales regions du cerveau qui jouent un role dans la maladie. Des rapports ont deja fait mention d&apos;anomalies de l&apos;integrite structurale du cingulum anterieur chez des patients schizophrenes. La presente etude a analyse la contribution potentielle des fluctuations de NRG1 dans les anomalies affectant le cingulum anterieur chez les participants atteints de schizophrenie. Methodes: Nous avons etudie 31 hommes atteints de schizophrenie et 36 hommes en bonne sante au moyen de techniques d&apos;imagerie par tenseur de diffusion afin d&apos;explorer le lien entre l&apos;anisotropie fractionnelle au niveau du cingulum anterieur et un polymorphisme de nucleotides simples (PNS8NRG221533: rs35753505) de la NRG1. Resultats: Conformement a des rapports anterieurs, l&apos;anisotropie fractionnelle s&apos;est revelee significativement moindre dans le cingulum anterieur du groupe atteint de schizophrenie. De plus, les resultats ont revele une interaction significative selon le groupe (schizophrenes c. temoins) en fonction du genotype (porteurs des alleles C/C et T, y compris CT et TT) entre la variation genetique de la NRG1 et le diagnostic de schizophrenie, de sorte que les patients porteurs de l&apos;allele T pour le PNS8NRG221533 presentaient une anisotropie fractionnelle significativement diminuee au niveau du cingulum anterieur, comparativement aux patients homozygotes pour l&apos;allele C et aux temoins en bonne sante porteurs de l&apos;allele T. Limites: Les limites de notre etude comprennent la petite taille de l&apos;echantillon du sous-groupe TT et l&apos;utilisation de l&apos;anisotropie fractionnelle comme seul indice de l&apos;integrite de la myeline. De plus, l&apos;utilisation de methodes d&apos;acquisition d&apos;image par tenseur de diffusion a limite notre capacite d&apos;analyser d&apos;autres regions cerebrales potentiellement en cause dans la schizophrenie. Conclusion: Selon nos resultats, les fluctuations de NRG1 pourraient jouer un role dans la physiopathologie des anomalies du cingulum anterieur observees chez les patients schizophrenes., Introduction Convergent findings implicate genes involved in white matter development in the pathophysiology of schizophrenia. (1-5) Neuregulin 1 (NRG1) has recently been shown to play a role in the development [...]

Glucagon is secreted from the [alpha]-cells of the pancreatic islets and regulates glucose homeostasis through modulation of hepatic glucose production. As elevated glucagon levels contribute to the pathophysiology of hyperglycemia in subjects with type 2 diabetes, reduction of glucagon receptor gene (Gcgr) activity represents a potential target for the treatment of T2DM. Herein, we review current concepts of glucagon action in hepatic and extrahepatic tissues and evaluate the therapeutic potential, mechanisms of action, and safety of reducing Gcgr signaling for the treatment of T2DM.

Endothelial cells (ECs) from different vascular beds display a remarkable heterogeneity in both structure and function. Phenotypic heterogeneity among arterial ECs is particularly relevant to atherosclerosis since the disease occurs predominantly in major arteries, which vary in their atherosusceptibility. To explore EC heterogeneity between typical atheroprone and atheroresistant arteries, we used DNA microarrays to compare gene expression profiles of freshly harvested porcine coronary (CECs) and iliac artery (IECs) ECs. Statistical analysis revealed 51 genes that were differentially expressed in CECs relative to IECs at a false discovery rate of 5%. Seventeen of these genes are known to be involved in atherogenesis. Consistent with coronary arteries being more atherosusceptible, almost all putative atherogenic genes were overexpressed in CECs, whereas all atheroprotective genes were downregulated, relative to IECs. A subset of the identified genes was validated by quantitative polymerase chain reaction (PCR). PCR results suggest that the differences in expression levels between CECs and IECs for the HOXA10 and HOXA9 genes were > 100-fold. Gene ontology (GO) and biological pathway analysis revealed a global expression difference between CECs and IECs. Genes in twelve GO categories, including complement immune activation, immunoglobulin-mediated response, and system development, were significantly upregulated in CECs. CECs also overexpressed genes involved in several inflammatory pathways, including the classical pathway of complement activation and the IGF-1-mediated pathway. The in vivo transcriptional differences between CECs and IECs found in this study may provide new insights into the factors responsible for coronary artery atherosusceptibility. vascular endothelium; atherosclerosis; pathophysiology; genomics

Atherosclerotic plaques can lead to partial vascular occlusions that produce abnormally high levels of arterial wall shear stress. Such pathophysiological shear stress can promote shear-induced platelet aggregation (SIPA), which has been linked to acute myocardial infarction, unstable angina, and stroke. This study investigated the role of the tyrosine kinase Syk in shear-induced human platelet signaling. The extent of Syk tyrosine phosphorylation induced by pathophysiological levels of shear stress (100 dyn/[cm.sup.2]) was significantly greater than that resulting from physiological shear stress (10 dyn/[cm.sup.2]). With the use of phospho-Syk specific antibodies, these data are the first to show that key regulatory sites of Syk at tyrosines 525/526 (Y525/526) and tyrosine 352 (Y352) were phosphorylated in response to pathophysiological shear stress. Increased phosphorylation at both sites was attenuated by pharmacological inhibition of Syk using two different Syk inhibitors, piceatannol and 3-(1-methyl-1H-indol-3-yl-methylene)-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide (OXSI-2), and by inhibition of upstream Src-family kinases (SFKs). Shear-induced response at the Syk 525/ 526 site was ADP dependent but not contingent on glycoprotein (GP) IIb-IIIa ligation or the generation of thromboxane (Tx) [A.sub.2]. Pretreatment with Syk inhibitors not only reduced SIPA and Syk phosphorylation in isolated platelets, but also diminished, up to 50%, the platelet-mediated thrombus formation when whole blood was perfused over type-III collagen. In summary, this study demonstrated that Syk is a key molecule in both SIPA and thrombus formation under flow. Pharmacological regulation of Syk may prove efficacious in treating occlusive vascular disease. GPIb; GPIIb-IIIa; signal transduction; thrombosis; collagen

A number of pathophysiological insults lead to accumulation of unfolded proteins in the endoplasmic reticulum (ER) and cause ER stress. In response to accumulation of unfolded/misfolded proteins, cells adapt themselves to the stress condition via the unfolded protein response (UPR). For the cells, UPR is a double-edged sword. It triggers both prosurvival and proapoptotic signals. ER stress and UPR may, theretbre, be involved in a diverse range of pathological situations. However, currently, information is limited regarding roles of ER stress and UPR in the renal pathophysiology. This review describes current knowledge on the relationship between ER stress and diseases and summarizes evidence for the link between ER stress/UPR and renal diseases. apoptosis; homeostasis

Recurrent and intermittent nocturnal hypoxia is characteristic of several diseases including chronic obstructive pulmonary disease, congestive heart failure, obesity-hypoventilation syndrome, and obstructive sleep apnea. The contribution of hypoxia to cardiovascular morbidity and mortality in these disease states is unclear, however. To investigate the impact of recurrent nocturnal hypoxia on hemodynamics, sympathetic activity, and vascular tone we evaluated 10 normal volunteers before and after 14 nights of nocturnal sustained hypoxia (mean oxygen saturation 84.2%, 9 h/night). Over the exposure, subjects exhibited ventilatory acclimatization to hypoxia as evidenced by an increase in resting ventilation (arterial [Pco.sub.2] 41.8 [+ or -] 1.5 vs. 37.5 [+ or -] 1.3 mmHg, mean [+ or -] SD; P < 0.05) and in the isocapnic hypoxic ventilatory response (slope 0.49 [+ or -] 0.1 vs. 1.32 [+ or -] 0.2 1/min per 1% fall in saturation; P < 0.05). Subjects exhibited a significant increase in mean arterial pressure (86.7 [+ or -] 6.1 vs. 90.5 [+ or -] 7.6 mmHg; P < 0.001), muscle sympathetic nerve activity (20.8 [+ or -] 2.8 vs. 28.2 [+ or -] 3.3 bursts/min; P < 0.01), and forearm vascular resistance (39.6 [+ or -] 3.5 vs. 47.5 [+ or -] 4.8 mmHg*[ml.sup.1] * 100 g tissue*min; P < 0.05). Forearm blood flow during acute isocapnic hypoxia was increased after exposure but during selective brachial intra-arterial vascular infusion of the alpha-blocker phentolamine it was unchanged after exposure. Finally, there was a decrease in reactive hyperemia to 15 min of forearm ischemia after the hypoxic exposure. Recurrent nocturnal hypoxia thus increases sympathetic activity and alters peripheral vascular tone. These changes may contribute to the increased cardiovascular and cerebrovascular risk associated with clinical diseases that are associated with chronic recurrent hypoxia. acclimatization; vascular resistance; pathophysiology; chronic obstructive pulmonary disease

Deficits in cholinergic function have been postulated to cause delirium and cognitive decline. This review examines current understanding of the cholinergic deficiency hypothesis in delirium by synthesizing evidence on potential pathophysiological pathways. Acetylcholine synthesis involves various precursors, enzymes, and receptors, and dysfunction in these components can lead to delirium. Insults to the brain, like ischemia and immunological stressors, can precipitously alter acetylcholine levels. Imbalances between cholinergic and other neurotransmitter pathways may result in delirium. Furthermore, genetic, enzymatic, and immunological overlaps exist between delirium and dementia related to the cholinergic pathway. Important areas for future research include identifying biomarkers, determining genetic contributions, and evaluating response to cholinergic drugs in delirium. Understanding how the cholinergic pathway relates to delirium may yield innovative approaches in the diagnosis, prevention, and treatment of this common, costly, and morbid condition. Key Words: Acetylcholine--Delirium--Delirium in older persons--Dementia--Cholinergic deficiency.

Mast cells are thought to participate in a wide variety of pathophysiological conditions. Mechanisms of regulation, however, of mast cell production and maturation are still to be elucidated. Mast cell developmental process is likely to be profoundly affected by cell-autonomous transcriptional regulators such as the GATA family and CCAAT/enhancer binding protein (C/EBP) family members. Extracellular regulators such as stem cell factor and IL-3 have essential roles in basal and inducible mast cell generation, respectively. The relationship, however, between the extracellular signaling and cellular transcriptional control is unclear, and the trigger of the mast cell development remains elusive. Notch signaling plays a fundamental role in the lymphopoietic compartment, but its role in myeloid differentiation is less clear. Here, we demonstrate that Notch signaling connects environmental cues and transcriptional control for mast cell fate decision. Delta1, an established Notch ligand, instructs bone marrow common myeloid progenitors and granulocyte-macrophage progenitors toward mast cell lineage at the expense of other granulocyte-macrophage lineages, depending on the function of the Notch2 gene. Notch2 signaling results in the up-regulation of Hes-1 and GATA3, whereas simultaneous overexpression of these transcription factors remarkably biases the progenitor fate toward the mast cell-containing colony-forming cells. C/EBP[alpha] mRNA was down-regulated in myeloid progenitors as a consequence of Hes-1 overexpression, in agreement with the recent proposal that the down-regulation of C/EBP[alpha] is necessary for mast cell fate determination. Taken together, signaling through Notch2 determines the fate of myeloid progenitors toward mast cell-producing progenitors, via coordinately up-regulating Hes-1 and GATA3. CCAAT/enhancer binding protein [alpha] | GATA3 | Hes-1 | Delta1 | myeloid progenitor

The molecular pathogenesis of cystic fibrosis (CF) liver disease is unknown. This study investigates its earliest pathophysiological manifestations employing a mouse model carrying [DELTA]F508, the commonest human CF mutation. We hypothesized that, if increased bile salt spillage into the colon occurs as in the human disease, then this should lead to a hydrophobic bile salt profile and to 'hyperbilirubinbilia' because of induced enterohepatic cycling of unconjugated bilirubin. Hyperbilirubinbilia may then lead to an increased bile salt-to-phospholipid ratio in bile and, following hydrolysis, precipitation of divalent metal salts of unconjugated bilirubin. We document in CF mice elevated fecal bile acid excretion and biliary secretion of more hydrophobic bile salts compared with control wild-type mice. Biliary secretion rates of bilirubin monoglucuronosides, bile salts, phospholipids, and cholesterol are increased significantly with an augmented bile salt-tophospholipid ratio. Quantitative histopathology of CF livers displays mild early cholangiopathy in [approximately equal to] 53% of mice and multifocal divalent metal salt deposition in cholangiocytes. We conclude that increased fecal bile acid loss leads to more hydrophobic bile salts in hepatic bile and to hyperbilirubinbilia, a major contributor in augmenting the bile salt-to-phospholipid ratio and endogenous [beta]-glucuronidase hydrolysis of bilirubin glucuronosides. The confluence of these perturbations damages intrahepatic bile ducts and facilitates entrance of unconjugated bilirubin into cholangiocytes. This study of the earliest stages of CF liver disease provides a framework for investigating the molecular pathophysiology of more advanced disease in murine models and in humans with CF. cystic fibrosis transmembrane conductance regulator; gallstones; enterohepatic cycling; bilirubin; metal salts

Rats of the JCR: LA-cp strain, which are homozygous for the cp gene (cp/cp), are obese, insulin-resistant, and hyperinsulinemic. They exhibit associated micro- and macrovascular disease and end-stage ischemic myocardial lesions and are highly stress sensitive. We subjected male cp/cp rats to pair feeding (providing the rats each day with the amount of food eaten by matched freely fed animals), a procedure that alters the diurnal feeding pattern, leading to a state of intermittent caloric restriction. Effects on insulin, glucose, and lipid metabolism, response to restraint stress, aortic contractile/relaxant response, and myocardial lesion frequency were investigated. Pair-fed young (12-wk-old) cp/cp rats had lower insulin and glucose levels (basal and following restraint), consistent with increased insulin sensitivity, but a greater increase in plasma nonesterified fatty acids in response to restraint. These effects were unrelated to lipolytic rates in adipose tissue but may be related to reduced fatty acid oxidation in skeletal muscle. Older (24-wk-old) pair-fed cp/cp rats had significantly reduced plasma triglyceride levels, improved micro- and macrovascular function, and reduced severity of ischemic myocardial lesions. These changes indicate a significant amelioration of end-stage disease processes in this animal model and the complexity of metabolic/physiological responses in studies involving alterations in food intake. The effects illustrate the sensitivity of the JCR:LA-cp rat, an animal model for the metabolic syndrome and associated cardiovascular disease, to the environmental and experimental milieu. Similar stress-related mechanisms may play a role in metabolically induced cardiovascular disease in susceptible human beings. metabolic syndrome; stress; fatty acids; vascular function; myocardial lesions doi: 10.1152/ajpendo.90257.2008.

Although deficiencies in the retromer sorting pathway have been linked to late-onset Alzheimer's disease, whether these deficiencies underlie the disease remains unknown. Here we characterized two genetically modified animal models to test separate but related questions about the effects that retromer deficiency has on the brain. First, testing for cognitive defects, we investigated retromer-deficient mice and found that they develop hippocampal-dependent memory and synaptic dysfunction, which was associated with elevations in endogenous A[beta] peptide. Second, testing for neurodegeneration and amyloid deposits, we investigated retromer-deficient flies expressing human wild-type amyloid precursor protein (APP) and human [beta]-site APP-cleaving enzyme (BACE) and found that they develop neuronal loss and human A[beta] aggregates. By recapitulating features of the disease, these animal models suggest that retromer deficiency observed in late-onset Alzheimer's disease can contribute to disease pathogenesis. flies | mice | pathophysiology

Primary cilia are ubiquitous cellular appendages that provide important yet not well understood sensory and signaling functions. Ciliary dysfunction underlies numerous human genetic disorders. However, the precise defects in cilia function and the basis of disease pathophysiology remain unclear. Here, we report that the proteins disrupted in the human ciliary disorder Bardet-Biedl syndrome (BBS) are required for the localization of G protein-coupled receptors to primary cilia on central neurons. We demonstrate a lack of ciliary localization of somatostatin receptor type 3 (Sstr3) and melanin-concentrating hormone receptor 1 (Mchr1) in neurons from mice lacking the Bbs2 or Bbs4 gene. Because Mchr1 is involved in the regulation of feeding behavior and BBS is associated with hyperphagia-induced obesity, our results suggest that altered signaling caused by mislocalization of ciliary signaling proteins underlies the BBS phenotypes. Our results also provide a potential molecular mechanism to link cilia defects with obesity. melanin-concentrating hormone receptor | neuronal cilia | obesity | somatostatin receptor 3 | type III adenylyl cyclase

In transmissible spongiform encephalopathies, the infectious material consists chiefly of a protein, the scrapie prion protein [PrP.sup.Sc], that carries no genetic coding material; however, prions are likely to have accomplices that chaperone their activity and promote the conversion of the cellular prion protein [PrP.sup.c] into the disease-causing isoform ([PrP.sup.Sc]). Recent studies from several laboratories indicate that [PrP.sup.C] recognizes many nucleic acids (NAs) with high affinities, and we correlate these findings with a possible pathophysiological role for this interaction. Thus, of the chaperones, NA is the most likely candidate for prions. The participation of NAs in prion propagation opens new avenues for developing new diagnostic tools and therapeutics to target prion diseases, as well as for understanding the function of [PrP.sup.C], probably as a NA chaperone.

TAZ (transcriptional coactivator with PDZ-binding motif), also called WWTRI (WW domain containing transcription regulator 1). is a 14-3-3-binding molecule homologous to Yes-associated protein. TAZ acts as a coactivator for several transcription factors as well as a modulator of membrane-associated PDZ domain-containing proteins, but its (patho)physiological roles remain unknown. Here we show that gene inactivation of TAZ in mice resulted in pathological changes in the kidney and lung that resemble the common human diseases polycystic kidney disease and pulmonary emphysema. Taz.-null/lacZ knockin mutant homozygotes demonstrated renal cyst formation as early as embryonic day 15.5 with dilatation of Bowman's capsules and proximal tubules, followed by pelvic dilatation and hydronephrosis. After birth, only one-fifth of TAZ-deficient homozygotes grew to adulthood and demonstrated multicystic kidneys with severe urinary concentrating dejects and polyuria. Furthermore, adult TAZ-deficient homozygotes exhibited diffuse emphysematous changes in the lung. Thus TAZ is essential for developmental mechanisms involved in kidney and lung organogenesis, whose disturbance may lead to the pathogenesis of common human diseases. renal disease: knockout mice; transcription factor

Calcineurin activation ameliorates the dystrophic pathology of hindlimb muscles in mdx mice and decreases their susceptibility to contraction damage. In mdx mice, the diaphragm is more severely affected than hindlimb muscles and more representative of Duchenne muscular dystrophy. The constitutively active calcineurin A[alpha] transgene (CnA[alpha]) was overexpressed in skeletal muscles of mdx (mdx can[[alpha].sup.*]) mice to test whether muscle morphology and function would be improved. Contractile function of diaphragm strips and extensor digitorum longus and soleus muscles from adult mdx CnA[[alpha].sup.*] and mdx mice was examined in vitro. Hindlimb muscles from mdx CnA[[alpha].sup.*] mice had a prolonged twitch time course and were more resistant to fatigue. Because of a slower phenotype and a decrease in fiber cross-sectional area, normalized force was lower in fast- and slow-twitch muscles of mdx CnA[[alpha].sup.*] than mdx mice. In the diaphragm, despite a slower phenotype and a ~35% reduction in fiber size, normalized force was preserved. This was likely mediated by the reduction in the area of the diaphragm undergoing degeneration (i.e., mononuclear cell and connective and adipose tissue infiltration). The proportion of centrally nucleated fibers was reduced in mdx CnA[[alpha].sup.*] compared with mdx mice, indicative of improved myofiber viability. In hindlimb muscles of mdx mice, calcineurin activation increased expression of markers of regeneration, particularly developmental myosin heavy chain isoform and myocyte enhancer factor 2A. Thus activation of the calcineurin signal transduction pathway has potential to ameliorate the mdx pathophysiology, especially in the diaphragm, through its effects on muscle degeneration and regeneration and endurance capacity. muscle regeneration; muscular dystrophy; skeletal muscle; muscle contraction

Objective: Converging evidence suggests that the subgenual cingulate (SGC) is implicated in regulation of mood and in the pathophysiology of mood disorders. Our objective was to carry out the first [...]

Hepatic fibrosis is the response of the liver to chronic injury and is associated with portal hypertension, progression to hepatic cirrhosis, liver failure, and high incidence of hepatocellular carcinoma. On a molecular level, a large number of signaling pathways have been shown to contribute to the activation of fibrogenic cell types and the subsequent accumulation of extracellular matrix in the liver. Recent evidence suggests that the endocannabinoid system is an important part of this complex signaling network. In the injured liver, the endocannabinoid system is upregulated both at the level of endocannabinoids and at the endocannabinoid receptors CB1 and CB2. The hepatic endocannabinoid system mediates both pro- and antifibrogenic effects by activating distinct signaling pathways that differentially affect proliferation and death of fibrogenic cell types. Here we will summarize current findings on the role of the hepatic endocannabinoid system in liver fibrosis and discuss emerging options for its therapeutic exploitation. hepatic stellate cell; cell death; anandamide; 2-arachidonoyl glycerol

Insulin resistance contributes to the pathophysiology of diabetes, obesity, and their cardiovascular complications. Mouse models of these human diseases are useful for gaining insight into pathophysiological mechanisms. The reference standard for measuring insulin sensitivity in both humans and animals is the euglycemic glucose clamp. Many studies have compared surrogate indexes of insulin sensitivity and resistance with glucose clamp estimates in humans. However, regulation of metabolic physiology in humans and rodents differs and comparisons between surrogate indexes and the glucose clamp have not been directly evaluated in rodents previously. Therefore, in the present study, we compared glucose clamp-derived measures of insulin sensitivity (GIR and S[I.sub.Clamp]) with surrogate indexes, including quantitative insulin-sensitivity check index (QUICKI), homeostasis model assessment (HOMA), 1/HOMA, log(HOMA), and 1/fasting insulin, using data from 87 mice with a wide range of insulin sensitivities. We evaluated simple linear correlations and performed calibration model analyses to evaluate the predictive accuracy of each surrogate. All surrogate indexes tested were modestly correlated with both GIR and S[I.sub.Clamp]. However, a stronger correlation between body weight per se and both GIR and S[I.sub.Clamp] was noted. Calibration analyses of surrogate indexes adjusted for body weight demonstrated improved predictive accuracy for GIR [e.g., R = 0.68, for QUICKI and log(HOMA)]. We conclude that linear correlations of surrogate indexes with clamp data and predictive accuracy of surrogate indexes in mice are not as substantial as in humans. This may reflect intrinsic differences between human and rodent physiology as well as increased technical difficulties in performing glucose clamps in mice. calibration model; quantitative insulin-sensitivity check index

Objective: The PDLIM5gene is known to interact specifically with the N-type calcium channel [alpha]-1B subunit and protein kinase C[epsilon] and is critical for rapid, efficient potentiation of the calcium channel [...]

Chemokines and chemokine receptors are widely expressed by cells of the immune and nervous systems. This review focuses on our current knowledge concerning the role of chemokines in the pathophysiology of chronic pain syndromes. Injury- or disease-induced changes in the expression of diverse chemokines and their receptors have been demonstrated in the neural and nonneural elements of pain pathways. Under these circumstances, chemokines have been shown to modulate the electrical activity of neurons by multiple regulatory pathways including increases in neurotransmitter release through Ca-dependent mechanisms and transactivation of transient receptor channels. Either of these mechanisms alone, or in combination, may contribute to sustained excitability of primary afferent and secondary neurons within spinal pain pathways. Another manner in which chemokines may influence sustained neuronal excitability may be their ability to function as excitatory neurotransmitters within the peripheral and central nervous system. As is the case for traditional neurotransmitters, injury-induced up-regulated chemokines are found within synaptic vesicles. Chemokines released after depolarization of the cell membrane can then act on other chemokine receptor-bearing neurons, glia, or immune cells. Because up-regulation of chemokines and their receptors may be one of the mechanisms that directly or indirectly contribute to the development and maintenance of chronic pain, these molecules may then represent novel targets for therapeutic intervention in chronic pain states.

Hemodynamics, muscle sympathetic nerve activity (MSNA), and forearm blood flow were evaluated in 12 normal subjects before, during (1 and 7 h), and after ventilatory acclimatization to hypoxia achieved with 8 h of continuous poikilocapnic hypoxia. All results are means [+ or -] SD. Subjects experienced mean oxygen saturation of 84.3 [+ or -] 2.3% during exposure. The exposure resulted in hypoxic acclimatization as suggested by end-tidal C[O.sub.2] [44.7 [+ or -] 2.7 (pre) vs. 39.5 [+ or -] 2.2 mmHg (post), P < 0.001] and by ventilatory response to hypoxia [1.2 [+ or -] 0.8 (pre) vs. 2.3 [+ or -] 1.3 1 x [min.sup.-1] x 1% fall in [saturation.sup.-1] (post), P < 0.05]. Subjects exhibited a significant increase in heart rate across the exposure that remained elevated even upon return to room air breathing compared with preexposure (67.3 [+ or -] 15.9 vs. 59.8 [+ or -] 12.1 beats/min, P < 0.008). Although arterial pressure exhibited a trend toward an increase across the exposure, this did not reach significance. MSNA initially increased from room air to poikilocapnic hypoxia (26.2 [+ or -] 10.3 to 32.0 [+ or -] 10.3 bursts/100 beats, not significant at 1 h of exposure); however, MSNA then decreased below the normoxic baseline despite continued poikilocapnic hypoxia (20.9 [+ or -] 8.0 bursts/100 beats, 7 h Hx vs. 1 h Hx; P < 0.008 at 7 h). MSNA decreased further after subjects returned to room air (16.6 [+ or -] 6.0 bursts/100 beats; P < 0.008 compared with baseline). Forearm conductance increased after exposure from 2.9 [+ or -] 1.5 to 4.3 [+ or -] 1.6 conductance units (P < 0.01). These findings indicate alterations of cardiovascular and respiratory control following 8 h of sustained hypoxia producing not only acclimatization but sympathoinhibition. chemosensitivity; vascular resistance; pathophysiology

Malaria has been a major selective force on the human population, and several erythrocyte polymorphisms have evolved that confer resistance to severe malaria. Plasmodium falciparum rosetting, a parasite virulence phenotype associated with severe malaria, is reduced in blood group O erythrocytes compared with groups A, B, and AB, but the contribution of the ABO blood group system to protection against severe malaria has received little attention. We hypothesized that blood group O may confer resistance to severe falciparum malaria through the mechanism of reduced rosetting. In a matched case-control study of 567 Malian children, we found that group O was present in only 21% of severe malaria cases compared with 44-45% of uncomplicated malaria controls and healthy controls. Group O was associated with a 66% reduction in the odds of developing severe malaria compared with the non-O blood groups (odds ratio 0.34, 95% confidence interval 0.19-0.61, P < 0.0005, severe cases versus uncomplicated malaria controls), in the same sample set, P. falciparum rosetting was reduced in parasite isolates from group O children compared with isolates from the non-O blood groups (P = 0.003, Kruskal-Wallis test). Statistical analysis indicated a significant interaction between host ABO blood group and parasite rosette frequency that supports the hypothesis that the protective effect of group O operates through the mechanism of reduced P, falciparum rosetting. This work provides insights into malaria pathogenesis and suggests that the selective pressure imposed by malaria may contribute to the variable global distribution of ABO blood groups in the human population. ABO | erythrocyte | pathogenesis | rosette formation | virulence

The correlation between the fibrillin-1 genotype and the nature and severity of the clinical phenotype is studied. It is concluded that the correlation found between different mutation types and clinical manifestations might indicate different underlying pathophysiologic mechanism, both genetic and functional.