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Find video protocols related to scientific articles indexed in Pubmed.
PCSK9 is a critical regulator of the innate immune response and septic shock outcome.
Sci Transl Med
PUBLISHED: 10-17-2014
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A decrease in the activity of proprotein convertase subtilisin/kexin type 9 (PCSK9) increases the amount of low-density lipoprotein (LDL) receptors on liver cells and, therefore, LDL clearance. The clearance of lipids from pathogens is related to endogenous lipid clearance; thus, PCSK9 may also regulate removal of pathogen lipids such as lipopolysaccharide (LPS). Compared to controls, Pcsk9 knockout mice displayed decreases in inflammatory cytokine production and in other physiological responses to LPS. In human liver cells, PCSK9 inhibited LPS uptake, a necessary step in systemic clearance and detoxification. Pharmacological inhibition of PCSK9 improved survival and inflammation in murine polymicrobial peritonitis. Human PCSK9 loss-of-function genetic variants were associated with improved survival in septic shock patients and a decrease in inflammatory cytokine response both in septic shock patients and in healthy volunteers after LPS administration. The PCSK9 effect was abrogated in LDL receptor (LDLR) knockout mice and in humans who are homozygous for an LDLR variant that is resistant to PCSK9. Together, our results show that reduced PCSK9 function is associated with increased pathogen lipid clearance via the LDLR, a decreased inflammatory response, and improved septic shock outcome.
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Preschool children's proto-episodic memory assessed by deferred imitation.
Memory
PUBLISHED: 10-14-2014
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In two experiments, both employing deferred imitation, we studied the developmental origins of episodic memory in two- to three-year-old children by adopting a "minimalist" view of episodic memory based on its What-When-Where ("WWW": spatiotemporal plus semantic) content. We argued that the temporal element within spatiotemporal should be the order/simultaneity of the event elements, but that it is not clear whether the spatial content should be egocentric or allocentric. We also argued that episodic recollection should be configural (tending towards all-or-nothing recall of the WWW elements). Our first deferred imitation experiment, using a two-dimensional (2D) display, produced superior-to-chance performance after 2.5 years but no evidence of configural memory. Moreover, performance did not differ from that on a What-What-What control task. Our second deferred imitation study required the children to reproduce actions on an object in a room, thereby affording layout-based spatial cues. In this case, not only was there superior-to-chance performance after 2.5 years but memory was also configural at both ages. We discuss the importance of allocentric spatial cues in episodic recall in early proto-episodic memory and reflect on the possible role of hippocampal development in this process.
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Diabetic neuropathies.
Continuum (Minneap Minn)
PUBLISHED: 10-10-2014
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This article provides an overview for understanding the diagnosis, pathogenesis, and management of diabetic neuropathy.
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Over-invasion by functionally equivalent invasive species.
Ecology
PUBLISHED: 09-19-2014
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Multiple invasive species have now established at most locations around the world, and the rate of new species invasions and records of new invasive species continue to grow. Multiple invasive species interact in complex and unpredictable ways, altering their invasion success and impacts on biodiversity. Incumbent invasive species can be replaced by functionally similar invading species through competitive processes; however the generalized circumstances leading to such competitive displacement have not been well investigated. The likelihood of competitive displacement is a function of the incumbent advantage of the resident invasive species and the propagule pressure of the colonizing invasive species. We modeled interactions between populations of two functionally similar invasive species and indicated the circumstances under which dominance can be through propagule pressure and incumbent advantage. Under certain circumstances, a normally subordinate species can be incumbent and reject a colonizing dominant species, or successfully colonize in competition with a dominant species during simultaneous invasion. Our theoretical results are supported by empirical studies of the invasion of islands by three invasive Rattus species. Competitive displacement is prominent in invasive rats and explains the replacement of R. exulans on islands subsequently invaded by European populations of R. rattus and R. norvegicus. These competition outcomes between invasive species can be found in a broad range of taxa and biomes, and are likely to become more common. Conservation management must consider that removing an incumbent invasive species may facilitate invasion by another invasive species. Under very restricted circumstances of dominant competitive ability but lesser impact, competitive displacement may provide a novel method of biological control.
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Identification of a Nonsynonymous Polymorphism in the SVEP1 Gene Associated With Altered Clinical Outcomes in Septic Shock.
Crit. Care Med.
PUBLISHED: 09-03-2014
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Mortality from septic shock is highly heritable. The identification of causal genetic factors is insufficient. To discover key contributors, we first identified nonsynonymous single-nucleotide polymorphisms in conserved genomic regions that are predicted to have significant effects on protein function. We then test the hypothesis that these nonsynonymous single-nucleotide polymorphisms across the genome alter clinical outcome of septic shock.
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A functional synonymous coding variant in the IL1RN gene is associated with survival in septic shock.
Am. J. Respir. Crit. Care Med.
PUBLISHED: 08-05-2014
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Death from infection is a highly heritable trait, yet there are few genetic variants with known mechanism influencing survival during septic shock.
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Long-term (10-year) mortality of younger previously healthy patients with severe sepsis/septic shock is worse than that of patients with nonseptic critical illness and of the general population.
Crit. Care Med.
PUBLISHED: 07-24-2014
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Long-term (1- to 10-year) outcomes after severe sepsis in previously healthy persons are unknown. We aimed to determine the 1- to 10-year mortality rates of previously healthy patients with severe sepsis and compare these to mortality rates of patients with nonseptic critical illness and the general population.
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Albumin administration in the acutely ill: what is new and where next?
Crit Care
PUBLISHED: 07-16-2014
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Albumin solutions have been used worldwide for the treatment of critically ill patients since they became commercially available in the 1940s. However, their use has become the subject of criticism and debate in more recent years. Importantly, all fluid solutions have potential benefits and drawbacks. Large multicenter randomized studies have provided valuable data regarding the safety of albumin solutions, and have begun to clarify which groups of patients are most likely to benefit from their use. However, many questions remain related to where exactly albumin fits within our fluid choices. Here, we briefly summarize some of the physiology and history of albumin use in intensive care before offering some evidence-based guidance for albumin use in critically ill patients.
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Legal and ethical implications in the evaluation and management of sports-related concussion.
Neurology
PUBLISHED: 07-09-2014
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To examine the ethical and legal issues physicians face when evaluating and managing athletes with sports-related concussions, and to offer guidance to physicians as they navigate these situations.
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Predictive performance of a physiologically based pharmacokinetic model of busulfan in children.
Pediatr Hematol Oncol
PUBLISHED: 07-09-2014
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A physiologically based pharmacokinetic (PBPK) model of the DNA-alkylating agent busulfan was slightly modified and scaled from adults to children in order to predict the systemic busulfan drug exposure in children. Capitalizing on the recent major software release of PK-Sim®, we refined our PBPK model by implementing glutathione S transferase (GST) in 11 organs using the software integrated enzyme expression database. In addition, two irreversible binding processes (i.e., DNA and plasma protein binding) were applied by using Koff and KD values. The model was scaled from adults to children. Simulations were computed and compared to concentration-time data after intravenous (i.v.) busulfan administration to 36 children. Based on the results, an age-dependent enzyme activity and maturation ratio was tailored and evaluated with an external dataset consisting of 23 children. Initial adult to children scaling indicated lower clearance values for children in comparison to adults. Subsequent age-dependent maturation ratio resulted in three different age groups: Activity of busulfan-glutathione conjugate formation was 80%, 61%, and 89% in comparison to adults for children with an age of up to 2 years, > 2-6 years, and > 6-18 years, respectively. Patients of the evaluation dataset were simulated with a mean percentage error (MPE) for all patients of 3.9% with 3/23 children demonstrating a MPE of > ±30%. The PBPK model parameterization sufficiently described the observed concentration-time data of the validation dataset while showing an adequate predictive performance. This PBPK model could be helpful to determine the first dose of busulfan in children.
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Brain diabetic neurodegeneration segregates with low intrinsic aerobic capacity.
Ann Clin Transl Neurol
PUBLISHED: 06-16-2014
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Diabetes leads to cognitive impairment and is associated with age-related neurodegenerative diseases including Alzheimer's disease (AD). Thus, understanding diabetes-induced alterations in brain function is important for developing early interventions for neurodegeneration. Low-capacity runner (LCR) rats are obese and manifest metabolic risk factors resembling human "impaired glucose tolerance" or metabolic syndrome. We examined hippocampal function in aged LCR rats compared to their high-capacity runner (HCR) rat counterparts.
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Serious adverse events associated with vasopressin and norepinephrine infusion in septic shock.
Crit. Care Med.
PUBLISHED: 06-12-2014
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The frequency, risk factors, and mortality rates of serious adverse events associated with the use of vasopressin and norepinephrine are not clear. The objectives of this study were to determine frequency, risk factors (including candidate gene polymorphisms), and outcomes of serious adverse events in septic shock patients.
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miR-21 normalizes vascular smooth muscle proliferation and improves coronary collateral growth in metabolic syndrome.
FASEB J.
PUBLISHED: 06-07-2014
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Inadequate cell proliferation is considered a major causative factor for impaired coronary collateral growth (CCG). Proangiogenic growth factors (GFs) stimulate cell proliferation, but their administration does not promote CCG in patients. These GFs are increased in patients with metabolic syndrome and in animal models, where CCG is impaired. Here, we investigated whether excessive cell proliferation underlies impaired CCG in metabolic syndrome. Normal [Sprague-Dawley (SD)] and metabolic syndrome [James C. Russell (JCR)] rats underwent repetitive ischemia (RI; transient, repetitive coronary artery occlusion and myocardial ischemia). We have shown that CCG was maximal at d 9 of RI in SD rats but did not occur in JCR rats. The increase in cell proliferation (PCNA, Ki-67, cyclin A, phospho- cdc2, p21Waf, p27Kip) was transient (?4-fold, d 3 RI) in SD rats but greater and sustained in JCR rats (?8- to 6-fold, d 3-9 RI). In JCR rats, this was associated with increased and sustained miR-21 expression and accumulation of proliferating synthetic vascular smooth muscle cells in the lumen of small arterioles, which failed to undergo outward expansion. Administration of anti-miR-21 blocked RI-induced cell proliferation and significantly improved CCG in JCR rats (?60%). miR-21-dependent excessive cell proliferation in the later stages of collateral remodeling correlates with impaired CCG in metabolic syndrome.-Hutcheson, R., Chaplin, J., Hutcheson, B., Borthwick, F., Proctor, S., Gebb, S., Jadhav, R., Smith, E., Russell, J. C., Rocic, P. miR-21 normalizes vascular smooth muscle proliferation and improves coronary collateral growth in metabolic syndrome.
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A double-blind, placebo-controlled study of edivoxetine as an adjunctive treatment for patients with major depressive disorder who are partial responders to selective serotonin reuptake inhibitor treatment.
J Affect Disord
PUBLISHED: 06-06-2014
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This phase 2 study examined the efficacy and tolerability of edivoxetine, a highly selective norepinephrine reuptake inhibitor, as an adjunctive treatment for patients with major depressive disorder (MDD) who have a partial response to selective serotonin reuptake inhibitor (SSRI) treatment.
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Interrelationship of CB1R and OBR pathways in regulation of metabolic, neuroendocrine, and behavioral responses to food restriction and voluntary wheel running.
J. Appl. Physiol.
PUBLISHED: 06-05-2014
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We hypothesized the cannabinoid-1 receptor and leptin receptor (ObR) operate synergistically to modulate metabolic, neuroendocrine, and behavioral responses of animals exposed to a survival challenge (food restriction and wheel running). Obese-prone (OP) JCR:LA-cp rats, lacking functional ObR, and lean-prone (LP) JCR:LA-cp rats (intact ObR) were assigned to OP-C and LP-C (control) or CBR1-antagonized (SR141716, 10 mg/kg body wt in food) OP-A and LP-A groups. After 32 days, all rats were exposed to 1.5-h daily meals without the drug and 22.5-h voluntary wheel running, a survival challenge that normally culminates in activity-based anorexia (ABA). Rats were removed from the ABA protocol when body weight reached 75% of entry weight (starvation criterion) or after 14 days (survival criterion). LP-A rats starved faster (6.44 ± 0.24 days) than LP-C animals (8.00 ± 0.29 days); all OP rats survived the ABA challenge. LP-A rats lost weight faster than animals in all other groups (P < 0.001). Consistent with the starvation results, LP-A rats increased the rate of wheel running more rapidly than LP-C rats (P = 0.001), with no difference in hypothalamic and primary neural reward serotonin levels. In contrast, OP-A rats showed suppression of wheel running compared with the OP-C group (days 6-14 of ABA challenge, P < 0.001) and decreased hypothalamic and neural reward serotonin levels (P < 0.01). Thus there is an interrelationship between cannabinoid-1 receptor and ObR pathways in regulation of energy balance and physical activity. Effective clinical measures to prevent and treat a variety of disorders will require understanding of the mechanisms underlying these effects.
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Dynamic facial expressions allow differentiation of displays intended to convey positive and hubristic pride.
Emotion
PUBLISHED: 05-26-2014
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Prior research has identified a facial expression for positive pride, but no expression for negative pride, hubris. In the present study, professional actors created expressions intended to convey hubris. In Study 1 (N = 52), participants were shown dynamic expressions and attributed confidence, positive valence, and positive personality traits to the positive pride expression, but conceit, neutral valence, and negative personality traits to the hubris expression. In Study 2 (N = 60), participants were more likely to attribute conceit to a dynamic hubris expression than a static one; no such difference was found for positive pride.
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Patient delay in cancer diagnosis: what do we really mean and can we be more specific?
BMC Health Serv Res
PUBLISHED: 05-16-2014
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Early diagnosis is a key focus of cancer control because of its association with survival. Delays in diagnosis can occur throughout the diagnostic pathway, within any one of its three component intervals: the patient interval, the primary care interval and the secondary care interval.
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High serum level of antithymocyte globulin immediately before graft infusion is associated with a low likelihood of chronic, but not acute, graft-versus-host disease.
Biol. Blood Marrow Transplant.
PUBLISHED: 04-07-2014
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Rabbit antithymocyte globulin (ATG) is administered during transplant conditioning to decrease the risk of both acute graft-versus-host disease (aGVHD) and chronic graft-versus-host disease (cGVHD). Here we evaluated the relationship between the serum concentration of ATG (capable of binding to lymphocytes) immediately before graft infusion (day 0) or on day +7 or +28 post-transplantation and the development of aGVHD or cGVHD. We studied 180 patients whose conditioning included 4.5 mg/kg antithymocyte globulin (ATG; Thymoglobulin). For aGVHD, we found no association with ATG levels on day 0. Nevertheless, high day +7 and +28 ATG levels were associated with a low likelihood of aGVHD. For cGVHD, high ATG levels at all 3 time points (days 0, +7, and +28) were associated with a low likelihood of cGVHD. In conclusion, high-dose ATG administration at the time of graft infusion appears to inhibit the development of cGVHD, but not aGVHD; however, higher ATG levels on days +7 and +28 are associated with lower rates of both aGVHD and cGVHD.
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Glacial forcing of central Indonesian hydroclimate since 60,000 y B.P.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 03-24-2014
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The Indo-Pacific warm pool houses the largest zone of deep atmospheric convection on Earth and plays a critical role in global climate variations. Despite the region's importance, changes in Indo-Pacific hydroclimate on orbital timescales remain poorly constrained. Here we present high-resolution geochemical records of surface runoff and vegetation from sediment cores from Lake Towuti, on the island of Sulawesi in central Indonesia, that continuously span the past 60,000 y. We show that wet conditions and rainforest ecosystems on Sulawesi present during marine isotope stage 3 (MIS3) and the Holocene were interrupted by severe drying between ?33,000 and 16,000 y B.P. when Northern Hemisphere ice sheets expanded and global temperatures cooled. Our record reveals little direct influence of precessional orbital forcing on regional climate, and the similarity between MIS3 and Holocene climates observed in Lake Towuti suggests that exposure of the Sunda Shelf has a weaker influence on regional hydroclimate and terrestrial ecosystems than suggested previously. We infer that hydrological variability in this part of Indonesia varies strongly in response to high-latitude climate forcing, likely through reorganizations of the monsoons and the position of the intertropical convergence zone. These findings suggest an important role for the tropical western Pacific in amplifying glacial-interglacial climate variability.
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Proficiency of nerve conduction using standard methods and reference values (cl. NPhys Trial 4).
Muscle Nerve
PUBLISHED: 03-16-2014
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The Cl. NPhys Trial 3 showed that attributes of nerve conduction (NC) were without significant intraobserver differences, although there were significant interobserver differences.
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Small acute increases in serum creatinine are associated with decreased long-term survival in the critically ill.
Am. J. Respir. Crit. Care Med.
PUBLISHED: 03-08-2014
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Long-term outcomes after acute kidney injury (AKI) are poorly described.
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Potential roles of PINK1 for increased PGC-1?-mediated mitochondrial fatty acid oxidation and their associations with Alzheimer disease and diabetes.
Mitochondrion
PUBLISHED: 02-18-2014
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Down-regulation of PINK1 and PGC-1? proteins is implicated in both mitochondrial dysfunction and oxidative stress potentially linking metabolic abnormality and neurodegeneration. Here, we report that PGC-1? and PINK1 expression is markedly decreased in Alzheimer disease (AD) and diabetic brains. We observed a significant down-regulation of PGC-1? and PINK1 protein expression in H2O2-treated cells but not in those cells treated with N-acetyl cysteine. The protein levels of two key enzymes of the mitochondrial ?-oxidation machinery, acyl-coenzyme A dehydrogenase, very long chain (ACADVL) and mitochondrial trifunctional enzyme subunit ? are significantly decreased in AD and diabetic brains. Moreover, we observed a positive relationship between ACADVL and 64kDa PINK1 protein levels in AD and diabetic brains. Overexpression of PGC-1? decreases lipid-droplet accumulation and increases mitochondrial fatty acid oxidation; down-regulation of PINK1 abolishes these effects. Together, these results provide new insights into potential cooperative roles of PINK1 and PGC-1? in mitochondrial fatty acid oxidation, suggesting possible regulatory roles for mitochondrial function in the pathogenesis of AD and diabetes.
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Prolonged QTc affects short-term and long-term outcomes in patients with normal left ventricular function undergoing cardiac surgery.
J. Thorac. Cardiovasc. Surg.
PUBLISHED: 02-04-2014
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Although it is known that preoperative decreased left ventricular ejection fraction (LVEF) is a risk for morbidity and mortality after cardiac surgery, there are no reliable markers of risk in patients with preserved LVEF. This study examines whether a prolonged QTc interval is associated with adverse outcomes in patients with preoperative LVEF greater than 40% undergoing cardiac surgery.
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Can thoracic impedance monitor the depth of chest compressions during out-of-hospital cardiopulmonary resuscitation?
Resuscitation
PUBLISHED: 01-23-2014
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To analyze the relationship between the depth of the chest compressions and the fluctuation caused in the thoracic impedance (TI) signal in out-of-hospital cardiac arrest (OHCA). The ultimate goal was to evaluate whether it is possible to identify compressions with inadequate depth using information of the TI waveform.
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The meta-genome of sepsis: host genetics, pathogens and the acute immune response.
J Innate Immun
PUBLISHED: 01-16-2014
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Severe infection and the patient response constitute sepsis. Here, we review the meta-genome (patient genetics, pathogen communities and host response) and its impact upon the outcome of severe sepsis. Patient genetics, both predisposition for infection and the subsequent response to infection are reviewed. The pathogen is discussed with particular emphasis upon the modern era of microbiome analysis and nucleic acid diagnostics. Finally, we discuss the host clinical and immune responses and present new data to suggest that the immune response is the key to understanding sepsis and improving a death rate of nearly 30%.
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Climate change, sea-level rise, and conservation: keeping island biodiversity afloat.
Trends Ecol. Evol. (Amst.)
PUBLISHED: 01-06-2014
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Island conservation programs have been spectacularly successful over the past five decades, yet they generally do not account for impacts of climate change. Here, we argue that the full spectrum of climate change, especially sea-level rise and loss of suitable climatic conditions, should be rapidly integrated into island biodiversity research and management.
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PGC-1? regulation of mitochondrial degeneration in experimental diabetic neuropathy.
Neurobiol. Dis.
PUBLISHED: 01-02-2014
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Mitochondrial degeneration is considered to play an important role in the development of diabetic peripheral neuropathy in humans. Mitochondrial degeneration and the corresponding protein regulation associated with the degeneration were studied in an animal model of diabetic neuropathy. PGC-1? and its-regulated transcription factors including TFAM and NRF1, which are master regulators of mitochondrial biogenesis, are significantly downregulated in streptozotocin diabetic dorsal root ganglion (DRG) neurons. Diabetic mice develop peripheral neuropathy, loss of mitochondria, decreased mitochondrial DNA content and increased protein oxidation. Importantly, this phenotype is exacerbated in PGC-1? (-/-) diabetic mice, which develop a more severe neuropathy with reduced mitochondrial DNA and a further increase in protein oxidation. PGC-1? (-/-) diabetic mice develop an increase in total cholesterol and triglycerides, and a decrease in TFAM and NRF1 protein levels. Loss of PGC-1? causes severe mitochondrial degeneration with vacuolization in DRG neurons, coupled with reduced state 3 and 4 respiration, reduced expression of oxidative stress response genes and an increase in protein oxidation. In contrast, overexpression of PGC-1? in cultured adult mouse neurons prevents oxidative stress associated with increased glucose levels. The study provides new insights into the role of PGC-1? in mitochondrial regeneration in peripheral neurons and suggests that therapeutic modulation of PGC-1? function may be an attractive approach for treatment of diabetic neuropathy.
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Immune cell subset counts associated with graft-versus-host disease.
Biol. Blood Marrow Transplant.
PUBLISHED: 01-02-2014
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Graft-versus-host disease (GVHD) is a major transplantation complication. The purpose of this study was to measure immune cell subsets by flow cytometry early after transplantation (before median day of GVHD onset) to identify subsets that may play a role in GVHD pathogenesis. We also measured the subsets later after transplantation to determine which subsets may be influenced by GVHD or its treatment. We studied 219 patients. We found that acute GVHD (aGVHD) was preceded by high counts of CD4 T cells and CD8 T cells. It was followed by low counts of total and naive B cells, total and cytolytic NK cells, and myeloid and plasmacytoid dendritic cells. Chronic GVHD (cGVHD) was preceded by low counts of memory B cells. In conclusion, both CD4 and CD8 T cells appear to play a role in the pathogenesis of aGVHD. Generation of B cells, NK cells, and dendritic cells may be hampered by aGVHD and/or its treatment. Memory B cells may inhibit the development of cGVHD.
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Cooperative behavior of the nuclear receptor superfamily and its deregulation in prostate cancer.
Carcinogenesis
PUBLISHED: 10-08-2013
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The current study aimed to assess the topology of the nuclear receptor (NR) superfamily in normal prostate epithelial cells and its distortion in prostate cancer. Both in vitro and in silico approaches were utilized to profile NRs expressed in non-malignant RWPE-1 cells, which were subsequently investigated by treating cells with 132 binary NR ligand combinations. Nine significant cooperative interactions emerged including both superadditive [22(R)-hydroxycholesterol and eicosatetraenoic acid] and subadditive [1?,25(OH)2D3 and chenodeoxycholic acid] cellular responses, which could be explained in part by cooperative control of cell-cycle progression and candidate gene expression. In addition, publicly available data were employed to assess NR expression in human prostate tissue. Common and significant loss of NR superfamily expression was established in publicly available data from prostate tumors, in part predicting parallel distortion of targeting microRNA. These findings suggest that the NR superfamily in the prostate cooperatively integrates signals from dietary, hormonal and metabolic cues, and is significantly distorted in prostate cancer.
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Down-regulation of hypothalamic pro-opiomelanocortin (POMC) expression after weaning is associated with hyperphagia-induced obesity in JCR rats overexpressing neuropeptide Y.
Br. J. Nutr.
PUBLISHED: 10-07-2013
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We hypothesised that hypothalamic feeding-related neuropeptides are differentially expressed in obese-prone and lean-prone rats and trigger overeating-induced obesity. To test this hypothesis, in the present study, we measured energy balance and hypothalamic neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) mRNA expressions in male JCR:LA-cp rats. We compared, in independent cohorts, free-feeding obese-prone (Obese-FF) and lean-prone (Lean-FF) rats at pre-weaning (10 d old), weaning (21-25 d old) and early adulthood (8-12 weeks). A group of Obese-pair-feeding (PF) rats pair-fed to the Lean-FF rats was included in the adult cohort. The body weights of 10-d-old Obese-FF and Lean-FF pups were not significantly different. However, when the pups were shifted from dams milk to solid food (weaning), the obese-prone rats exhibited more energy intake over the days than the lean-prone rats and higher body and fat pad weights and fasting plasma glucose, leptin, insulin and lipid levels. These differences were consistent with higher energy consumption and lower energy expenditure. In the young adult cohort, the differences between the Obese-FF and Lean-FF rats became more pronounced, yielding significant age effects on most of the parameters of the metabolic syndrome, which were reduced in the Obese-PF rats. The obese-prone rats displayed higher NPY expression than the lean-prone rats at pre-weaning and weaning, and the expression levels did not differ by age. In contrast, POMC expression exhibited significant age-by-genotype differences. At pre-weaning, there was no genotype difference in POMC expression, but in the weanling cohort, obese-prone pups exhibited lower POMC expression than the lean-prone rats. This genotype difference became more pronounced at adulthood. Overall, the development of hyperphagia-induced obesity in obese-prone JCR rats is related to POMC expression down-regulation in the presence of established NPY overexpression.
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Distinct neural circuits subserve interpersonal and non-interpersonal emotions.
Soc Neurosci
PUBLISHED: 09-14-2013
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Emotions elicited by interpersonal versus non-interpersonal experiences have different effects on neurobiological functioning in both animals and humans. However, the extent to which the brain circuits underlying interpersonal and non-interpersonal emotions are distinct still remains unclear. The goal of our study was to assess whether different neural circuits are implicated in the processing of arousal and valence of interpersonal versus non-interpersonal emotions. During functional magnetic resonance imaging, participants imagined themselves in emotion-eliciting interpersonal or non-interpersonal situations and then rated the arousal and valence of emotions they experienced. We identified (1) separate neural circuits that are implicated in the arousal and valence dimensions of interpersonal versus non-interpersonal emotions, (2) circuits that are implicated in arousal and valence for both types of emotion, and (3) circuits that are responsive to the type of emotion, regardless of the valence or arousal level of the emotion. We found extensive recruitment of limbic (for arousal) and temporal-parietal (for valence) systems associated with processing of specifically interpersonal emotions compared to non-interpersonal ones. The neural bases of interpersonal and non-interpersonal emotions may, therefore, be largely distinct.
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Noncanonical Nuclear Factor Kappa B (NF-?B) Signaling and Potential for Therapeutics in Sepsis.
Curr Infect Dis Rep
PUBLISHED: 08-27-2013
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NF-?B signaling plays a central role in the pathophysiology of severe sepsis and septic shock. Despite tremendous and missed efforts, novel therapeutics for severe sepsis and septic shock are still needed. Many drugs have been designed to target the canonical NF-?B signaling pathway with limited success, potentially due to the nonspecificity of the drugs for other kinases and the interaction of canonical signaling with other pathways. Here, we review the canonical and noncanonical signaling pathways of NF-?B, the cross talk and negative regulation of the two pathways, and the potential for therapeutics arising from the noncanonical NF-?B pathway in relation to the pathophysiology of septic shock.
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A trial of proficiency of nerve conduction: greater standardization still needed.
Muscle Nerve
PUBLISHED: 07-17-2013
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The aim of this study was to test the proficiency (accuracy among evaluators) of measured attributes of nerve conduction (NC).
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Vasopressin compared with norepinephrine augments the decline of plasma cytokine levels in septic shock.
Am. J. Respir. Crit. Care Med.
PUBLISHED: 06-26-2013
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Changes in plasma cytokine levels may predict mortality, and therapies (vasopressin versus norepinephrine) could change plasma cytokine levels in early septic shock.
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Americans and Palestinians judge spontaneous facial expressions of emotion.
Emotion
PUBLISHED: 06-24-2013
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The claim that certain emotions are universally recognized from facial expressions is based primarily on the study of expressions that were posed. The current study was of spontaneous facial expressions shown by aborigines in Papua New Guinea (Ekman, 1980); 17 faces claimed to convey one (or, in the case of blends, two) basic emotions and five faces claimed to show other universal feelings. For each face, participants rated the degree to which each of the 12 predicted emotions or feelings was conveyed. The modal choice for English-speaking Americans (n = 60), English-speaking Palestinians (n = 60), and Arabic-speaking Palestinians (n = 44) was the predicted label for only 4, 5, and 4, respectively, of the 17 faces for basic emotions, and for only 2, 2, and 2, respectively, of the 5 faces for other feelings. Observers endorsed the predicted emotion or feeling moderately often (65%, 55%, and 44%), but also denied it moderately often (35%, 45%, and 56%). They also endorsed more than one (or, for blends, two) label(s) in each face-on average, 2.3, 2.3, and 1.5 of basic emotions and 2.6, 2.2, and 1.5 of other feelings. There were both similarities and differences across culture and language, but the emotional meaning of a facial expression is not well captured by the predicted label(s) or, indeed, by any single label.
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Cardiac ischemia in patients with septic shock randomized to vasopressin or norepinephrine.
Crit Care
PUBLISHED: 06-20-2013
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Cardiac troponins are sensitive and specific biomarkers of myocardial necrosis. We evaluated troponin, CK, and ECG abnormalities in patients with septic shock and compared the effect of vasopressin (VP) versus norepinephrine (NE) on troponin, CK, and ECGs.
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Update in sepsis 2012.
Am. J. Respir. Crit. Care Med.
PUBLISHED: 06-18-2013
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Pivotal sepsis clinical trials and preclinical research in 2012 are reviewed. For interventions ranging from synthetic complex starch solutions to recombinant human activated protein C, large multicenter randomized controlled trials generally failed to show benefit and some even demonstrated harm in the intervention group. In smaller innovative clinical trials simple interventions such as external cooling to control fever and biomarker-guided weaning from mechanical ventilation found potential benefit. Biomarkers for sepsis, including multimarker panels, are increasingly showing promise for clinical application. Breakthroughs in basic research in sepsis continue to highlight the complexity of the systemic inflammatory response and its consequences. A series of publications in AJRCCM follow the septic inflammatory response starting from intracellular structures and organelles to mitochondria and the cytoskeleton. Additional publications explore the key leukocyte subsets acting in sepsis, highlighting the underappreciated role of helper T-cell type 2-related pathways. Cellular remnants in the form of microparticles contribute to coagulopathy and further organ dysfunction. As a consequence, we suggest that sepsis may be the paradigm disease or condition requiring personalized care first to discover and validate new therapies and second to increase survival.
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Encephalitozoon intestinalis infection increases host cell mutation frequency.
Infect. Agents Cancer
PUBLISHED: 06-11-2013
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Microsporidia are obligate intracellular opportunistic fungi that cause significant pathology in immunocompromised hosts. However, 11 percent of immunocompetent individuals in the general population are microsporidia-seropositive, indicating that severe immune suppression may not be a prerequisite for infection. Encephalitozoon intestinalis is transmitted in contaminated water and initially infects gastro-intestinal enterocytes, leading to diarrheal disease. This organism can also disseminate to many other organs. A recent report suggests that microsporidia can establish persistent infections, which anti-fungal treatment does not eradicate. Like other intracellular pathogens, microsporidia infection stresses the host cell and infected individuals have elevated hydrogen peroxide and free radical levels.
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Establishing a target exposure for once-daily intravenous busulfan given with fludarabine and thymoglobulin before allogeneic transplantation.
Biol. Blood Marrow Transplant.
PUBLISHED: 05-27-2013
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A combination of fludarabine (Flu) and daily i.v. busulfan (Bu) is well tolerated and effective in patients undergoing allogeneic hematopoietic stem cell transplantation. Although there is some evidence that Bu exposures exceeding 6000 ?M/min may lead to excessive toxicity, there is little information on the effect of exposures below this level on outcomes. We studied Bu exposure, as measured by area under the concentration-time curve (AUC), in 158 patients with various hematologic malignancies in an attempt to identify an optimal range for targeted therapy. The preparative chemotherapy regimen comprised Flu 50 mg/m(2) on days -6 to -2 and i.v. Bu 3.2 mg/kg on days -5 to -2 inclusive. Graft-versus-host disease (GVHD) prophylaxis included methotrexate, cyclosporin A, and antithymocyte globulin. Patients with Bu exposures below the median AUC of 4439 ?M/min were at increased risk for acute GVHD grade II-IV (hazard ratio [HR], 2.30; 95% confidence interval [CI], 1.19 to 4.49; P = .014). Those in the highest and lowest Bu exposure quartiles (daily AUC <3814 ?M/min and >4993 ?M/min) had an increased risk of nonrelapse mortality (subdistribution HR, 3.32; 95% CI, 1.46 to 7.54; P = .004), as well as worse disease-free survival (HR, 1.81; 95% CI, 1.09 to 2.99; P = .021) and overall survival (HR, 1.94; 95% CI, 1.12 to 3.37; P = .018). Bu exposures between 4440 and 4993 ?M/min were accompanied by the lowest risk of both nonrelapse mortality and acute GVHD.
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Empirical correction of thermal responses in the Solar Occultation for Ice Experiment nitric oxide measurements and initial data validation results.
Appl Opt
PUBLISHED: 05-15-2013
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The Solar Occultation for Ice Experiment (SOFIE) makes broadband transmission measurements centered at 5.32 ?m to determine the concentration profile of nitric oxide (NO). These measurements show a signal oscillation due to detector temperature variations that severely limit the accuracy of NO retrievals if corrections are not applied. An empirical correction was developed to remove this instrumental error. This paper describes the correction, its impact on the retrieval, and presents a comparison from 87 to 105 km versus coincident atmospheric chemistry experiment-Fourier transform spectrometer (ACE-FTS) measurements. The southern hemisphere (SH) shows excellent agreement between the datasets, with statistically insignificant differences. The northern hemisphere (NH) SOFIE measurements exhibit a low bias of -18.5% compared to ACE-FTS. NH measurements (sunrise observations) are still under study, and only SH NO data (sunset observations) are currently publicly available as of SOFIE data version 1.2.
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A novel PGC-1? isoform in brain localizes to mitochondria and associates with PINK1 and VDAC.
Biochem. Biophys. Res. Commun.
PUBLISHED: 05-01-2013
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Peroxisome proliferator-activated receptor-gamma co-activator 1? (PGC-1?) and PTEN-induced putative kinase 1 (PINK1) are powerful regulators of mitochondrial function. Here, we report that a previously unrecognized, novel 35 kDa PGC-1? isoform localizes to the mitochondrial inner membrane and matrix in brain as determined by protease protection and carbonate extraction assays, as well as by immunoelectron microscopy. Immunoelectron microscopy and import experiments in vitro revealed that 35 kDa PGC-1? colocalizes and interacts with the voltage-dependent anion channel (VDAC), and that its import depends on VDAC. Valinomycin treatment which depolarizes the membrane potential, abolished mitochondrial localization of the 35 kDa PGC-1?. Using blue native-PAGE, co-immunoprecipitation, and immunoelectron microscopy analyses, we found that the 35 kDa PGC-1? binds and colocalizes with PINK1 in brain mitochondria. This is the first report regarding mitochondrial localization of a novel 35 kDa PGC-1? isoform and its association with PINK1, suggesting possible regulatory roles for mitochondrial function in the brain.
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Physiologically based pharmacokinetic modelling of Busulfan: a new approach to describe and predict the pharmacokinetics in adults.
Cancer Chemother. Pharmacol.
PUBLISHED: 04-25-2013
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A physiologically based pharmacokinetic (PBPK) model was established and evaluated describing the pharmacokinetics (PK) of the DNA-alkylating agent Busulfan in adults in order to predict the systemic Busulfan drug exposure in both plasma and toxicity-related organs.
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Impaired coronary collateral growth in the metabolic syndrome is in part mediated by matrix metalloproteinase 12-dependent production of endostatin and angiostatin.
Arterioscler. Thromb. Vasc. Biol.
PUBLISHED: 04-18-2013
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We have previously shown that transient coronary artery occlusion stimulated coronary collateral growth (CCG) in healthy (Sprague Dawley) but not in metabolic syndrome (JCR:LA-cp [JCR] ) rats. Here, we sought to determine whether matrix metalloproteinases (MMPs) negatively regulate CCG in the metabolic syndrome via release of endostatin and angiostatin.
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Overexpression of SIRT1 protein in neurons protects against experimental autoimmune encephalomyelitis through activation of multiple SIRT1 targets.
J. Immunol.
PUBLISHED: 04-01-2013
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Treatment of experimental autoimmune encephalomyelitis (EAE) with resveratrol, an activator of sirtuin 1 (SIRT1), reduces disease severity. This suggested that activators of SIRT1, a highly conserved NAD-dependent protein deacetylase, might have immune-modulating or neuroprotective therapeutic effects in EAE. Previously, we showed that SIRT1 expression increases in EAE, suggesting that it is an adaptive response. In this study, we investigated the potential function of SIRT1 in regulating EAE using SIRT1-overexpressing mice. The current studies examine potential neuroprotective and immunomodulatory effects of SIRT1 overexpression in chronic EAE induced by immunization of C57BL/6 mice with myelin oligodendrocyte glycoprotein peptide 35-55. SIRT1 suppressed EAE clinical symptoms compared with wild-type EAE mice and prevented or altered the phenotype of inflammation in spinal cords; as a result, demyelination and axonal injury were reduced. Significant neuroprotective effects were observed, with fewer apoptotic cells found in the spinal cords of SIRT1-overexpressing EAE mice associated with increased brain-derived neurotrophic factor and NAD levels. Earlier, we showed that brain-derived neurotrophic factor and NAD play crucial neuroprotective roles in EAE. These results suggest that SIRT1 reduces neuronal loss in this chronic demyelinating disease model and that this is associated with a reduction in inflammation.
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Pyroclastic passage zones in glaciovolcanic sequences.
Nat Commun
PUBLISHED: 03-29-2013
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Volcanoes are increasingly recognized as agents and recorders of global climate variability, although deciphering the linkages between planetary climate and volcanism is still in its infancy. The growth and emergence of subaqueous volcanoes produce passage zones, which are stratigraphic surfaces marking major transitions in depositional environments. In glaciovolcanic settings, they record the elevations of syn-eruptive englacial lakes. Thus, they allow for forensic recovery of minimum ice thicknesses. Here we present the first description of a passage zone preserved entirely within pyroclastic deposits, marking the growth of a tephra cone above the englacial lake level. Our discovery requires extension of the passage-zone concept to accommodate explosive volcanism and guides future studies of hundreds of glaciovolcanic edifices on Earth and Mars. Our recognition of pyroclastic passage zones increases the potential for recovering transient paleolake levels, improving estimates of paleo-ice thicknesses and providing new constraints on paleoclimate models that consider the extents and timing of planetary glaciations.
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Childrens recognition of disgust in others.
Psychol Bull
PUBLISHED: 03-06-2013
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Disgust has been theorized to be a basic emotion with a facial signal that is easily, universally, automatically, and perhaps innately recognized by observers from an early age. This article questions one key part of that theory: the hypothesis that children recognize disgust from its purported facial signal. Over the first 5 years, children experience disgust, produce facial expressions of disgust, develop a concept of disgust, understand and produce the word disgust or a synonym, know about disgusts causes and consequences, and infer disgust in others from a situation or a behavior. Yet, only gradually do these children come to "recognize" disgust specifically from the "disgust face" found in standardized sets of the facial expressions of basic emotions. Improvement is gradual, with more than half of children matching the standard disgust face to disgust only at around 9 years of age and with subsequent improvement continuing gradually until the late teens or early adulthood. Up to age 8, a majority of children studied believe that the standard disgust face indicates anger. Rather than relying on an already known signal value, children may be actively learning to interpret the expression.
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Prior caloric restriction increases survival of prepubertal obese- and PCOS-prone rats exposed to a challenge of time-limited feeding and physical activity.
J. Appl. Physiol.
PUBLISHED: 02-28-2013
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We hypothesized that a polycystic ovary syndrome (PCOS) background associated with obese-prone genotype, coupled with preconditioning by caloric restriction, would confer a survival benefit in genetically prepubertal obese/PCOS (O/PCOS)-prone rats faced with an unpredictable challenge of food shortage. Female, juvenile JCR:LA-cp rats, O/PCOS- and lean-prone, were exposed to 1.5 h of daily meals and 22.5 h of voluntary wheel-running, a procedure that leads to activity anorexia (AA). One week before the AA challenge (AAC), O/PCOS-prone rats were freely fed (O/PCOS-FF) or pair fed (O/PCOS-FR) to lean-prone, free-feeding animals (Lean-FF). O/PCOS-FR and lean-prone, food-restricted (Lean-FR) groups were matched on relative average caloric intake. Animals were removed from protocol at 75% of initial body weight (starvation criterion) or after 14 days (survival criterion). The AAC induced weight loss in all rats, but there were significant effects of both genotype and feeding history on weight loss (lean-prone rats exhibited a higher rate of weight loss than O/PCOS-prone; P < 0.001), and rats with prior caloric restriction retained more weight than those free fed previously (90.68 ± 0.59% vs. 85.47 ± 0.46%; P < 0.001). The daily rate of running was higher in lean-prone rats compared with O/PCOS-prone. This difference in running rate correlated with differences in mean days of survival. All O/PCOS-FR rats survived at day 14. O/PCOS-FF rats survived longer (10.00 ± 0.97 days) than Lean-FR (6.17 ± 1.58 days) and Lean-FF (4.33 ± 0.42 days) rats (P < 0.05). Thus preconditioning by caloric restriction induces a substantial survival advantage, beyond genotype alone, in prepubertal O/PCOS-prone rats.
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A story superiority effect for disgust, fear, embarrassment, and pride.
Br J Dev Psychol
PUBLISHED: 02-22-2013
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Past studies found that, for preschoolers, a story specifying a situational cause and behavioural consequence is a better cue to fear and disgust than is the facial expression of those two emotions, but the facial expressions used were static. Two studies (Study 1: N = 68, 36-68 months; Study 2: N = 72, 49-90 months) tested whether this effect could be reversed when the expressions were dynamic and included facial, postural, and vocal cues. Children freely labelled emotions in three conditions: story, still face, and dynamic expression. Story remained a better cue than still face or dynamic expression for fear and disgust and also for the later emerging emotions of embarrassment and pride.
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The within-subjects design in the study of facial expressions.
Cogn Emot
PUBLISHED: 02-08-2013
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The common within-subjects design of studies on the recognition of emotion from facial expressions allows the judgement of one face to be influenced by previous faces, thus introducing the potential for artefacts. The present study (N=344) showed that the canonical "disgust face" was judged as disgusted, provided that the preceding set of faces included "anger expressions", but was judged as angry when the preceding set of faces excluded anger but instead included persons who looked sad or about to be sick. Chinese observers showed lower recognition of the "disgust face" than did American observers. Chinese observers also showed lower recognition of the "fear face" when responding in Chinese than in English.
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MicroRNA-145 restores contractile vascular smooth muscle phenotype and coronary collateral growth in the metabolic syndrome.
Arterioscler. Thromb. Vasc. Biol.
PUBLISHED: 02-07-2013
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Transient, repetitive occlusion stimulates coronary collateral growth (CCG) in normal animals. Vascular smooth muscle cells (VSMCs) switch to synthetic phenotype early in CCG, then return to contractile phenotype. CCG is impaired in the metabolic syndrome. We determined whether impaired CCG was attributable to aberrant VSMC phenotypic modulation by miR-145-mediated mechanisms, and whether restoration of physiological miR-145 levels in metabolic syndrome (JCR rat) improved CCG.
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Packed red cell transfusions alter mesenteric arterial reactivity and nitric oxide pathway in preterm lambs.
Pediatr. Res.
PUBLISHED: 02-05-2013
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Background:Cases of necrotizing enterocolitis occurring within 48?h of packed red blood cell (PRBC) transfusions are increasingly being described in observational studies. Transfusion-associated gut injury is speculated to result from an abnormal mesenteric vascular response to transfusion. However, the mechanism of disruption of the balance between mesenteric vasoconstriction and relaxation following transfusion is not known.Methods:Preterm lambs (n = 16, 134 d gestation; term: 145-147 d) were delivered and ventilated for 24?h. All the lambs received orogastric feeds with colostrum. In addition, 10 of these lambs received PRBC transfusions. Vasoreactivity was evaluated in isolated mesenteric arterial rings using norepinephrine and endothelin-1 as vasoconstrictors. Endothelium-dependent (A23187, a calcium ionophore) and endothelium-independent (SNAP) nitric oxide (NO) donors were used as vasorelaxants. Mesenteric arterial endothelial NO synthase (eNOS), soluble guanylyl cyclase (sGC), and phosphodiesterase 5 (PDE5) mRNA analyses and protein assays were performed.Results:Transfusion with PRBC significantly increased mesenteric vasoconstriction to norepinephrine and endothelin-1 and impaired relaxation to A23187 and SNAP. Mesenteric arterial eNOS protein decreased following PRBC transfusion. No significant changes were noted in sGC and PDE5 mRNA or protein assays.Conclusion:PRBC transfusion in enterally fed preterm lambs promotes mesenteric vasoconstriction and impairs vasorelaxation by reducing mesenteric arterial eNOS.
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Role of pulmonary artery reactivity and nitric oxide in injury and inflammation following lung contusion.
Shock
PUBLISHED: 02-01-2013
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The mechanisms contributing to hypoxia in lung contusion (LC) remain unclear and not temporally associated with the peak onset of acute inflammation. We investigated the role of oxidative stress in alteration of pulmonary arterial (PA) reactivity following LC. In addition, the role of antioxidants in reversing this process was examined. PaO2 and PA reactivity were measured in rats subjected to bilateral LC. Rings were pretreated with a nitric oxide synthase (NOS) inhibitor, L-nitro arginine (10(-3) M), or PEG-superoxide dismutase (SOD) and PEG-catalase (CAT), or both (L-nitro arginine + SOD/CAT). Rings were constricted with norepinephrine and relaxed with an NOS agonist (A23187) or NO donor (SNAP [S-nitrosyl amino penicillamine]). Immunochemical and mass spectrometric quantification for nitrotyrosine was performed. Rats were hypoxemic at 4 h after contusion compared with controls, but recovered by 24 h (PaO(2)/FIO(2) ratio: baseline, 443 ± 28; 4 h, 288 ± 46; and 24 h, 417 ± 23). Pulmonary arterial constriction to NOS inhibition and relaxation to A23187 were impaired 4 h after LC. Pulmonary arterial relaxation to SNAP was decreased at 4 and 24 h after LC. These alterations in PA reactivity were reversed by SOD/CAT pretreatment. SOD1 and 2 mRNA were upregulated, and soluble guanylyl cyclase mRNA was downregulated 24 h after LC. Immunohistochemistry and mass spectrometry revealed that levels of 3-nitrotyrosine were increased markedly at 4 h following LC consistent with superoxide generation and formation of peroxynitrite. Collectively, these data suggest that consumption of NO due to excess superoxide resulting in peroxynitrite formation leads to diminished vascular reactivity following LC.
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One size does not fit all in severe infection: obesity alters outcome, susceptibility, treatment, and inflammatory response.
Crit Care
PUBLISHED: 01-21-2013
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Obesity is an increasingly common comorbidity in critically ill patients. Whether obesity alters sepsis outcome, susceptibility, treatment, and response is not completely understood.
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Cytokines and signaling molecules predict clinical outcomes in sepsis.
PLoS ONE
PUBLISHED: 01-01-2013
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Inflammatory response during sepsis is incompletely understood due to small sample sizes and variable timing of measurements following the onset of symptoms. The vasopressin in septic shock trial (VASST) compared the addition of vasopressin to norepinephrine alone in patients with septic shock. During this study plasma was collected and 39 cytokines measured in a 363 patients at both baseline (before treatment) and 24 hours. Clinical features relating to both underlying health and the acute organ dysfunction induced by the severe infection were collected during the first 28 days of admission.
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Imaging findings associated with cognitive performance in primary lateral sclerosis and amyotrophic lateral sclerosis.
Dement Geriatr Cogn Dis Extra
PUBLISHED: 01-01-2013
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Executive dysfunction occurs in many patients with amyotrophic lateral sclerosis (ALS), but it has not been well studied in primary lateral sclerosis (PLS). The aims of this study were to (1) compare cognitive function in PLS to that in ALS patients, (2) explore the relationship between performance on specific cognitive tests and diffusion tensor imaging (DTI) metrics of white matter tracts and gray matter volumes, and (3) compare DTI metrics in patients with and without cognitive and behavioral changes.
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Hydrocortisone normalizes oxygenation and cGMP regulation in lambs with persistent pulmonary hypertension of the newborn.
Am. J. Physiol. Lung Cell Mol. Physiol.
PUBLISHED: 12-23-2011
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In the pulmonary vasculature, cGMP levels are regulated by soluble guanylate cyclase (sGC) and phosphodiesterase 5 (PDE5). We previously reported that lambs with persistent pulmonary hypertension of the newborn (PPHN) demonstrate increased reactive oxygen species (ROS) and altered sGC and PDE5 activity, with resultant decreased cGMP. The objective of this study was to evaluate the effects of hydrocortisone on pulmonary vascular function, ROS, and cGMP in the ovine ductal ligation model of PPHN. PPHN lambs were ventilated with 100% O(2) for 24 h. Six lambs received 5 mg/kg hydrocortisone every 8 h times three doses (PPHN-hiHC), five lambs received 3 mg/kg hydrocortisone followed by 1 mg·kg(-1)·dose(-1) times two doses (PPHN-loHC), and six lambs were ventilated with O(2) alone (PPHN). All groups were compared with healthy 1-day spontaneously breathing lambs (1DSB). O(2) ventilation of PPHN lambs decreased sGC activity, increased PDE5 activity, and increased ROS vs. 1DSB lambs. Both hydrocortisone doses significantly improved arterial-to-alveolar ratios relative to PPHN lambs, decreased PDE5 activity, and increased cGMP relative to PPHN lambs. High-dose hydrocortisone also increased sGC activity, decreased PDE5 expression, decreased ROS, and increased total vascular SOD activity vs. PPHN lambs. These data suggest that hydrocortisone treatment in clinically relevant doses improves oxygenation and decreases hyperoxia-induced changes in sGC and PDE5 activity, increasing cGMP levels. Hydrocortisone reduces ROS levels in part by increasing SOD activity in PPHN lambs ventilated with 100% O(2.) We speculate that hydrocortisone increases cGMP by direct effects on sGC and PDE5 expression and by attenuating abnormalities induced by oxidant stress.
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Apocynin improves oxygenation and increases eNOS in persistent pulmonary hypertension of the newborn.
Am. J. Physiol. Lung Cell Mol. Physiol.
PUBLISHED: 12-23-2011
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NADPH oxidase is a major source of superoxide anions in the pulmonary arteries (PA). We previously reported that intratracheal SOD improves oxygenation and restores endothelial nitric oxide (NO) synthase (eNOS) function in lambs with persistent pulmonary hypertension of the newborn (PPHN). In this study, we determined the effects of the NADPH oxidase inhibitor apocynin on oxygenation, reactive oxygen species (ROS) levels, and NO signaling in PPHN lambs. PPHN was induced in lambs by antenatal ligation of the ductus arteriosus 9 days prior to delivery. Lambs were treated with vehicle or apocynin (3 mg/kg intratracheally) at birth and then ventilated with 100% O(2) for 24 h. A significant improvement in oxygenation was observed in apocynin-treated lambs after 24 h of ventilation. Contractility of isolated fifth-generation PA to norepinephrine was attenuated in apocynin-treated lambs. PA constrictions to NO synthase (NOS) inhibition with N-nitro-l-arginine were blunted in PPHN lambs; apocynin restored contractility to N-nitro-l-arginine, suggesting increased NOS activity. Intratracheal apocynin also enhanced PA relaxations to the eNOS activator A-23187 and to the NO donor S-nitrosyl-N-acetyl-penicillamine. Apocynin decreased the interaction between NADPH oxidase subunits p22(phox) and p47(phox) and decreased the expression of Nox2 and p22(phox) in ventilated PPHN lungs. These findings were associated with decreased superoxide and 3-nitrotyrosine levels in the PA of apocynin-treated PPHN lambs. eNOS protein expression, endothelial NO levels, and tetrahydrobiopterin-to-dihydrobiopterin ratios were significantly increased in PA from apocynin-treated lambs, although cGMP levels did not significantly increase and phosphodiesterase-5 activity did not significantly decrease. NADPH oxidase inhibition with apocynin may improve oxygenation, in part, by attenuating ROS-mediated vasoconstriction and by increasing NOS activity.
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Low cytomegalovirus-specific T-cell counts at reactivation are associated with progression to high-level viremia or disease in seropositive recipients of hematopoietic cell grafts from seropositive but not seronegative donors.
Cytotherapy
PUBLISHED: 12-07-2011
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Identifying patients who spontaneously resolve cytomegalovirus (CMV) reactivation could spare these patients from the toxicity of antiviral drugs such as ganciclovir. The role of CMV-specific T cells in clearing CMV viremia in patients who do not receive ganciclovir has not been evaluated. We assessed this in patients with CMV viremia between 50 and 50 000 genome copies/mL, because our threshold for initiating ganciclovir is 50 000 copies/mL.
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Shoulder pain in amyotrophic lateral sclerosis.
J Clin Neuromuscul Dis
PUBLISHED: 11-21-2011
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To determine the frequency of shoulder pain in our amyotrophic lateral sclerosis (ALS) population and to explore potential associations with demographic and clinical features.
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Feeding history and obese-prone genotype increase survival of rats exposed to a challenge of food restriction and wheel running.
Obesity (Silver Spring)
PUBLISHED: 10-20-2011
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We hypothesized that obese-prone genotype and history of food restriction confer a survival advantage to genetically obese animals under environmental challenge. Male juvenile JCR:LA-cp rats, obese-prone and lean-prone, were exposed to 1.5 h daily meals and 22.5-h voluntary wheel running, a procedure inducing activity anorexia (AA). One week before the AA challenge, obese-prone rats were freely fed (obese-FF), or pair fed (obese-PF) to lean-prone, free-feeding rats (lean-FF). Animals were removed from protocol at 75% of initial body weight (starvation criterion) or after 14 days (survival criterion). AA challenge induced weight loss in all rats, but percent weight loss was more rapid and sustained in lean-FF rats than in obese-FF or obese-PF animals (P < 0.04). Weight loss was significantly higher in obese-FF rats than obese-PF rats, 62% of which achieved survival criterion and stabilized with zero weight loss. Obese-PF rats survived longer, on average (12.0 ± 1.1 day) than obese-FF (8.2 ± 1.1 day) and lean-FF rats (3.5 ± 0.2 day) (P < 0.02). Wheel running increased linearly in all groups; lean-FF increased more rapidly than obese-FF (P < 0.05); obese-PF increased at an intermediate rate (P < 0.02), and those rats that survived stabilized daily rates of wheel running. Prior food restriction of juvenile obese-prone rats induces a survival benefit beyond genotype, that is related to achievement of homeostasis. This metabolic adaptive process may help explain the development of human obesity in the presence of an unstable food environment which subsequently transitions to an abundant food supply.
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Childrens understanding of nonverbal expressions of pride.
J Exp Child Psychol
PUBLISHED: 09-08-2011
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To chart the developmental path of childrens attribution of pride to others, we presented children (4 years 0 month to 11 years 11 months of age, N=108) with video clips of head-and-face, body posture, and multi-cue (both head-and-face and body posture simultaneously) expressions that adults consider to convey pride. Across age groups, 4- and 5-year-olds did not attribute pride to any expression presented, 6- and 7-year-olds attributed pride only to the multi-cue expression, and 8- to 11-year-olds attributed pride to both the head-and-face and multi-cue expressions. Children of all ages viewed the postural expression as anger rather than pride. Developmentally, pride is first attributed only when several cues are present and only later when a single cue (head-and-face) is present.
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Agreement in electrocardiogram interpretation in patients with septic shock.
Crit. Care Med.
PUBLISHED: 08-19-2011
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The reliability of electrocardiogram interpretation to diagnose myocardial ischemia in critically ill patients is unclear. In adults with septic shock, we assessed intra- and inter-rater agreement of electrocardiogram interpretation, and the effect of knowledge of troponin values on these interpretations.
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Metabolic imaging: a link between lactate dehydrogenase A, lactate, and tumor phenotype.
Clin. Cancer Res.
PUBLISHED: 08-15-2011
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We compared the metabolic profiles and the association between LDH-A expression and lactate production in two isogenic murine breast cancer cell lines and tumors (67NR and 4T1). These cell lines were derived from a single mammary tumor and have different growth and metabolic phenotypes.
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Bench-to-bedside review: Vasopressin in the management of septic shock.
Crit Care
PUBLISHED: 08-11-2011
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This review of vasopressin in septic shock differs from previous reviews by providing more information on the physiology and pathophysiology of vasopressin and vasopressin receptors, particularly because of recent interest in more specific AVPR1a agonists and new information from the Vasopressin and Septic Shock Trial (VASST), a randomized trial of vasopressin versus norepinephrine in septic shock. Relevant literature regarding vasopressin and other AVPR1a agonists was reviewed and synthesized. Vasopressin, a key stress hormone in response to hypotension, stimulates a family of receptors: AVPR1a, AVPR1b, AVPR2, oxytocin receptors and purinergic receptors. Rationales for use of vasopressin in septic shock are as follows: first, a deficiency of vasopressin in septic shock; second, low-dose vasopressin infusion improves blood pressure, decreases requirements for norepinephrine and improves renal function; and third, a recent randomized, controlled, concealed trial of vasopressin versus norepinephrine (VASST) suggests low-dose vasopressin may decrease mortality of less severe septic shock. Previous clinical studies of vasopressin in septic shock were small or not controlled. There was no difference in 28-day mortality between vasopressin-treated versus norepinephrine-treated patients (35% versus 39%, respectively) in VASST. There was potential benefit in the prospectively defined stratum of patients with less severe septic shock (5 to 14 ?g/minute norepinephrine at randomization): vasopressin may have lowered mortality compared with norepinephrine (26% versus 36%, respectively, P = 0.04 within stratum). The result was robust: vasopressin also decreased mortality (compared with norepinephrine) if less severe septic shock was defined by the lowest quartile of arterial lactate or by use of one (versus more than one) vasopressor at baseline. Other investigators found greater hemodynamic effects of higher dose of vasopressin (0.06 units/minute) but also unique adverse effects (elevated liver enzymes and serum bilirubin). Use of higher dose vasopressin requires further evaluation of efficacy and safety. There are very few studies of interactions of therapies in critical care--or septic shock--and effects on mortality. Therefore, the interaction of vasopressin infusion, corticosteroid treatment and mortality of septic shock was evaluated in VASST. Low-dose vasopressin infusion plus corticosteroids significantly decreased 28-day mortality compared with corticosteroids plus norepinephrine (44% versus 35%, respectively, P = 0.03; P = 0.008 interaction statistic). Prospective randomized controlled trials would be necessary to confirm this interesting interaction. In conclusion, low-dose vasopressin may be effective in patients who have less severe septic shock already receiving norepinephrine (such as patients with modest norepinephrine infusion (5 to 15 ?g/minute) or low serum lactate levels). The interaction of vasopressin infusion and corticosteroid treatment in septic shock requires further study.
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A user-friendly integrated monitor-adhesive patch for long-term ambulatory electrocardiogram monitoring.
J Electrocardiol
PUBLISHED: 08-03-2011
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Compliance to long-term ambulatory electrocardiogram monitoring is important for diagnosis in patients with cardiac arrhythmia. This requires a system with a minimal impact on daily activities.
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Pulmonary hemodynamics and vascular reactivity in asphyxiated term lambs resuscitated with 21 and 100% oxygen.
J. Appl. Physiol.
PUBLISHED: 07-28-2011
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An increase in oxygen tension is an important factor in decreasing pulmonary vascular resistance (PVR) at birth. Birth asphyxia results in acidosis and increased PVR. We determined the effect of resuscitation with 21 vs. 100% O(2) on pulmonary hemodynamics, pulmonary arterial (PA) reactivity, and oxidant stress in a lamb model of in utero asphyxia. Term fetal lambs were acutely asphyxiated by intrauterine umbilical cord occlusion for 10 min resulting in acidosis (pH 6.96 ± 0.05 and Pco(2) 103 ± 5 Torr), bradycardia, systemic hypotension, and increased PVR. Lambs were treated with 30 min of resuscitation with 21% or 100% O(2) (n = 6 each). Pa(O(2)) was significantly elevated with 100% O(2) resuscitation compared with 21% O(2) (430 ± 38 vs. 64 ± 8 Torr), but changes in pH and Pa(CO(2)) were similar. The 100% O(2) induced greater increase in pulmonary blood flow and decrease in PVR at 1 min of life, but subsequent values were similar to 21% O(2) group between 2 and 30 min of life. Oxygen uptake from the lung and systemic oxygen extraction was similar between the two groups. Pulmonary arteries showed increased staining for superoxide anions and increased contractility to norepinephrine following resuscitation with 100% O(2). The increased PA contractility induced by 100% O(2) was reversed by scavenging superoxide anions with superoxide dismutase and catalase. We conclude that resuscitation of asphyxiated lambs with 100% O(2) increases Pa(O(2)) but does not improve lung oxygen uptake, decrease PVR at 30 min, or increase systemic oxygen extraction ratios. Furthermore, 100% O(2) also induces oxidative stress and increases PA contractility. These findings support the new neonatal resuscitation guidelines recommending 21% O(2) for initial resuscitation of asphyxiated neonates.
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IL17A genetic variation is associated with altered susceptibility to Gram-positive infection and mortality of severe sepsis.
Crit Care
PUBLISHED: 07-27-2011
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Interleukin 17A (IL17A) plays a key role in host defense against microbial infection including Gram-positive bacteria. Genetic factors contribute to the host defense, but the role of IL17A single nucleotide polymorphisms (SNPs) has not yet been investigated in severe sepsis. Therefore, we hypothesized that SNPs in the IL17A gene alter susceptibility to infection and clinical outcome of severe sepsis.
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MMPs 2 and 9 are essential for coronary collateral growth and are prominently regulated by p38 MAPK.
J. Mol. Cell. Cardiol.
PUBLISHED: 07-25-2011
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Transient, repetitive ischemia (RI) stimulates coronary collateral growth (CCG) in normal, healthy (SD) rats, which requires p38 MAPK activation. In contrast, RI does not induce CCG in the metabolic syndrome (JCR) rats, which is associated with lack of p38 MAPK activation. The functional consequences of p38 MAPK activation in CCG remain unknown. Theoretically, effective collateral growth would require extracellular matrix remodeling; however, direct assessment as well as identification of proteases responsible for this degradation are lacking. In this study, we investigated the role of p38 MAPK in the regulation of matrix metalloproteinases 2 and 9 (MMPs 2 and 9) and their requirement for CCG in SD vs. JCR rats. The rats underwent the RI protocol (8 LAD occlusions, 40s each, every 20min, in 8h cycles for 0, 3, 6, or 9days). MMP expression was measured in the ischemic, collateral-dependent zone (CZ) and the normal zone (NZ) by Western blot, and MMP activity by zymography. Expression and activation of MMP 2 and 9 were significantly increased (~3.5 fold) on day 3 of RI in the CZ of SD rats. In vivo p38 MAPK inhibition completely blocked RI-induced MMP 2 and 9 expression and activation. MMP activation correlated with increased degradation of components of the basement membrane and the vascular elastic laminae: elastin (~3 fold), laminin (~3 fold) and type IV collagen (~2 fold). This was blocked by MMP 2 and 9 inhibition, which also abolished RI-induced CCG. In contrast, in JCR rats, RI did not induce expression or activation of MMP 2 or 9 and there was no associated degradation of elastin, laminin or type IV collagen. In conclusion, MMP 2 and 9 activation is essential for CCG and is mediated, in part, by p38 MAPK. Furthermore, compromised CCG in the metabolic syndrome may be partially due to the lack of p38 MAPK-dependent activation of MMP 2 and 9 and resultant decreased extracellular matrix degradation.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.