Showing papers by "Case Western Reserve University published in 2001"
TL;DR: The results of an international collaboration to produce and make freely available a draft sequence of the human genome are reported and an initial analysis is presented, describing some of the insights that can be gleaned from the sequence.
Abstract: The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.
22,269 citations
TL;DR: Comparative genomic analysis indicates vertebrate expansions of genes associated with neuronal function, with tissue-specific developmental regulation, and with the hemostasis and immune systems are indicated.
Abstract: A 2.91-billion base pair (bp) consensus sequence of the euchromatic portion of the human genome was generated by the whole-genome shotgun sequencing method. The 14.8-billion bp DNA sequence was generated over 9 months from 27,271,853 high-quality sequence reads (5.11-fold coverage of the genome) from both ends of plasmid clones made from the DNA of five individuals. Two assembly strategies-a whole-genome assembly and a regional chromosome assembly-were used, each combining sequence data from Celera and the publicly funded genome effort. The public data were shredded into 550-bp segments to create a 2.9-fold coverage of those genome regions that had been sequenced, without including biases inherent in the cloning and assembly procedure used by the publicly funded group. This brought the effective coverage in the assemblies to eightfold, reducing the number and size of gaps in the final assembly over what would be obtained with 5.11-fold coverage. The two assembly strategies yielded very similar results that largely agree with independent mapping data. The assemblies effectively cover the euchromatic regions of the human chromosomes. More than 90% of the genome is in scaffold assemblies of 100,000 bp or more, and 25% of the genome is in scaffolds of 10 million bp or larger. Analysis of the genome sequence revealed 26,588 protein-encoding transcripts for which there was strong corroborating evidence and an additional approximately 12,000 computationally derived genes with mouse matches or other weak supporting evidence. Although gene-dense clusters are obvious, almost half the genes are dispersed in low G+C sequence separated by large tracts of apparently noncoding sequence. Only 1.1% of the genome is spanned by exons, whereas 24% is in introns, with 75% of the genome being intergenic DNA. Duplications of segmental blocks, ranging in size up to chromosomal lengths, are abundant throughout the genome and reveal a complex evolutionary history. Comparative genomic analysis indicates vertebrate expansions of genes associated with neuronal function, with tissue-specific developmental regulation, and with the hemostasis and immune systems. DNA sequence comparisons between the consensus sequence and publicly funded genome data provided locations of 2.1 million single-nucleotide polymorphisms (SNPs). A random pair of human haploid genomes differed at a rate of 1 bp per 1250 on average, but there was marked heterogeneity in the level of polymorphism across the genome. Less than 1% of all SNPs resulted in variation in proteins, but the task of determining which SNPs have functional consequences remains an open challenge.
12,098 citations
TL;DR: This study randomly assigned patients who arrived at an urban emergency department with severe sepsis or septic shock to receive either six hours of early goal-directed therapy or standard therapy (as a control) before admission to the intensive care unit.
Abstract: Background Goal-directed therapy has been used for severe sepsis and septic shock in the intensive care unit. This approach involves adjustments of cardiac preload, afterload, and contractility to balance oxygen delivery with oxygen demand. The purpose of this study was to evaluate the efficacy of early goal-directed therapy before admission to the intensive care unit. Methods We randomly assigned patients who arrived at an urban emergency department with severe sepsis or septic shock to receive either six hours of early goal-directed therapy or standard therapy (as a control) before admission to the intensive care unit. Clinicians who subsequently assumed the care of the patients were blinded to the treatment assignment. In-hospital mortality (the primary efficacy outcome), end points with respect to resuscitation, and Acute Physiology and Chronic Health Evaluation (APACHE II) scores were obtained serially for 72 hours and compared between the study groups. Results Of the 263 enrolled patients, 130 were ...
8,811 citations
TL;DR: The authors found that bad is stronger than good, as a general principle across a broad range of psychological phenomena, such as bad emotions, bad parents, bad feedback, and bad information is processed more thoroughly than good.
Abstract: The greater power of bad events over good ones is found in everyday events, major life events (e.g., trauma), close relationship outcomes, social network patterns, interpersonal interactions, and learning processes. Bad emotions, bad parents, and bad feedback have more impact than good ones, and bad information is processed more thoroughly than good. The self is more motivated to avoid bad self-definitions than to pursue good ones. Bad impressions and bad stereotypes are quicker to form and more resistant to disconfirmation than good ones. Various explanations such as diagnosticity and salience help explain some findings, but the greater power of bad events is still found when such variables are controlled. Hardly any exceptions (indicating greater power of good) can be found. Taken together, these findings suggest that bad is stronger than good, as a general principle across a broad range of psychological phenomena.
5,340 citations
TL;DR: This work model NCSs with packet dropout and multiple-packet transmission as asynchronous dynamical systems and analyze their stability using stability regions and a hybrid systems technique, and discusses methods to compensate network-induced delay.
Abstract: First, we review some previous work on networked control systems (NCSs) and offer some improvements. Then, we summarize the fundamental issues in NCSs and examine them with different underlying network-scheduling protocols. We present NCS models with network-induced delay and analyze their stability using stability regions and a hybrid systems technique. Following that, we discuss methods to compensate network-induced delay and present experimental results over a physical network. Then, we model NCSs with packet dropout and multiple-packet transmission as asynchronous dynamical systems and analyze their stability. Finally, we present our conclusions.
3,467 citations
TL;DR: Despite the devastating clinical consequences of aneuploidy, relatively little is known of how trisomy and monosomy originate in humans, but recent molecular and cytogenetic approaches are now beginning to shed light on the non-disjunctional processes that lead to aneuPLoidy.
Abstract: Aneuploidy (trisomy or monosomy) is the most commonly identified chromosome abnormality in humans, occurring in at least 5% of all clinically recognized pregnancies. Most aneuploid conceptuses perish in utero, which makes this the leading genetic cause of pregnancy loss. However, some aneuploid fetuses survive to term and, as a class, aneuploidy is the most common known cause of mental retardation. Despite the devastating clinical consequences of aneuploidy, relatively little is known of how trisomy and monosomy originate in humans. However, recent molecular and cytogenetic approaches are now beginning to shed light on the non-disjunctional processes that lead to aneuploidy.
2,200 citations
TL;DR: The observations indicate that increased oxidative damage is an early event in AD that decreases with disease progression and lesion formation and suggest that AD is associated with compensatory changes that reduce damage from reactive oxygen.
Abstract: Recently, we demonstrated a significant increase of an oxidized nucleoside derived from RNA, 8-hydroxyguanosine (8OHG), and an oxidized amino acid, nitrotyrosine in vulnerable neurons of patients with Alzheimer disease (AD). To determine whether oxidative damage is an early- or end-stage event in the process of neurodegeneration in AD, we investigated the relationship between neuronal 8OHG and nitrotyrosine and histological and clinical variables, i.e. amyloid-beta (A beta) plaques and neurofibrillary tangles (NFT), as well as duration of dementia and apolipoprotein E (ApoE) genotype. Our findings show that oxidative damage is quantitatively greatest early in the disease and reduces with disease progression. Surprisingly, we found that increases in A beta deposition are associated with decreased oxidative damage. These relationships are more significant in ApoE epsilon4 carriers. Moreover, neurons with NFT show a 40%-56% decrease in relative 8OHG levels compared with neurons free of NFT. Our observations indicate that increased oxidative damage is an early event in AD that decreases with disease progression and lesion formation. These findings suggest that AD is associated with compensatory changes that reduce damage from reactive oxygen.
1,799 citations
Baylor College of Medicine1, University of Arkansas for Medical Sciences2, University of Kansas3, Oregon Health & Science University4, Duke University5, Veterans Health Administration6, University of California, San Diego7, Case Western Reserve University8, University of Pittsburgh9, University of California, Los Angeles10
TL;DR: Dementia criteria for dementia have improved since the 1994 practice parameter, and further research is needed to improve clinical definitions of dementia and its subtypes, as well as to determine the utility of various instruments of neuroimaging, biomarkers, and genetic testing in increasing diagnostic accuracy.
Abstract: Article abstract—Objective: To update the 1994 practice parameter for the diagnosis of dementia in the elderly. Background: The AAN previously published a practice parameter on dementia in 1994. New research and clinical developments warrant an update of some aspects of diagnosis. Methods: Studies published in English from 1985 through 1999 were identified that addressed four questions: 1) Are the current criteria for the diagnosis of dementia reliable? 2) Are the current diagnostic criteria able to establish a diagnosis for the prevalent dementias in the elderly? 3) Do laboratory tests improve the accuracy of the clinical diagnosis of dementing illness? 4) What comorbidities should be evaluated in elderly patients undergoing an initial assessment for dementia? Recommendations: Based on evidence in the literature, the following recommendations are made. 1) The DSM-III-R definition of dementia is reliable and should be used (Guideline). 2) The National Institute of Neurologic, Communicative Disorders and Stroke‐AD and Related Disorders Association (NINCDS-ADRDA) or the Diagnostic and Statistical Manual, 3rd edition, revised (DSM-IIIR) diagnostic criteria for AD and clinical criteria for Creutzfeldt‐Jakob disease (CJD) have sufficient reliability and validity and should be used (Guideline). Diagnostic criteria for vascular dementia, dementia with Lewy bodies, and frontotemporal dementia may be of use in clinical practice (Option) but have imperfect reliability and validity. 3) Structural neuroimaging with either a noncontrast CT or MR scan in the initial evaluation of patients with dementia is appropriate. Because of insufficient data on validity, no other imaging procedure is recommended (Guideline). There are currently no genetic markers recommended for routine diagnostic purposes (Guideline). The CSF 14-3-3 protein is useful for confirming or rejecting the diagnosis of CJD (Guideline). 4) Screening for depression, B12 deficiency, and hypothyroidism should be performed (Guideline). Screening for syphilis in patients with dementia is not justified unless clinical suspicion for neurosyphilis is present (Guideline). Conclusions: Diagnostic criteria for dementia have improved since the 1994 practice parameter. Further research is needed to improve clinical definitions of dementia and its subtypes, as well as to determine the utility of various instruments of neuroimaging, biomarkers, and genetic testing in increasing diagnostic accuracy.
1,662 citations
TL;DR: In this article, the ADAMTS family of zinc metalloproteinase genes (ADAMTS13) was identified as the molecular mechanism responsible for TTP, and it was shown that the deficiency of ADADTS13 is the molecular mechanisms responsible for the development of TTP.
Abstract: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening systemic illness of abrupt onset and unknown cause. Proteolysis of the blood-clotting protein von Willebrand factor (VWF) observed in normal plasma is decreased in TTP patients. However, the identity of the responsible protease and its role in the pathophysiology of TTP remain unknown. We performed genome-wide linkage analysis in four pedigrees of humans with congenital TTP and mapped the responsible genetic locus to chromosome 9q34. A predicted gene in the identified interval corresponds to a segment of a much larger transcript, identifying a new member of the ADAMTS family of zinc metalloproteinase genes (ADAMTS13). Analysis of patients' genomic DNA identified 12 mutations in the ADAMTS13 gene, accounting for 14 of the 15 disease alleles studied. We show that deficiency of ADAMTS13 is the molecular mechanism responsible for TTP, and suggest that physiologic proteolysis of VWF and/or other ADAMTS13 substrates is required for normal vascular homeostasis.
1,629 citations
TL;DR: The studies described here form the basis for investigations into the molecular mechanisms of Candida biofilm biology and antifungal resistance and provide the means to design novel therapies for biofilm-based infections.
Abstract: Biofilms are a protected niche for microorganisms, where they are safe from antibiotic treatment and can create a source of persistent infection. Using two clinically relevant Candida albicans biofilm models formed on bioprosthetic materials, we demonstrated that biofilm formation proceeds through three distinct developmental phases. These growth phases transform adherent blastospores to well-defined cellular communities encased in a polysaccharide matrix. Fluorescence and confocal scanning laser microscopy revealed that C. albicans biofilms have a highly heterogeneous architecture composed of cellular and noncellular elements. In both models, antifungal resistance of biofilm-grown cells increased in conjunction with biofilm formation. The expression of agglutinin-like (ALS) genes, which encode a family of proteins implicated in adhesion to host surfaces, was differentially regulated between planktonic and biofilm-grown cells. The ability of C. albicans to form biofilms contrasts sharply with that of Saccharomyces cerevisiae, which adhered to bioprosthetic surfaces but failed to form a mature biofilm. The studies described here form the basis for investigations into the molecular mechanisms of Candida biofilm biology and antifungal resistance and provide the means to design novel therapies for biofilm-based infections.
1,543 citations
TL;DR: The in vivo evaluation of tissue responses to biomaterials, medical devices, and prostheses to determine intended performance characteristics and safety or biocompatibility considerations is described.
Abstract: ▪ Abstract All materials intended for application in humans as biomaterials, medical devices, or prostheses undergo tissue responses when implanted into living tissue. This review first describes fundamental aspects of tissue responses to materials, which are commonly described as the tissue response continuum. These actions involve fundamental aspects of tissue responses including injury, inflammatory and wound healing responses, foreign body reactions, and fibrous encapsulation of the biomaterial, medical device, or prosthesis. The second part of this review describes the in vivo evaluation of tissue responses to biomaterials, medical devices, and prostheses to determine intended performance characteristics and safety or biocompatibility considerations. While fundamental aspects of tissue responses to materials are important from research and development perspectives, the in vivo evaluation of tissue responses to these materials is important for performance, safety, and regulatory reasons.
TL;DR: Morphometric analysis showed that mitochondria are significantly reduced in Alzheimer's disease, and the relationship shown here between the site and extent of mitochondrial abnormalities and oxidative damage suggests an intimate and early association between these features in dementia.
Abstract: The finding that oxidative damage, including that to nucleic acids, in Alzheimer's disease is primarily limited to the cytoplasm of susceptible neuronal populations suggests that mitochondrial abnormalities might be part of the spectrum of chronic oxidative stress of Alzheimer's disease. In this study, we used in situ hybridization to mitochondrial DNA (mtDNA), immunocytochemistry of cytochrome oxidase, and morphometry of electron micrographs of biopsy specimens to determine whether there are mitochondrial abnormalities in Alzheimer's disease and their relationship to oxidative damage marked by 8-hydroxyguanosine and nitrotyrosine. We found that the same neurons showing increased oxidative damage in Alzheimer's disease have a striking and significant increase in mtDNA and cytochrome oxidase. Surprisingly, much of the mtDNA and cytochrome oxidase is found in the neuronal cytoplasm and in the case of mtDNA, the vacuoles associated with lipofuscin. Morphometric analysis showed that mitochondria are significantly reduced in Alzheimer's disease. The relationship shown here between the site and extent of mitochondrial abnormalities and oxidative damage suggests an intimate and early association between these features in Alzheimer's disease.
TL;DR: Three experiments found that believing that one's bad mood was frozen (unchangeable) eliminated the tendency to eat fattening snacks, seek immediate gratification, and engage in frivolous procrastination during emotional distress.
Abstract: Why do people's impulse controls break down during emotional distress? Some theories propose that distress impairs one's motivation or one's ability to exert self-control, and some postulate self-destructive intentions arising from the moods. Contrary to those theories, Three experiments found that believing that one's bad mood was frozen (unchangeable) eliminated the tendency to eat fattening snacks (Experiment 1), seek immediate gratification (Experiment 2), and engage in frivolous procrastination (Experiment 3). The implication is that when people are upset, they indulge immediate impulses to make themselves feel better, which amounts to giving short-term affect regulation priority over other self-regulatory goals.
TL;DR: In this article, the authors developed a refined multidimensional measure of intrapreneurship to be cross-culturally generalizable because its refined dimensions' scales include only cross-culture comparable items.
TL;DR: By understanding the complex, multistep and multifactorial differentiation pathway from MSC to functional tissues, it might be possible to manipulate MSCs directly in vivo to cue the formation of elaborate, composite tissues in situ.
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TL;DR: Conceptual integration—“blending”—is a general cognitive operation on a par with analogy, recursion, mental modeling, conceptual categorization, and framing that yields products that frequently become entrenched in conceptual structure and grammar.
Abstract: This is an expanded version of Gilles Fauconnier and Mark Turner. 1998. "Conceptual Integration Networks." Cognitive Science 22:2 (April-June 1998), 133-187. Conceptual integration - "blending" - is a general cognitive operation on a par with analogy, recursion, mental modeling, conceptual categorization, and framing. It serves a variety of cognitive purposes. It is dynamic, supple, and active in the moment of thinking. It yields products that frequently become entrenched in conceptual structure and grammar, and it often performs new work on its previously entrenched products as inputs. Blending is easy to detect in spectacular cases but it is for the most part a routine, workaday process that escapes detection except on technical analysis. It is not reserved for special purposes, and is not costly.In blending, structure from input mental spaces is projected to a separate, blended mental space. The projection is selective. Through completion and elaboration, the blend develops structure not provided by the inputs. Inferences, arguments, and ideas developed in the blend can have effect in cognition, leading us to modify the initial inputs and to change our view of the corresponding situations.Blending operates according to a set of uniform structural and dynamic principles. It additionally observes a set of optimality principles.
TL;DR: Conditions under which it is possible to prove the existence of continuous state feedback control laws that achieve global strong stability (GSS) in the sense of Kurzweil (1956) are described.
Abstract: We present a continuous feedback approach to the problem of global strong stabilization, for genuinely nonlinear systems that may not be stabilized, even locally, by any smooth feedback. We describe conditions under which it is possible to prove, while no smooth controllers exist, the existence of continuous state feedback control laws that achieve global strong stability (GSS) in the sense of Kurzweil (1956). The proof is constructive and carried out by developing a machinery, which combines the theory of homogeneous systems with the idea of adding a power integrator, for the explicit construction of globally stabilizing continuous controllers. We then illustrate, by means of examples, how this machinery can be used to overcome the topological obstruction caused by smooth feedback, and hence resulting in new solutions to a variety of open control problems, including global stabilization of an underactuated unstable two degree of freedom mechanical system.
TL;DR: Ramipril, compared with amlodipine, retards renal disease progression in patients with hypertensive renal disease and proteinuria and may offer benefit to patients without proteinuria.
Abstract: ContextIncidence of end-stage renal disease due to hypertension has increased
in recent decades, but the optimal strategy for treatment of hypertension
to prevent renal failure is unknown, especially among African Americans.ObjectiveTo compare the effects of an angiotensin-converting enzyme (ACE) inhibitor
(ramipril), a dihydropyridine calcium channel blocker (amlodipine), and a β-blocker
(metoprolol) on hypertensive renal disease progression.Design, Setting, and ParticipantsInterim analysis of a randomized, double-blind, 3 × 2 factorial
trial conducted in 1094 African Americans aged 18 to 70 years with hypertensive
renal disease (glomerular filtration rate [GFR] of 20-65 mL/min per 1.73 m2) enrolled between February 1995 and September 1998. This report compares
the ramipril and amlodipine groups following discontinuation of the amlodipine
intervention in September 2000.InterventionsParticipants were randomly assigned to receive amlodipine, 5 to 10 mg/d
(n = 217), ramipril, 2.5 to 10 mg/d (n = 436), or metoprolol, 50 to 200 mg/d
(n = 441), with other agents added to achieve 1 of 2 blood pressure goals.Main Outcome MeasuresThe primary outcome measure was the rate of change in GFR; the main
secondary outcome was a composite index of the clinical end points of reduction
in GFR of more than 50% or 25 mL/min per 1.73 m2, end-stage renal
disease, or death.ResultsAmong participants with a urinary protein to creatinine ratio of >0.22
(corresponding approximately to proteinuria of more than 300 mg/d), the ramipril
group had a 36% (2.02 [SE, 0.74] mL/min per 1.73 m2/y) slower mean
decline in GFR over 3 years (P = .006) and a 48%
reduced risk of the clinical end points vs the amlodipine group (95% confidence
interval [CI], 20%-66%). In the entire cohort, there was no significant difference
in mean GFR decline from baseline to 3 years between treatment groups (P = .38). However, compared with the amlodipine group,
after adjustment for baseline covariates the ramipril group had a 38% reduced
risk of clinical end points (95% CI, 13%-56%), a 36% slower mean decline in
GFR after 3 months (P = .002), and less proteinuria
(P<.001).ConclusionRamipril, compared with amlodipine, retards renal disease progression
in patients with hypertensive renal disease and proteinuria and may offer
benefit to patients without proteinuria.
TL;DR: Rat marrow-derived MSCs were ex vivo culture-expanded, labeled with 111In-oxine, and infused into syngeneic rats via intra-artery, intravenous and intraperitoneal cavity infusions, indicating multiple homing sites for injected M SCs and that the distribution of MSCS can be influenced by administration of vasodilator.
Abstract: Bone marrow-derived mesenchymal stem cells (MSCs) have the potential to differentiate along different mesenchymal lineages including those forming bone, cartilage, tendon, fat, muscle and marrow stroma that supports hematopoiesis. This differentiation potential makes MSCs candidates for cell-based therapeutic strategies for mesenchymal tissue injuries and for hematopoietic disorders by both local and systemic application. In the present study, rat marrow-derived MSCs were ex vivo culture-expanded, labeled with (111)In-oxine, and infused into syngeneic rats via intra-artery (i.a.), intravenous (i.v.) and intraperitoneal cavity (i.p.) infusions. In addition, for i.a. and i.v. infusions, a vasodilator, sodium nitroprusside, was administered prior to the cell infusion and examined for its effect on MSC circulation. The dynamic distribution of infused MSCs was monitored by real-time imaging using a gamma camera immediately after infusion and at 48 h postinfusion. After 48 h, radioactivity in excised organs, including liver, lungs, kidneys, spleen and long bones, was measured in a gamma well counter and expressed as a percentage of injected doses. After both i.a. and i.v. infusion, radioactivity associated with MSCs was detected primarily in the lungs and then secondarily in the liver and other organs. When sodium nitroprusside was used, more labeled MSCs cleared the lungs resulting in a larger proportion detected in the liver. Most importantly, the homing of labeled MSCs to the marrow of long bones was significantly increased by the pretreatment with vasodilator. These results indicate multiple homing sites for injected MSCs and that the distribution of MSCs can be influenced by administration of vasodilator.
TL;DR: This review focuses on new insights into the protein kinaseRNA‐regulated (PRKR) protein, which have been made possible with the availability of PRKR‐null mice, and focuses particularly on the functions of the ISGs identified by analyzing microarray data.
Abstract: Interferons (IFNs) are a family of multifunctional cytokines that activate transcription of subsets of genes. The gene products induced by IFNs are responsible for IFN antiviral, antiproliferative, and immunomodulatory properties. To obtain a more comprehensive list and a better understanding of the genes regulated by IFNs, we compiled data from many experiments, using two different microarray formats. The combined data sets identified >300 IFN-stimulated genes (ISGs). To provide new insight into IFN-induced cellular phenotypes, we assigned these ISGs to functional categories. The data are accessible on the World Wide Web at http://www.lerner.ccf.org/labs/williams/, including functional categories and individual genes listed in a searchable database. The entries are linked to GenBank and Unigene sequence information and other resources. The goal is to eventually compile a comprehensive list of all ISGs. Recognition of the functions of the ISGs and their specific roles in the biological effects of IFNs is leading to a greater appreciation of the many facets of these intriguing and essential cytokines. This review focuses on the functions of the ISGs identified by analyzing the microarray data and focuses particularly on new insights into the protein kinase RNA-regulated (PRKR) protein, which have been made possible with the availability of PRKR-null mice.
TL;DR: Umbilical-cord blood from unrelated donors can restore hematopoiesis in adults who receive myeloablative therapy and is associated with acceptable rates of severe acute and chronic GVHD.
Abstract: Background Umbilical-cord blood from unrelated donors who are not HLA-identical with the recipients can restore hematopoiesis after myeloablative therapy in children. We studied the use of transplantation of umbilical-cord blood to restore hematopoiesis in adults. Methods Sixty-eight adults with life-threatening hematologic disorders received intensive chemotherapy or total-body irradiation and then transplants of HLA-mismatched umbilical-cord blood. We evaluated the outcomes in terms of hematologic reconstitution, the occurrence of acute and chronic graft-versus-host disease (GVHD), relapses, and event-free survival. Results Of the 68 patients, 48 (71 percent) received grafts of umbilical-cord blood that were mismatched for two or more HLA antigens. Of the 60 patients who survived 28 days or more after transplantation, 55 had neutrophil engraftment at a median of 27 days (range, 13 to 59). The estimated probability of neutrophil recovery in the 68 patients was 0.90 (95 percent confidence interval, 0.85 t...
TL;DR: Data demonstrate that ligands of RAGE can induce sustained activation of NF-kappaB as a result of increased levels of de novo synthesized NF-KappaBp65 overriding endogenous negative feedback mechanisms and thus might contribute to the persistent NF- kappaB activation observed in hyperglycemia and possibly other chronic diseases.
Abstract: Activation of the transcription factor nuclear factor-kappaB (NF-kappaB) has been suggested to participate in chronic disorders, such as diabetes and its complications. In contrast to the short and transient activation of NF-kappaB in vitro, we observed a long-lasting sustained activation of NF-kappaB in the absence of decreased IkappaBalpha in mononuclear cells from patients with type 1 diabetes. This was associated with increased transcription of NF-kappaBp65. A comparable increase in NF-kappaBp65 antigen and mRNA was also observed in vascular endothelial cells of diabetic rats. As a mechanism, we propose that binding of ligands such as advanced glycosylation end products (AGEs), members of the S100 family, or amyloid-beta peptide (Abeta) to the transmembrane receptor for AGE (RAGE) results in protein synthesis-dependent sustained activation of NF-kappaB both in vitro and in vivo. Infusion of AGE-albumin into mice bearing a beta-globin reporter transgene under control of NF-kappaB also resulted in prolonged expression of the reporter transgene. In vitro studies showed that RAGE-expressing cells induced sustained translocation of NF-kappaB (p50/p65) from the cytoplasm into the nucleus for >1 week. Sustained NF-kappaB activation by ligands of RAGE was mediated by initial degradation of IkappaB proteins followed by new synthesis of NF-kappaBp65 mRNA and protein in the presence of newly synthesized IkappaBalpha and IkappaBbeta. These data demonstrate that ligands of RAGE can induce sustained activation of NF-kappaB as a result of increased levels of de novo synthesized NF-kappaBp65 overriding endogenous negative feedback mechanisms and thus might contribute to the persistent NF-kappaB activation observed in hyperglycemia and possibly other chronic diseases.
TL;DR: It is argued that the ability to detect and label emotion cues facilitates positive social interactions and that a deficit in this ability contributes to behavioral and learning problems.
Abstract: Following leads from differential emotions theory and empirical research, we evaluated an index of emotion knowledge as a long-term predictor of positive and negative social behavior and academic competence in a sample of children from economically disadvantaged families (N = 72). The index of emotion knowledge represents the child's ability to recognize and label emotion expressions. We administered control and predictor measures when the children were 5 years old and obtained criterion data at age 9. After controlling for verbal ability and temperament, our index of emotion knowledge predicted aggregate indices of positive and negative social behavior and academic competence. Path analysis showed that emotion knowledge mediated the effect of verbal ability on academic competence. We argue that the ability to detect and label emotion cues facilitates positive social interactions and that a deficit in this ability contributes to behavioral and learning problems. Our findings have implications for primary ...
TL;DR: For instance, this paper found that men have more frequent and more intense sexual desires than women, as reflected in spontaneous thoughts about sex, frequency and variety of sexual fantasies, desired frequency of intercourse, desired number of partners, masturbation, willingness to forego sex, initiating versus refusing sex, making sacrifices for sex, and other measures.
Abstract: The sex drive refers to the strength of sexual motivation. Across many different studies and measures, men have been shown to have more frequent and more intense sexual desires than women, as reflected in spontaneous thoughts about sex, frequency and variety of sexual fantasies, desired frequency of intercourse, desired number of partners, masturbation, liking for various sexual practices, willingness to forego sex, initiating versus refusing sex, making sacrifices for sex, and other measures. No contrary findings (indicating stronger sexual motivation among women) were found. Hence we conclude that the male sex drive is stronger than the female sex drive. The gender difference in sex drive should not be generalized to other constructs such as sexual or orgasmic capacity, enjoyment of sex, or extrinsically motivated sex.
TL;DR: Results indicate that H-Ras up-regulates theglut1 promoter, at least in part, by increasing HIF-1α protein levels leading to transactivation of promoter through the HIF1 binding site.
TL;DR: Atrial fibrillation is a ubiquitous yet diverse cardiac arrhythmia whose incidence increases with age; with most forms of cardiac and some pulmonary diseases; and with a number of metabolic, toxic, endocrine, or genetic abnormalities.
Abstract: Atrial fibrillation (AF) is a ubiquitous yet diverse cardiac arrhythmia whose incidence increases with age; with most forms of cardiac and some pulmonary diseases; and with a number of metabolic, toxic, endocrine, or genetic abnormalities.1 2 Classification of clinical AF subtypes can be achieved on the basis of the ease by which episodes of the arrhythmia terminate as follows3 : “Paroxysmal” AF refers to episodes that generally stop spontaneously after no more than a few days. “Persistent” AF occurs less frequently than paroxysmal AF and, rather than self-terminating, requires cardioversion to restore sinus rhythm. “Permanent” AF cannot be converted to sinus rhythm. These terms apply strictly to chronic AF, because a single episode of the arrhythmia cannot be fully categorized. Although there are some mixed patterns, they generally derive from physician impatience for early cardioversion or from pragmatic clinical considerations (eg, to avoid thrombus formation or hemodynamic decompensation).
Patients initially presenting with paroxysmal AF often progress to longer, non–self-terminating bouts. An exception may be paroxysmal AF during intense vagotonia. Moreover, AF initially responsive to pharmacological or electrical cardioversion tends to become resistant and cannot then be converted to sinus rhythm. To some extent, the failure of the physician to suggest or the patient to accept further cardioversion attempts may lead to diagnosis of “permanent” AF. Thus, the “point of no return” may be determined by true pathophysiological abnormalities or may merely be an artifact of clinical pragmatism.
Effective prevention is essential in managing this arrhythmia whose occurrence is widespread, progression is relentless, and morbidity and mortality are significant. To focus on means for prevention necessitates considering both clinical risk factors and pathophysiology.
AF derives from a complex continuum predisposing factors, summarized in Table 1⇓. In the West, about 5% of the population >65 years of age …
TL;DR: The results suggest that real-time OCT has potential applications in glaucoma evaluation and refractive surgery and high-speed OCT at 1310-nm wavelength is a potentially useful technique for noninvasive assessment of anterior segment structures.
Abstract: Background Recent advances in high-speed scanning technology have enabled a new generation of optical coherence tomographic (OCT) systems to perform imaging at video rate. Here, a handheld OCT probe capable of imaging the anterior segment of the eye at high frame rates is demonstrated for the first time. Objective To demonstrate real-time OCT imaging of anterior segment structures. Design Survey of anterior segment structures in normal human subjects. Setting Laboratory. Main Outcome Measures Achieving real-time imaging of the anterior segment, satisfactory image quality, and convenience of a handheld probe. Results Optical coherence tomographic imaging of the anterior segment of the eyes of human subjects was performed using 1310-nm wavelength light with an image rate of 8 frames per second. Imaging trials demonstrated clear resolution of corneal epithelium and stroma, sclerocorneal junction, sclera, iris pigment epithelium and stroma, and anterior lens capsule. The anterior chamber angle was clearly visualized. Limited imaging of the ciliary body was performed. Real-time imaging of pupillary constriction in response to light stimulus was also performed. Conclusion High-speed OCT at 1310-nm wavelength is a potentially useful technique for noninvasive assessment of anterior segment structures. Clinical Relevance Our results suggest that real-time OCT has potential applications in glaucoma evaluation and refractive surgery.
TL;DR: The study found that influence of group cohesion over social presence is additive, rather than substitutive, to that of media condition, and played a more important role than social presence in determining the degree of consensus among group members in computer-mediated communication environments.
Abstract: Organizations deploy advanced communication media such as audio and videoconferencing to enhance and extend group communication interactions. However, established groups (i.e., groups with a history of working together) can view and use the same technology differently from groups without any past experiences of working together. This study examines the relative influences of media condition and group cohesion on social presence, task participation, and group consensus. Results from a controlled laboratory experiment with 45 triads of college students working on a decision-making task showed that media condition (audio conferencing vs. desktop videoconferencing) has significantly smaller influences on social presence and task participation than group cohesion in established groups. The study found that influence of group cohesion over social presence is additive, rather than substitutive, to that of media condition. The study also established that task participation played a more important role than social presence in determining the degree of consensus among group members in computer-mediated communication environments.
TL;DR: Mechanisms of mitochondrial-derived myocyte injury and the involvement of mitochondria in the pathogenesis of specific cardiac disease states (ischemia, reperfusion, aging, ischemic preconditioning, and cardiomyopathy) are addressed.
TL;DR: Although originally believed to be a benign clinical entity, nonalcoholic steatohepatitis is now recognized as a cause of progressive fibrotic liver disease with adverse clinical sequelae.
Abstract: Nonalcoholic steatohepatitis, along with other forms of nonalcoholic fatty liver disease, is a chronic liver disease that is attracting increasing significance. It is a clinicopathologic syndrome that was originally described in obese, diabetic females who denied alcohol use but in whom the hepatic histology was consistent with alcoholic hepatitis. This typical patient profile has been expanded and is now recognized to occur even in normal weight males without overt abnormalities in carbohydrate metabolism. Although originally believed to be a benign clinical entity, nonalcoholic steatohepatitis is now recognized as a cause of progressive fibrotic liver disease with adverse clinical sequelae. It is important to emphasize that nonalcoholic steatohepatitis is best considered one type of a larger spectrum of nonalcoholic fatty liver disease that is a consequence of insulin resistance and ranges from fat alone to fat plus inflammation, fat plus ballooning degeneration, and nonalcoholic steatohepatitis, the latter being the most serious form. As with any disease, the clinical importance of nonalcoholic steatohepatitis is related to its prevalence and natural history. Recent studies using different methodologies indicate that in the general population the prevalence of fatty liver and nonalcoholic steatohepatitis is approximately 20% and 3%, respectively. These prevalence rates are increased in certain subpopulations such as obesity and type II diabetes. Of greater concern is the recognition that cirrhosis and liver-related deaths occur in approximately 20% and 8% of these patients, respectively, over a 10-year period. Risk factors for these adverse clinical symptoms include patients older than the age of 45, the presence of diabetes or obesity, an aspartate aminotransferase/alanine aminotransferase ratio > 1 and hepatic histology. However, a number of important unresolved issues must be clarified before the true natural history of this disease can be fully understood.