CiteULike: Tag disease

Rapid selection of accessible and cleavable sites in RNA by Escherichia coli RNase P and random external guide sequences

Eirik Lundblad — 2008-02-17T10:55:53-00:00

Proceedings of the National Academy of Sciences (8 February 2008), 0711977105.

A method of inhibiting the expression of particular genes by using external guide sequences (EGSs) has been improved in its rapidity and specificity. Random EGSs that have 14-nt random sequences are used in the selection procedure for an EGS that attacks the mRNA for a gene in a particular location. A mixture of the random EGSs, the particular target RNA, and RNase P is used in the diagnostic procedure, which, after completion, is analyzed in a gel with suitable control lanes. Within a few hours, the procedure is complete. The action of EGSs designed by an older method is compared with EGSs designed by the random EGS method on mRNAs from two bacterial pathogens. 10.1073/pnas.0711977105

Origins of major human infectious diseases

Nathan Wolfe — 2007-05-17T12:42:57-00:00

Nature, Vol. 447, No. 7142. (17 May 2007), pp. 279-283.

Gut inflammation and spondyloarthropathies.

F De Keyser — 2008-02-12T22:11:32-00:00

Curr Rheumatol Rep, Vol. 4, No. 6. (December 2002), pp. 525-532.

Spondyloarthropathies (SpA) are a group of related disorders with common clinical and genetic characteristics. The prototype disease in this group is ankylosing spondylitis; other entities include reactive arthritis, psoriatic arthritis, and arthritis in patients with inflammatory bowel disease. Over recent years, there has been a special interest in the relation between spondylitis/synovitis and gut inflammation in patients with SpA. Two thirds of patients with undifferentiated SpA show histologic signs of gut inflammation, and a fraction of these patients go on to develop clinically overt Crohn's disease. In this review, the authors will focus on 1) the growing evidence that has been provided that gut inflammation in SpA is immunologically related to Crohn's disease, based on the molecular characterization of the inflammation (lymphocyte homing markers and ligands, T cell cytokines, macrophage markers, and serology); and 2) on the therapeutic implications resulting from this concept. The recent introduction and positioning of anti-tumor necrosis factor-alpha therapy in patients with ankylosing spondylitis and other types of SpA is, in large part, based on this concept.

The role of gut inflammation in the pathogenesis of spondyloarthropathies.

H Mielants — 2008-02-12T22:08:10-00:00

Acta Clin Belg, Vol. 51, No. 5. (1996), pp. 340-349.

The concept of spondyloarthropathy (SpA) gathers together a group of chronic diseases with common clinical, biological, genetic and therapeutic characteristics. The concept forms a distinct entity, different from other rheumatic diseases. The target organs are not only the joint, but also the axial skeleton, the enthesis, the eye, the gut, urogenital tract, the skin and sometimes the heart. The prevalence of this entity in the general population is estimated 1%, equal to the prevalence of rheumatoid arthritis. Genetical predisposition (HLA-B27) is one of the clues to the pathogenesis of the disease. Since reactive arthritis is induced by specific urogenital or enterogenic bacteriae, and since the gut is implicated in different forms of spondyloarthropathies, especially in IBD, it was clear that the gut could play an important role by permitting exogenous factors to enter the body. This hypothesis was the rationale for investigating the gut in the spondyloarthropathies by performing ileocolonoscopies. In the first ileocolonoscopic studies of SpA patients, histological signs of gut inflammation were found in a relatively great number of patients, mostly without any clinical intestinal manifestations. These lesions were not seen in other inflammatory joint diseases. Further ileocolonoscopic studies confirmed the strong relationship between gut and joint inflammation. In patients in whom a second ileocolonoscopy was performed, remission of the joint inflammation was always connected with a disappearance of the gut inflammation, whereas persistence of locomotor inflammation was mostly associated to the persistence of gut inflammation. The hypothesis was proposed that some patients with a spondyloarthropathy had a form of subclinical Crohn's disease in which the locomotor inflammation was the only clinical expression. This hypothesis was confirmed in prospective long-term studies in which the ileocolonoscoped patients were reviewed 2 to 9 years later: about 6% of SpA patients not presenting any sign of Crohn's disease at first investigation but demonstrating gut inflammation on biopsy, developed full-blown Crohn's disease. The discovery of subclinical gut inflammation in the SpA had therapeutic consequences. Sulphasalazine (SASP) has been proven to be an active drug in the treatment of IBD. Since the gut could play a crucial role in SpA, it was logic to use this drug in the treatment of this disease. Multiple open and double-blind studies have proven the effectiveness of this drug in SpA; recent studies concluded that the beneficial effect of the drug in this disease entity is more prominent on the peripheral arthritis than on the axial disease.

Widespread amphibian extinctions from epidemic disease driven by global warming

Alan Pounds — 2006-01-12T03:44:31-00:00

Nature, Vol. 439, No. 7073., pp. 161-167.

An ecological and evolutionary perspective on humanâmicrobe mutualism and disease

Les Dethlefsen — 2007-10-20T17:10:38-00:00

Nature, Vol. 449, No. 7164. (17 October 2007), pp. 811-818.

Host-Parasite Relations, Vectors, and the Evolution of Disease Severity

PW Ewald — 2008-04-21T05:15:24-00:00

Annual Review of Ecology and Systematics, Vol. 14, No. 1. (1983), pp. 465-485.

Urbanization and the ecology of wildlife diseases

Catherine Bradley — 2008-03-24T06:38:11-00:00

Trends in Ecology & Evolution, Vol. 22, No. 2. (February 2007), pp. 95-102.

Urbanization is intensifying worldwide, with two-thirds of the human population expected to reside in cities within 30 years. The role of cities in human infectious disease is well established, but less is known about how urban landscapes influence wildlife-pathogen interactions. Here, we draw on recent advances in wildlife epidemiology to consider how environmental changes linked with urbanization can alter the biology of hosts, pathogens and vectors. Although urbanization reduces the abundance of many wildlife parasites, transmission can, in some cases, increase among urban-adapted hosts, with effects on rarer wildlife or those living beyond city limits. Continued rapid urbanization, together with risks posed by multi-host pathogens for humans and vulnerable wildlife populations, emphasize the need for future research on wildlife diseases in urban landscapes.

Seasonality and the dynamics of infectious diseases

Sonia Altizer — 2006-03-30T14:33:32-00:00

Ecology Letters, Vol. 9, No. 4. (April 2006), pp. 467-484.

Allelic association and disease mapping.

S Ennis — 2007-04-03T09:54:01-00:00

Brief Bioinform, Vol. 2, No. 4. (December 2001), pp. 375-387.

The application of allelic association to map genes for complex traits, particularly using high-density maps of single nucleotide polymorphisms in candidate regions, is an area of very active research. Here we present some aspects of the methodology and applications to both major gene mapping, which illustrates the effectiveness of the method, and oligogenes, where methods are still in flux and for which there have been relatively few successes to date. Several important considerations emerge, including the selection of the optimal metric for measuring association and the importance of modelling the decline in association with distance given the variability in association in a candidate region. The Malecot model of association with distance is shown to have a resolution of greater than 50 kilobases but the available evidence suggests that considerably higher resolution might be achieved with dense single nucleotide polymorphism (SNP) maps.

Discovery of Novel Targets of Quinoline Drugs in the Human Purine Binding Proteome

Paul Graves — 2008-01-03T16:03:59-00:00

Mol Pharmacol, Vol. 62, No. 6. (1 December 2002), pp. 1364-1372.

The quinolines have been used in the treatment of malaria, arthritis, and lupus for many years, yet the precise mechanism of their action remains unclear. In this study, we used a functional proteomics approach that exploited the structural similarities between the quinoline compounds and the purine ring of ATP to identify quinoline-binding proteins. Several quinoline drugs were screened by displacement affinity chromatography against the purine binding proteome captured with [gamma]-phosphate-linked ATP-Sepharose. Screening of the human red blood cell purine binding proteome identified two human proteins, aldehyde dehydrogenase 1 (ALDH1) and quinone reductase 2 (QR2). In contrast, no proteins were detected upon screening of the Plasmodium falciparum purine binding proteome with the quinolines. In a complementary approach, we passed cell lysates from mice, red blood cells, or P. falciparum over hydroxychloroquine- or primaquine-Sepharose. Consistent with the displacement affinity chromatography screen, ALDH and QR2 were the only proteins recovered from mice and human red blood cell lysate and no proteins were recovered from P. falciparum. Furthermore, the activity of QR2 was potently inhibited by several of the quinolines in vitro. Our results show that ALDH1 and QR2 are selective targets of the quinolines and may provide new insights into the mechanism of action of these drugs. 10.1124/mol.62.6.1364

Targeting Tyrosine Kinases in Cancer: The Second Wave

Jose Baselga — 2006-05-30T07:39:39-00:00

Science, Vol. 312, No. 5777. (26 May 2006), pp. 1175-1178.

One of the most exciting developments in cancer research in recent years has been the clinical validation of molecularly targeted drugs that inhibit the action of pathogenic tyrosine kinases. Treatment of appropriately selected patients with these drugs can alter the natural history of their disease and improve survival. The clinical validation of these "first-generation" tyrosine kinase inhibitors has been the prelude to a second wave of advances in molecular targeting that is expected to further change the way we classify and treat cancer. Efforts are now being directed at identifying the tumor subtypes and patients who will benefit the most from these drugs. In addition, new compounds that circumvent acquired resistance to the first-generation tyrosine kinase inhibitors are being tested in patients with refractory disease. Agents directed against new molecular targets are also being explored. 10.1126/science.1125951

The human disease network

Kwang-Il Goh — 2007-05-23T08:39:54-00:00

PNAS, Vol. 104, No. 21. (22 May 2007), pp. 8685-8690.

A network of disorders and disease genes linked by known disorder-gene associations offers a platform to explore in a single graph-theoretic framework all known phenotype and disease gene associations, indicating the common genetic origin of many diseases. Genes associated with similar disorders show both higher likelihood of physical interactions between their products and higher expression profiling similarity for their transcripts, supporting the existence of distinct disease-specific functional modules. We find that essential human genes are likely to encode hub proteins and are expressed widely in most tissues. This suggests that disease genes also would play a central role in the human interactome. In contrast, we find that the vast majority of disease genes are nonessential and show no tendency to encode hub proteins, and their expression pattern indicates that they are localized in the functional periphery of the network. A selection-based model explains the observed difference between essential and disease genes and also suggests that diseases caused by somatic mutations should not be peripheral, a prediction we confirm for cancer genes. 10.1073/pnas.0701361104

Human disease classification in the postgenomic era: A complex systems approach to human pathobiology

Joseph Loscalzo — 2007-07-11T18:26:11-00:00

Mol Syst Biol, Vol. 3 (10 July 2007)

A linguistic model for the rational design of antimicrobial peptides

Christopher Loose — 2006-10-18T20:12:56-00:00

Nature, Vol. 443, No. 7113., pp. 867-869.

Tyrosine kinase inhibitors: a new approach for asthma

Fred Wong — 2006-05-28T15:30:08-00:00

Biochimica et Biophysica Acta (BBA) - Proteins & Proteomics, Vol. 1697, No. 1-2. (11 March 2004), pp. 53-69.

The pathogenesis of allergic asthma involves the interplay of inflammatory cells and airway-resident cells, and of their secreted mediators including cytokines, chemokines, growth factors and inflammatory mediators. Receptor tyrosine kinases are important for the pathogenesis of airway remodeling. Activation of epidermal growth factor (EGF) receptor kinase and platelet-derived growth factor (PDGF) receptor kinase leads to hyperplasia of airway smooth muscle cells, epithelial cells and goblet cells. Stimulation of non-receptor tyrosine kinases (e.g. Lyn, Lck, Syk, ZAP-70, Fyn, Btk, Itk) is the earliest detectable signaling response upon antigen-induced immunoreceptor activation in inflammatory cells. Cytokine receptor dimerization upon ligand stimulation induces activation of Janus tyrosine kinases (JAKs), leading to recruitment and phosphorylation of signal transducer and activator of transcription (STAT) for selective gene expression regulation. Activation of chemokine receptors can trigger JAK-STAT pathway, Lck, Fyn, Lyn, Fgr, and Syk/Zap-70 to induce chemotaxis of inflammatory cells. Inhibitors of tyrosine kinases have been shown in vitro to block growth factor-induced hyperplasia of airway-resident cells; antigen-induced inflammatory cell activation and cytokine synthesis; cytokine-mediated pro-inflammatory gene expression in inflammatory and airway cells; and chemokine-induced chemotaxis of inflammatory cells. Recently, anti-inflammatory effects of tyrosine kinase inhibitors (e.g. genistein, tyrphostin AG213, piceatannol, tyrphostin AG490, WHI-P97, WHI-P131, Syk antisense) in animal models of allergic asthma have been reported. Therefore, development of inhibitors of tyrosine kinases can be a very attractive strategy for the treatment of asthma.

One Bit of Advice

Harry Richard — 2005-02-23T06:38:16-00:00

The results in this paper show that coNP is contained in NP with 1 bit of advice (denoted NP=1) if and only if the Polynomial Hierarchy (PH) collapses to D , the second level of the Boolean Hierarchy (BH). Previous work showed that BH D =) coNP NP=poly. The stronger assumption that PH D in the new result allows the length of the advice function to be reduced to a single bit and also makes the converse true. The one-bit case can be generalized to any constant k: PH BH 2 k ...

A case of unilateral neglect in Huntington's disease.

AK Ho — 2008-03-01T13:09:35-00:00

Neurocase, Vol. 9, No. 3. (June 2003), pp. 261-273.

Unilateral neglect, an attentional deficit in detecting and acting on information coming from one side of space, is a relatively common consequence of right hemisphere stroke. Although neglect has been observed following damage to a variety of brain structures, to date no reports exist of neglect phenomena arising from Huntington's Disease (HD). However, reports in the animal and human literature suggest that neglect is possible following damage to a primary site for Huntington's pathology, the basal ganglia. Here we present a patient (BG) with genetically proven HD who, in the context of the mild intellectual, executive and attentional impairments associated with the disorder, showed a remarkably severe and stable neglect for left space. MRI and electrophysiological results make it unlikely that the spatial bias could be accounted for by basic sensory loss. In addition, behavioural investigation indicated that, although BG's neglect operated in a very striking manner along body-centred co-ordinates (missing almost all information presented to her left), more general limitations in visual attention were apparent to the left-side of information presented entirely to the right of the body midline. Further evidence is presented showing that the neglect was manifest on tactile and auditory tasks as well as those presented in the visual domain. The presence of neglect in HD in this case is novel and somewhat puzzling, particularly as flourodeoyglucose positron emission tomography revealed bilateral caudate hypoperfusion. Reducing the statistical threshold on this analysis revealed a potential frontal hypometabolism that was more marked in the right than left hemisphere. However, as this was only apparent at a threshold below that normally considered acceptable (due to the resulting number of false positives), this possible account of the neglect must be viewed very cautiously.

Role of molecular cell biology in understanding disease.

J Savill — 2006-03-09T01:46:16-00:00

BMJ, Vol. 314, No. 7075. (18 January 1997), pp. 203-206.

Molecular techniques have revolutionised our knowledge of cell and tissue function in both health and disease. We already have new and powerful treatments based on an understanding of communication between cells by messenger molecules called cytokines. Furthermore, there is great therapeutic promise in defining molecules which regulate cell adhesion, motility, proliferation, survival, and death. Rational manipulation of cell and tissue function for therapeutic ends may be much closer than you think.

Catalytic antibodies in healthy humans and patients with autoimmune and viral diseases.

GA Nevinsky — 2006-01-17T21:05:57-00:00

J Cell Mol Med, Vol. 7, No. 3. (p 2003), pp. 265-276.

Antibodies have been first characterized as proteins produced by the immune system solely for binding other molecules, called antigens, with the goal of eliciting immune response. In this classical conception, antibodies act similarly to enzymes in specific binding to different molecules but cannot catalyze their chemical conversion. However, in 1986 the first monoclonal catalytic antibodies against a chemically stable analog of the transition state of a reaction were obtained and termed abzymes (Abzs). At present, artificial monoclonal Abzs catalyzing more than 100 distinct chemical reactions have been obtained. The discovery of IgG specifically hydrolyzing intestinal vasoactive peptide in the blood serum of asthma patients stimulated studies of natural Abzs. Numerous Abzs discovered afterwards in sera of patients with various autoimmune diseases, viral disorders, or in the milk of healthy mothers, are capable of hydrolyzing proteins, DNA, RNA, polysaccharides, or nucleotides, as well as to phosphorylate proteins and lipids. The phenomenon of catalysis by auto-Abzs is more and more in research focus. In this review we summarize new data on Abzs applications in basic science, medicine and biotechnology.

p53 in health and disease

Karen Vousden — 2007-03-24T18:09:51-00:00

Nature Reviews Molecular Cell Biology, Vol. 8, No. 4., pp. 275-283.

Advances in mechanisms of genetic instability related to hereditary neurological diseases.

RD Wells — 2006-02-16T19:48:47-00:00

Nucleic Acids Res, Vol. 33, No. 12. (2005), pp. 3785-3798.

Substantial progress has been realized in the past several years in our understanding of the molecular mechanisms responsible for the expansions and deletions (genetic instabilities) of repeating tri-, tetra- and pentanucleotide repeating sequences associated with a number of hereditary neurological diseases. These instabilities occur by replication, recombination and repair processes, probably acting in concert, due to slippage of the DNA complementary strands relative to each other. The biophysical properties of the folded-back repeating sequence strands play a critical role in these instabilities. Non-B DNA structural elements (hairpins and slipped structures, DNA unwinding elements, tetraplexes, triplexes and sticky DNA) are described. The replication mechanisms are influenced by pausing of the replication fork, orientation of the repeat strands, location of the repeat sequences relative to replication origins and the flap endonuclease. Methyl-directed mismatch repair, nucleotide excision repair, and repair of damage caused by mutagens are discussed. Genetic recombination and double-strand break repair advances in Escherichia coli, yeast and mammalian models are reviewed. Furthermore, the newly discovered capacities of certain triplet repeat sequences to cause gross chromosomal rearrangements are discussed.

The expanding universe of prion diseases.

JC Watts — 2006-05-18T01:28:37-00:00

PLoS Pathog, Vol. 2, No. 3. (March 2006)

Prions cause fatal and transmissible neurodegenerative disease. These etiological infectious agents are formed in greater part from a misfolded cell-surface protein called PrP(C). Several mammalian species are affected by the diseases, and in the case of "mad cow disease" (BSE) the agent has a tropism for humans, with negative consequences for agribusiness and public health. Unfortunately, the known universe of prion diseases is expanding. At least four novel prion diseases-including human diseases variant Creutzfeldt-Jakob disease (vCJD) and sporadic fatal insomnia (sFI), bovine amyloidotic spongiform encephalopathy (BASE), and Nor98 of sheep-have been identified in the last ten years, and chronic wasting disease (CWD) of North American deer (Odocoileus Specis) and Rocky Mountain elk (Cervus elaphus nelsoni) is undergoing a dramatic spread across North America. While amplification (BSE) and dissemination (CWD, commercial sourcing of cervids from the wild and movement of farmed elk) can be attributed to human activity, the origins of emergent prion diseases cannot always be laid at the door of humankind. Instead, the continued appearance of new outbreaks in the form of "sporadic" disease may be an inevitable outcome in a situation where the replicating pathogen is host-encoded.

Mechanisms of disease: beta-adrenergic receptors--alterations in signal transduction and pharmacogenomics in heart failure.

DS Feldman — 2005-11-04T22:01:06-00:00

Nat Clin Pract Cardiovasc Med, Vol. 2, No. 9. (September 2005), pp. 475-483.

Beta-adrenergic signaling is an important regulator of myocardial function. During the progression of heart failure (HF), a reproducible series of biochemical events occurs that affects beta-adrenergic receptor (beta-AR) signaling and cardiac function. Furthermore, there are pathophysiologic alterations in the expression and regulation of proteins that are regulated by beta-ARs during HF. Analyses of these complex signaling pathways have led to a better understanding of HF mechanisms and the use of beta-adrenergic antagonists, which have notably altered HF-related morbidity and mortality. Despite therapeutic advances that have affected beta-AR signaling, HF remains a leading cause of hospitalization and a principal cause of death in industrialized nations. In this review, we summarize current insights into beta-adrenergic signal-transduction pathways, the best-described beta-AR polymorphisms, and therapies that target the beta-AR pathway in HF.

Recruitment of beta-arrestin2 to the dopamine D2 receptor: Insights into anti-psychotic and anti-parkinsonian drug receptor signaling.

Ib V Klewe — 2008-05-13T15:23:32-00:00

Neuropharmacology (8 April 2008)

Drugs acting at dopamine D2-like receptors play a pivotal role in the treatment of both schizophrenia and Parkinson's disease. Recent studies have demonstrated a role for G-protein independent D2 receptor signaling pathways acting through beta-arrestin. In this study we describe the establishment of a Bioluminescence Resonance Energy Transfer (BRET) assay for measuring dopamine induced recruitment of human beta-arrestin2 to the human dopamine D2 receptor. Dopamine, as well as the dopamine receptor agonists pramipexole and quinpirole, acted as full agonists in the assay as reflected by their ability to elicit marked concentration dependent increases in the BRET signal signifying beta-arrestin2 recruitment to the D2 receptor. As expected from their effect on G-protein coupling and cAMP levels mediated through the D2 receptor RNPA, pergolide, apomorphine, ropinirole, bromocriptine, 3PPP, terguride, aripiprazole, SNPA all acted as partial agonists with decreasing efficacy in the BRET assay. In contrast, a wide selection of typical and atypical anti-psychotics was incapable of stimulating beta-arrestin2 recruitment to the D2 receptor. Moreover, we observed that haloperidol, sertindole, olanzapine, clozapine and ziprasidone all fully inhibited the dopamine induced beta-arrestin2 recruitment to D2 receptor (short variant) in a concentration dependent manner. We conclude that most anti-psychotics are incapable of stimulating beta-arrestin2 recruitment to the dopamine D2 receptor, in accordance with their antagonistic properties at the level of G-protein coupling.

Missense mutations in transmembrane domains of proteins: phenotypic propensity of polar residues for human disease.

AW Partridge — 2006-01-27T14:30:56-00:00

Proteins, Vol. 54, No. 4. (1 March 2004), pp. 648-656.

Previous experiments on the cystic fibrosis transmembrane conductance regulator suggested that non-native polar residues within membrane domains can compromise protein structure/function. However, depending on context, replacement of a native residue by a non-native residue can result either in genetic disease or in benign effects (e.g., polymorphisms). Knowledge of missense mutations that frequently cause protein malfunction and subsequent disease can accordingly reveal information as to the impact of these residues in local protein environments. We exploited this concept by performing a statistical comparison of disease-causing mutations in protein membrane-spanning domains versus soluble domains. Using the Human Gene Mutation Database of 240 proteins (including 80 membrane proteins) associated with human disease, we compared the relative phenotypic propensity to cause disease of the 20 naturally occurring amino acids when removed from-or inserted into-native protein sequences. We found that in transmembrane domains (TMDs), mutations involving polar residues, and ionizable residues in particular (notably arginine), are more often associated with protein malfunction than soluble proteins. To further test the hypothesis that interhelical cross-links formed by membrane-embedded polar residues stabilize TMDs, we compared the occurrence of such residues in the TMDs of mesophilic and thermophilic prokaryotes. Results showed a significantly higher proportion of ionizable residues in thermophilic organisms, reinforcing the notion that membrane-embedded electrostatic interactions play critical roles in TMD stability.

A polymorphism within a conserved beta(1)-adrenergic receptor motif alters cardiac function and beta-blocker response in human heart failure.

SB Liggett — 2006-09-05T10:37:17-00:00

Proc Natl Acad Sci U S A, Vol. 103, No. 30. (25 July 2006), pp. 11288-11293.

Heterogeneity of heart failure (HF) phenotypes indicates contributions from underlying common polymorphisms. We considered polymorphisms in the beta(1)-adrenergic receptor (beta(1)AR), a beta-blocker target, as candidate pharmacogenomic loci. Transfected cells, genotyped human nonfailing and failing ventricles, and a clinical trial were used to ascertain phenotype and mechanism. In nonfailing and failing isolated ventricles, beta(1)-Arg-389 had respective 2.8 +/- 0.3- and 4.3 +/- 2.1-fold greater agonist-promoted contractility vs. beta(1)-Gly-389, defining enhanced physiologic coupling under relevant conditions of endogenous expression and HF. The beta-blocker bucindolol was an inverse agonist in failing Arg, but not Gly, ventricles, without partial agonist activity at either receptor; carvedilol was a genotype-independent neutral antagonist. In transfected cells, bucindolol antagonized agonist-stimulated cAMP, with a greater absolute decrease observed for Arg-389 (435 +/- 80 vs. 115 +/- 23 fmol per well). Potential pathophysiologic correlates were assessed in a placebo-controlled trial of bucindolol in 1,040 HF patients. No outcome was associated with genotype in the placebo group, indicating little impact on the natural course of HF. However, the Arg-389 homozygotes treated with bucindolol had an age-, sex-, and race-adjusted 38% reduction in mortality (P = 0.03) and 34% reduction in mortality or hospitalization (P = 0.004) vs. placebo. In contrast, Gly-389 carriers had no clinical response to bucindolol compared with placebo. Those with Arg-389 and high baseline norepinephrine levels trended toward improved survival, but no advantage with this allele and exaggerated sympatholysis was identified. We conclude that beta(1)AR-389 variation alters signaling in multiple models and affects the beta-blocker therapeutic response in HF and, thus, might be used to individualize treatment of the syndrome.

Pharmacogenomic and structural analysis of constitutive g protein-coupled receptor activity.

MJ Smit — 2007-04-17T11:34:10-00:00

Annu Rev Pharmacol Toxicol, Vol. 47 (2007), pp. 53-87.

G protein-coupled receptors (GPCRs) respond to a chemically diverse plethora of signal transduction molecules. The notion that GPCRs also signal without an external chemical trigger, i.e., in a constitutive or spontaneous manner, resulted in a paradigm shift in the field of GPCR pharmacology. The discovery of constitutive GPCR activity and the fact that GPCR binding and signaling can be strongly affected by a single point mutation drew attention to the evolving area of GPCR pharmacogenomics. For a variety of GPCRs, point mutations have been convincingly linked to human disease. Mutations within conserved motifs, known to be involved in GPCR activation, might explain the properties of some naturally occurring, constitutively active GPCR variants linked to disease. In this review, we provide a brief historical introduction to the concept of constitutive receptor activity and the pharmacogenomic and structural aspects of constitutive receptor activity.

Clinical consequences of ADR2 polymorphisms

Hawkins — 2008-03-01T16:05:41-00:00

Pharmacogenomics, Vol. 9, No. 3. (March 2008), pp. 349-358.

Structural and dynamical changes in an alpha-subunit of a heterotrimeric G protein along the activation pathway.

Ned Van Eps — 2006-10-27T11:09:45-00:00

Proc Natl Acad Sci U S A (19 October 2006)

The Galpha subunits of heterotrimeric G proteins (Galphabetagamma) mediate signal transduction via activation by receptors and subsequent interaction with downstream effectors. Crystal structures indicate that conformational changes in "switch" sequences of Galpha, controlled by the identity of the bound nucleotide (GDP and GTP), modulate binding affinities to the Gbetagamma subunits, receptor, and effector proteins. To investigate the solution structure and dynamics of Galphai1 through the G protein cycle, nitroxide side chains (R1) were introduced at sites in switch II and at a site in helix alpha4, a putative effector binding region. In the inactive Galphai1(GDP) state, the EPR spectra are compatible with conformational polymorphism in switch II. Upon complex formation with Gbetagamma, motions of R1 are highly constrained, reflecting direct contact interactions at the Galphai1-Gbeta interface; remarkably, the presence of R1 at the sites investigated does not substantially affect the binding affinity. Complex formation between the heterotrimer and activated rhodopsin leads to a dramatic change in R1 motion at residue 217 in the receptor-binding alpha2/beta4 loop and smaller allosteric changes at the Galphai1-Gbetagamma interface distant from the receptor binding surface. Upon addition of GTPgammaS, the activated Galphai1(GTP) subunit dissociates from the complex, and switch II is transformed to a unique conformation similar to that in crystal structures but with a flexible backbone. A previously unreported activation-dependent change in alpha4, distant from the interaction surface, supports a role for this helix in effector binding.

Disease in History: Frames and Framers

Charles Rosenberg — 2007-02-04T14:36:51-00:00

In some ways disease does not exist until we agree that it does-by perceiving, naming, and responding to it. These acts of agreement have during the past century become increasingly central to social as well as medical thought. What is often overlooked, however, is the process of disease definition itself-the fashioning of explanatory "frames" for understanding disease-and the consequence of those definitions, once they are agreed upon, in the lives of individuals, in the making and discussion of social policy, and in the structuring of medical care. More study is needed of the individual experience of disease in time and place, the relation of culture to definition of disease, and the role of the state in defining and responding to disease.

Automated attention flags in chronic disease care planning.

JR Warren — 2005-10-14T15:14:10-00:00

Med J Aust, Vol. 175, No. 6. (17 September 2001), pp. 308-312.

OBJECTIVES: To assess the value of computerised decision support in the management of chronic respiratory disease by comparing agreement between three respiratory specialists, general practitioners (care coordinators), and decision support software. METHODS: Care guidelines for two chronic obstructive pulmonary disease projects of the SA HealthPlus Coordinated Care Trial were formulated. Decision support software, Care Plan On-Line (CPOL), was created to represent the intent of these guidelines via automated attention flags to appear in patients' electronic medical records. For a random sample of 20 patients with care plans, decisions about the use of nine additional services (eg, smoking cessation, pneumococcal vaccination) were compared between the respiratory specialists, the patients' GPs and the CPOL attention flags. RESULTS: Agreement among the specialists was at the lower end of moderate (intraclass correlation coefficient [ICC], 0.48; 95% CI, 0.39-0.56), with a 20% rate of contradictory decisions. Agreement with recommendations of specialists was moderate to poor for GPs (kappa, 0.49; 95% CI, 0.33-0.66) and moderate to good for CPOL (kappa, 0.72; 95% CI, 0.55-0.90). CPOL agreement with GPs was moderate to poor (kappa, 0.41; 95% CI, 0.24-0.58). GPs were less likely than specialists or CPOL to decide in favour of an additional service (P<0.001). CPOL was 87% accurate as an indicator of specialist decisions. It gave a 16% false-positive rate according to specialist decisions, and flagged 61% of decisions where GPs said No and specialists said Yes. CONCLUSIONS: Automated decision support may provide GPs with improved access to the intent of guidelines; however, further investigation is required.

A universal mechanism ties genotype to phenotype in trinucleotide diseases

Shai Kaplan — 2007-10-22T08:43:47-00:00

PLoS Computational Biology, Vol. preprint, No. 2007. (1 October 2007), e235.eor.

Trinucleotide hereditary diseases such as Huntington and Friedreich's Ataxia are cureless diseases associated with inheriting an abnormally large number of DNA trinucleotide repeats in a gene. The genes associated with different diseases are unrelated and harbor a trinucleotide repeat in different functional regions, therefore it is striking that many of these diseases have similar correlations between their genotype, namely the number of inherited repeats, and age of onset and progression phenotype. These correlations remain unexplained despite more than a decade of research. Although mechanisms have been proposed for several trinucleotide diseases, none of the proposals, being disease-specific, can account for the commonalities among these diseases. Here we propose a universal mechanism in which length-dependent somatic repeat expansion occurs during the patient's lifetime towards a pathological threshold. Our mechanism uniformly explains for the first time the genotype-phenotype correlations common to trinucleotide disease and is well-supported by both experimental and clinical data. In addition, mathematical analysis of the mechanism provides for the first time simple explanations to a wide range of phenomena such as the exponential decrease of the age-of-onset curve, similar onset but faster progression in homozygote vs. heterozygote HD patients and correlation of age of onset with length of the short allele but not with the long allele in Friedreich's Ataxia. If our proposed universal mechanism proves to be the core component of the actual mechanisms of specific trinucleotide diseases, it would open the search for a uniform treatment for all these diseases, possibly by delaying the somatic expansion process.

Gene expression profiling predicts clinical outcome of breast cancer.

LJ van 't Veer — 2006-02-14T07:49:54-00:00

Nature, Vol. 415, No. 6871. (31 January 2002), pp. 530-536.

Breast cancer patients with the same stage of disease can have markedly different treatment responses and overall outcome. The strongest predictors for metastases (for example, lymph node status and histological grade) fail to classify accurately breast tumours according to their clinical behaviour. Chemotherapy or hormonal therapy reduces the risk of distant metastases by approximately one-third; however, 70-80% of patients receiving this treatment would have survived without it. None of the signatures of breast cancer gene expression reported to date allow for patient-tailored therapy strategies. Here we used DNA microarray analysis on primary breast tumours of 117 young patients, and applied supervised classification to identify a gene expression signature strongly predictive of a short interval to distant metastases ('poor prognosis' signature) in patients without tumour cells in local lymph nodes at diagnosis (lymph node negative). In addition, we established a signature that identifies tumours of BRCA1 carriers. The poor prognosis signature consists of genes regulating cell cycle, invasion, metastasis and angiogenesis. This gene expression profile will outperform all currently used clinical parameters in predicting disease outcome. Our findings provide a strategy to select patients who would benefit from adjuvant therapy.

Gene prioritization through genomic data fusion

Stein Aerts — 2006-05-06T03:29:27-00:00

Nature Biotechnology, Vol. 24, No. 5. (05 May 2006), pp. 537-544.

Mendelian Inheritance in Man and its online version, OMIM.

Victor McKusick — 2007-10-09T19:20:36-00:00

Am J Hum Genet, Vol. 80, No. 4. (April 2007), pp. 588-604.

Modelling genotype-phenotype relationships and human disease with genetic interaction networks

Ben Lehner — 2007-08-27T14:12:27-00:00

J Exp Biol, Vol. 210, No. 9. (1 May 2007), pp. 1559-1566.

Probably all heritable traits, including disease susceptibility, are affected by interactions between mutations in multiple genes. We understand little, however, about how genes interact to produce phenotypes, and there is little power to detect interactions between genes in human population studies. An alternative approach towards understanding how mutations combine to produce phenotypes is to construct systematic genetic interaction networks in model organisms. Here I describe the methods that are being used to map genetic interactions in yeast and C. elegans, and the insights that these networks provide for human disease. I also discuss the mechanistic interpretation of genetic interaction networks, how genetic interactions can be used to understand gene function, and methods that have been developed to predict genetic interactions on a genome-wide scale. 10.1242/jeb.002311

Pain Disability Among Older Adults With Arthritis

Nadine James — 2004-12-28T17:09:44-00:00

Journal of Aging and Health, Vol. 17, No. 1., 56.

Conformationally altered p53: a novel Alzheimer's disease marker?

C Lanni — 2007-08-09T00:41:02-00:00

Molecular Psychiatry, Vol. aop, No. current.

C-Reactive Protein, Inflammatory Conditions, and Cardiovascular Disease Risk

Ravi Dhingra — 2008-02-18T09:26:46-00:00

The American Journal of Medicine, Vol. 120, No. 12. (December 2007), pp. 1054-1062.

Background It is uncertain to what extent high C-reactive protein (CRP) concentrations reflect the presence of inflammatory conditions in the community.Methods We evaluated 3782 Framingham Offspring Study participants (mean age 55 years; 52% women) free of baseline cardiovascular disease. Logistic regression models examined the prevalence of common inflammatory conditions by CRP categories, while a separate matched case-referent analysis evaluated the prevalence of uncommon inflammatory conditions. Cox models were used to assess the influence of common inflammatory conditions on relations between CRP and incident cardiovascular disease.Results Common inflammatory conditions were reported by nearly half of the participants; these individuals were more likely to have markedly high CRP concentrations (>10 mg/L, P for trend = .001). In multivariable models, there were increased odds of having at least one common inflammatory condition with CRP concentrations of 1-3.0, 3.01-10, and >10 mg/L, compared with the referent category (<1 mg/L); the respective odds ratios with 95% confidence intervals were 1.41 (1.07-1.86), 1.45 (1.07-1.98), and 1.64 (1.09-2.47) in men, and 1.08 (0.82-1.43), 1.07 (0.80-1.44), and 1.38 (0.97-1.96) in women. In case-referent analyses, uncommon inflammatory conditions were more common in individuals with CRP >10 mg/L compared with those with CRP <1 mg/L (12.1% vs 6.6%; P = .0001). In multivariable models, higher CRP categories were not associated with incident cardiovascular disease, and with additional adjustment for inflammatory conditions, results remained unchanged.Conclusion There is high prevalence of common and uncommon inflammatory conditions in individuals with high CRP concentrations. Higher CRP concentrations should be interpreted with caution in cardiovascular disease risk assessment.

Chronic disease management systems registries in rural health care.

A Skinner — 2006-07-19T17:46:18-00:00

Rural Policy Brief, Vol. 11, No. 1 (PB2006-1). (May 2006), pp. 1-8.

Health care quality is being addressed from a variety of policy perspectives. The 2001 Institute of Medicine report, Crossing the Quality Chasm, calls for sweeping action involving a five-part strategy for change in the U.S. health care system. This agenda for change includes use of evidence-based approaches to address common conditions, the majority of which are chronic. A Chronic Disease Management System (CDMS), or registry, is a tool that helps providers efficiently collect and analyze patient information to promote quality care for the rural population. CDMSs can provide a technological entry point for the impending use of Electronic Medical Records. A CDMS is a patient-centered electronic database tool that helps providers diagnose, treat, and manage chronic diseases. The purpose of this brief is to discuss the different types of CDMSs used by a sample of 14 state organizations and 19 local rural clinics in Maine, Nebraska, New Mexico, South Carolina, Washington, and Wisconsin. As part of a larger study examining the challenges and innovations in implementing disease management programs in rural areas, we conducted interviews with national, state, and local contacts. During interviews, respondents helped us understand the usefulness and functionalities of commonly used CDMSs in rural facilities. Our focus was on the use of CDMSs in the management of diabetes, a disease prevalent in rural populations. Key Findings: (1) CDMSs are readily available to rural clinics and are being implemented and maintained by clinic staff with minimal expenditures for technology. (2) Use of a standardized system in a collaborative helps provide data comparisons and share costs involved with technical assistance services across the group.

Use of medical informatics for management of multiple sclerosis using a chronic-care model.

MJ Hatzakis — 2006-07-19T17:44:05-00:00

J Rehabil Res Dev, Vol. 43, No. 1. (b 2006), pp. 1-16.

The mission of the Multiple Sclerosis Centers of Excellence (MSCoEs) is to optimize the services veterans with multiple sclerosis (MS) receive across the U.S. Veterans Health Administration. To accomplish this mission, the MSCoE West has adopted a collaborative chronic-disease management strategy along the lines of the model described by Wagner and colleagues. This model describes an organized, integrated, proactive, and population-based approach to patient care that includes healthcare delivery system change and patient-based self-management. While Wagner's model is described independent of information technology, the majority of actions called for in that model benefit tremendously from the application of a powerful and well-integrated informatics infrastructure designed to serve and support populations with chronic disease. Key elements such as goals and actions encourage high-quality care for those with chronic illnesses.

Disease management. Technology-driven outcomes.

T Perry — 2007-02-03T15:15:14-00:00

Health Manag Technol, Vol. 25, No. 1. (January 2004), pp. 40-43.

Information technology will play a significant role in identifying those interventions that generate best outcomes.

High quality care for people with chronic diseases.

T Groves — 2006-08-21T18:53:48-00:00

BMJ, Vol. 330, No. 7492. (19 March 2005), pp. 609-610.

Indiana chronic disease management program risk stratification analysis.

J Li — 2006-12-22T17:18:36-00:00

Med Care, Vol. 43, No. 10. (October 2005), pp. 979-984.

OBJECTIVE: The objective of this study was to compare the ability of risk stratification models derived from administrative data to classify groups of patients for enrollment in a tailored chronic disease management program. SUBJECTS: This study included 19,548 Medicaid patients with chronic heart failure or diabetes in the Indiana Medicaid data warehouse during 2001 and 2002. MEASURES: To predict costs (total claims paid) in FY 2002, we considered candidate predictor variables available in FY 2001, including patient characteristics, the number and type of prescription medications, laboratory tests, pharmacy charges, and utilization of primary, specialty, inpatient, emergency department, nursing home, and home health care. METHODS: We built prospective models to identify patients with different levels of expenditure. Model fit was assessed using R statistics, whereas discrimination was assessed using the weighted kappa statistic, predictive ratios, and the area under the receiver operating characteristic curve. RESULTS: We found a simple least-squares regression model in which logged total charges in FY 2002 were regressed on the log of total charges in FY 2001, the number of prescriptions filled in FY 2001, and the FY 2001 eligibility category, performed as well as more complex models. This simple 3-parameter model had an R of 0.30 and, in terms in classification efficiency, had a sensitivity of 0.57, a specificity of 0.90, an area under the receiver operator curve of 0.80, and a weighted kappa statistic of 0.51. CONCLUSION: This simple model based on readily available administrative data stratified Medicaid members according to predicted future utilization as well as more complicated models.

The Indiana Chronic Disease Management Program

Marc Rosenman — 2006-03-10T13:46:19-00:00

The Milbank Quarterly, Vol. 84, No. 1. (March 2006), pp. 135-163.

Disease management interventions to improve outcomes in congestive heart failure.

JL Roglieri — 2007-12-14T05:58:17-00:00

Am J Manag Care, Vol. 3, No. 12. (December 1997), pp. 1831-1839.

This study is part of a planned 24-month, multicenter, longitudinal comparison of a comprehensive congestive heart failure (CHF) disease management program and was designed to determine effectiveness after 12 months of implementation. The impact of interventions such as telemonitoring of patients, post-hospitalization follow-up, and provider education on selected primary outcomes (hospital admission and readmission rates, length of stay, total hospital days, and emergency room utilization) in a managed care setting was evaluated. Subjects in the study included all participants in the managed care plan, as well as 149 selected program participants. The effects of the program were analyzed for pure CHF and CHF-related diagnoses, with outcomes for the third quarter of 1996 (postintervention follow-up) being compared with those for the third quarter of 1995 (preintervention baseline). Overall, the data demonstrated significantly reduced admission and readmission rates for patients with the pure CHF diagnosis. Among the entire CHF patient population, the third quarter admission rate declined 63% (P = 0.00002), and the 30-day and 90-day readmission rates declined 75% (P = 0.02) and 74% (P = 0.004), respectively. Among program participants with pure CHF diagnoses, the 30-day readmission rate was reduced to 0, and an 83% reduction occurred for both the third quarter admission (P = 0.008) and 90-day readmission (P = 0.06) rates. In addition, the average length of stay for patients with CHF-related diagnoses was significantly reduced among both plan participants (P = 0.03) and program participants (P = 0.001). Reductions were also seen in total hospital days and emergency room utilization. These data thus indicate that a comprehensive disease management program can reduce healthcare utilization not only among CHF patients in the program but also among the entire managed care plan population.

Disease registries.

M Colias — 2005-05-12T18:14:57-00:00

Hosp Health Netw, Vol. 79, No. 2. (February 2005)

Five years ago, only a handful of pioneering providers knew anything about chronic disease registries, but pressure to better manage chronic illnesses has pushed them into the spotlight. Proponents say registries, which track key data for patients with specific diseases, are a relatively simple step toward a broader disease management program.

Monitoring in chronic disease: a rational approach.

P Glasziou — 2005-05-12T18:12:23-00:00

BMJ, Vol. 330, No. 7492. (19 March 2005), pp. 644-648.

Economic effectiveness of disease management programs: a meta-analysis.

DS Krause — 2005-05-12T18:10:02-00:00

Dis Manag, Vol. 8, No. 2. (April 2005), pp. 114-134.

The economic effectiveness of disease management programs, which are designed to improve the clinical and economic outcomes for chronically ill individuals, has been evaluated extensively. A literature search was performed with MEDLINE and other published sources for the period covering January 1995 to September 2003. The search was limited to empirical articles that measured the direct economic outcomes for asthma, diabetes, and heart disease management programs. Of the 360 articles and presentations evaluated, only 67 met the selection criteria for meta-analysis, which included 32,041 subjects. Although some studies contained multiple measurements of direct economic outcomes, only one average effect size per study was included in the meta-analysis. Based on the studies included in the research, a meta-analysis provided a statistically significant answer to the question of whether disease management programs are economically effective. The magnitude of the observed average effect size for equally weighted studies was 0.311 (95% CI = 0.272-0.350). Statistically significant differences of effect sizes by study design, disease type and intensity of disease management program interventions were not found after a moderating variable, disease severity, was taken into consideration. The results suggest that disease management programs are more effective economically with severely ill enrollees and that chronic disease program interventions are most effective when coordinated with the overall level of disease severity. The findings can be generalized, which may assist health care policy makers and practitioners in addressing the issue of providing economically effective care for the growing number of individuals with chronic illness. (Disease Management 2005;8:114-134).