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Disease Mechanisms (disease + mechanism)
Selected AbstractsSYMPOSIUM: New Disease Mechanisms in Multiple SclerosisBRAIN PATHOLOGY, Issue 2 2007Hans Lassmann No abstract is available for this article. [source] Disease mechanisms leading to impaired blood flow in glaucomaACTA OPHTHALMOLOGICA, Issue 2009D GHERGHEL Purpose SIS lecture Methods Literature search Results Although primary open-angle glaucoma (POAG), is associated more closely with elevated intraocular pressure (IOP), other risk factors already implicated in the aetiology of this disease and especially in the aetiology of normal-tension glaucoma are: abnormal ocular circulation, ocular and systemic vascular dysregulation, as well as systemic blood pressure (BP) alterations. Oxidative stress, which occurs as a result of an imbalance between generation of reactive oxygen species (ROS) and antioxidant defence mechanisms and is implicated in the pathogenesis of disorders ranging from atherosclerosis to neurodegenerative disorders, diabetes and aging, may also contribute to the general vascular disturbances observed in glaucoma. Moreover, increasing evidence shoes that oxidative stress plays a role in promoting endothelial dysfunction, which is a key factor in progression of vascular diseases. Indeed, glaucomatous optic nerve damage has been related to endothelial damage/dysfunction. This presentation explores the role of various ocular and systemic circulatory factors in the pathogenesis of glaucomatous neuropathy. [source] Actin mutations in hypertrophic and dilated cardiomyopathy cause inefficient protein folding and perturbed filament formationFEBS JOURNAL, Issue 8 2005Søren Vang Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are the most common hereditary cardiac conditions. Both are frequent causes of sudden death and are often associated with an adverse disease course. Alpha-cardiac actin is one of the disease genes where different missense mutations have been found to cause either HCM or DCM. We have tested the hypothesis that the protein-folding pathway plays a role in disease development for two actin variants associated with DCM and six associated with HCM. Based on a cell-free coupled translation assay the actin variants could be graded by their tendency to associate with the chaperonin TCP-1 ring complex/chaperonin containing TCP-1 (TRiC/CCT) as well as their propensity to acquire their native conformation. Some variant proteins are completely stalled in a complex with TRiC and fail to fold into mature globular actin and some appear to fold as efficiently as the wild-type protein. A fraction of the translated polypeptide became ubiquitinated and detergent insoluble. Variant actin proteins overexpressed in mammalian cell lines fail to incorporate into actin filaments in a manner correlating with the degree of misfolding observed in the cell-free assay; ranging from incorporation comparable to wild-type actin to little or no incorporation. We propose that effects of mutations on folding and fiber assembly may play a role in the molecular disease mechanism. [source] The full spectrum of holoprosencephaly-associated mutations within the ZIC2 gene in humans predicts loss-of-function as the predominant disease mechanism,,HUMAN MUTATION, Issue 4 2009Erich Roessler Abstract Mutations of the ZIC2 transcription factor gene are among the most common heterozygous variations detected in holoprosencephaly (HPE) patients, a patient group who lack critical midline forebrain specification due to defective embryonic signaling during development. Recent studies indicate that complete deficiency of the related murine Zic2 transcription factor can also be a contributing factor to variable midline deficiencies, presenting during mid-gastrulation, that could explain similar forebrain anomalies in this model system. Here we collect and summarize all available mutations in the human ZIC2 gene detected in HPE patients (21 published and 62 novel). Our analysis corroborates this mechanism proposed in mice by predicting loss-of-function as the likely pathogenetic mechanism common to most, if not all, of these mutations in HPE. Published 2009 Wiley-Liss, Inc. [source] Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis: a case series of nine patients and review of the literatureINTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 5 2007Camille E. Introcaso MD Background, Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis (NFD/NSF) is a fibrosing cutaneous disorder recently recognized to have systemic manifestations. The disease is characterized clinically by an acute onset of hardening and thickening of the skin of the extremities and trunk, often resulting in flexion contractures, and histologically by an increase in spindle-shaped cells, collagen, and sometimes mucin deposition in the dermis. The only common exposure amongst patients is acute or chronic renal failure. The pathophysiology of the disease remains to be elucidated, and there is currently no consistently effective treatment for this unremitting disease. Methods, We report a case series of nine patients seen at the University of Pennsylvania between 1998 and mid-2004. The clinical, laboratory, and pathologic data of these patients are reviewed. Results, All patients had renal disease, received peritoneal or hemodialysis, and five had received at least one renal transplant. All patients had characteristic fibrotic cutaneous lesions involving the trunk, extremities, or both, and eight of the nine patients had scleral plaques. There were no other common findings amongst the histories, medications, or laboratory results of the patients. Conclusion, Our report confirms the clinical and histologic characteristics of NFD that have been described previously, and raises new issues regarding the possible subtypes. A review of the current literature stresses that further basic science and translational studies are necessary to understand the disease mechanism and to propose effective therapy, and emphasizes the importance of recognizing the systemic effects of NFD. [source] Autoantigens in systemic autoimmunity: critical partner in pathogenesisJOURNAL OF INTERNAL MEDICINE, Issue 6 2009A. Rosen Abstract. Understanding the mechanisms of human autoimmune rheumatic diseases presents a major challenge, due to marked complexity involving multiple domains, including genetics, environment and kinetics. In spite of this, the immune response in each of these diseases is largely specific, with distinct autoantibodies associated with different disease phenotypes. Defining the basis of such specificity will provide important insights into disease mechanism. Accumulating data suggest an interesting paradigm for antigen selection in autoimmunity, in which target tissue and immune effector pathways form a mutually reinforcing partnership. In this model, distinct autoantibody patterns in autoimmunity may be viewed as the integrated, amplified output of several interacting systems, including: (i) the specific target tissue, (ii) the immune effector pathways that modify antigen structure and cause tissue damage and dysfunction, and (iii) the homeostatic pathways activated in response to damage (e.g. regeneration/differentiation/cytokine effects). As unique antigen expression and structure may occur exclusively under these amplifying circumstances, it is useful to view the molecules targeted as ,neo-antigens', that is, antigens expressed under specific conditions, rather than ubiquitously. This model adds an important new dynamic element to selection of antigen targets in autoimmunity, and suggests that the amplifying loop will only be identified by studying the diseased target tissue in vivo. [source] Genomics and Cardiovascular DiseaseJOURNAL OF NURSING SCHOLARSHIP, Issue 4 2005Lorraine Frazier Purpose: To describe genetic knowledge and discovery in the area of cardiovascular disease (CVD) and to discuss how these new advances will influence the clinical care of affected people. Organizing Framework: A selective review of the literature is presented on the disease mechanism of both the Mendelian and multifactorial genetic cardiovascular conditions. A case study approach is used to illustrate how the genetic paradigm affects the healthcare experience of a family affected with familial hypertrophic cardiomyopathy. Findings: The current state of CVD treatment remains complex. An understanding of genomic concepts and a genome-based approach is necessary to determine: (a) the risk of CVD susceptibility beyond traditional risk factors; (b) early detection of illness; (c) response to treatment; and (d) molecular taxonomy of the disease. Conclusions: The results of genetic research, education, and teaching will lead to a new understanding of genes and pathways, resulting in powerful new therapeutic approaches to CVD. The challenge is to translate genetic discoveries into clinical practice that ultimately leads to preventing CVD and reducing mortality. [source] Hypercalcemia in Cats: A Retrospective Study of 71 Cases (1991,1997)JOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 2 2000Karine CM. A retrospective study was conducted to characterize the diseases, clinical findings, and clinicopathologic and ultrasonographic findings associated with hypercalcemia (serum calcium concentration >11 mg/dL) in 71 cats presented to North Carolina State University Veterinary Teaching Hospital. The 3 most common diagnoses were neoplasia (n = 21), renal failure (n = 18), and urolithiasis (n = 11). Primary hyperparathyroidism was diagnosed in 4 cats. Lymphoma and squamous cell carcinoma were the most frequently diagnosed tumors. Calcium oxalate uroliths were diagnosed in 8 of 11 cats with urolithiasis. Cats with neoplasia had a higher serum calcium concentration (13.5 ± 2.5 mg/dL) than cats with renal failure or urolithiasis and renal failure (11.5 ± 0.4 mg/dL; P <.03). Serum phosphorus concentration was higher in cats with renal failure than in cats with neoplasia (P < .004). Despite the fact that the majority of cats with uroliths were azotemic, their serum urea nitrogen and creatinine concentrations and urine specific gravity differed from that of cats with renal failure. Additional studies are warranted to determine the underlying disease mechanism in the cats we identified with hypercalcemia and urolithiasis. We also identified a small number of cats with diseases that are not commonly reported with hypercalcemia. Further studies are needed to determine whether an association exists between these diseases and hypercalcemia, as well as to characterize the underlying pathophysiologic mechanism for each disease process. [source] Improvement in hepatopulmonary syndrome after methadone withdrawal: A case report with implications for disease mechanismLIVER TRANSPLANTATION, Issue 7 2010Edmund M. T. Lau Spontaneous resolution of hepatopulmonary syndrome (HPS) without liver transplantation or improvement in the underlying liver disease has rarely been reported in the literature. Increased endogenous production of nitric oxide has been implicated in the pathogenesis of HPS. We report the case of a 50-year-old man with hepatitis C cirrhosis who demonstrated dramatic improvement in HPS after withdrawal from chronic methadone therapy. We speculate on the potential role of opiate receptors in the pulmonary vasculature and their effect on nitric oxide signaling as a potential mechanism accounting for the patient's clinical improvement. Liver Transpl 16:870,873, 2010. © 2010 AASLD. [source] Translational experimental therapeutics: The translation of laboratory-based discovery into disease-related therapyMOUNT SINAI JOURNAL OF MEDICINE: A JOURNAL OF PERSONALIZED AND TRANSLATIONAL MEDICINE, Issue 1 2007Karl Kieburtz MD Abstract In the past decade, there has been an increasing emphasis on laboratory-based translational research. This has led to significant scientific advances in our understanding of disease mechanisms and in the development of novel approaches to therapy such as gene therapy, RNA interference, and stem cells. However, the translation of these remarkable scientific achievements into new and effective disease-modifying therapies has lagged behind these scientific accomplishments. We use the term "translational experimental therapeutics" to describe the pathway between the discovery of a basic disease mechanism or novel therapeutic approach and its translation into an effective treatment for patients with a specific disease. In this article, we review the components of this pathway, and discuss issues that might impede this process. Only by optimizing this pathway can we realize the full therapeutic potential of current scientific discoveries and translate the astounding advances that have been accomplished in the laboratory into effective treatments for our patients. Mt Sinai J Med 74: 7-14, 2007. Copyright © 2007 Mount Sinai School of Medicine [source] CFTR: More than just a chloride channelPEDIATRIC PULMONOLOGY, Issue 4 2005Anil Mehta MBBS, FRCP (Edin), FRCPCH Abstract This review examines the cystic fibrosis transmembrane conductance regulator (CFTR) protein. After summarizing the ion channels regulated by CFTR, the review focuses on the functions of CFTR that do not relate directly to a disease mechanism based on a channelopathy. The key concept is that newly synthesized CFTR has to enter lipid vesicles which bud from the endoplasmic reticulum. This is abnormally low in ,F508 CFTR. Normal wild type vesicular CFTR enters a recycling pool of lipid vesicles which transiently dock with the apical membrane only for CFTR to be retrieved shortly after into a sub-apical recycling compartment. This retrieval is abnormally fast in ,F508 CFTR. The review discusses the relationship between this process and the difficult topic of fat metabolism and then explores the possible links between abnormal fatty acid turnover and inflammatory cascades that are abnormal in cystic fibrosis. Finally the review concentrates on the emerging functions of a protein kinase (AMP-activated kinase) which is bound near the C terminus of the CFTR protein whose functions could intergrate some of the abnormalities in lipid metabolism that result from mislocalization of CFTR in clinical disease. Pediatr Pulmonol. 2005; 39:292,298. © 2004 Wiley-Liss, Inc. [source] Comparative proteomic analysis of differentially expressed proteins in primary retinoblastoma tumorsPROTEOMICS - CLINICAL APPLICATIONS, Issue 4 2010Kandalam Mallikarjuna Abstract Purpose: To understand the disease mechanism and to identify the potential tumor markers that would help in therapeutics, comparative proteomic analysis of 29 retinoblastoma (RB) tumors was performed using 14 non-neoplastic retinas (age ranged from 45 to 89 years) as control tissues. Experimental design: 2-DE and MALDI-TOF-TOF MS/MS were used to identify differentially expressed proteins. Results: Twenty-seven distinct differentially expressed proteins were identified, including 16 upregulated 11 downregulated proteins. Significantly, higher mRNA levels of apolipoprotein A1 (p<0.001), transferrin (TF; p<0.001), CRABP2 (p<0.001), ,-crystallin A (CRYAA; p<0.001) were observed in RBs when compared with normal retinas and hence are consistent with the proteomic data. Immunohistochemistry was also performed for selected proteins on paraffin RB blocks to confirm protein expression. RB with invasion showed significantly higher expression by 2-DE-MS/MS analysis of CRABP2 (p<0.001), peroxiredoxin 6 (p=0.025), apolipoprotein A1 (p<0.001), recoverin (p<0.001). Conclusions and clinical relevance: Thus, this study provides a dynamic protein profile of RB tumors, which could provide clues to study the mechanisms of RB oncogenesis and possibly be developed as potential biomarkers for prognosis and therapy. [source] Alpha-1-antitrypsin and complement component C7 are involved in asthma exacerbationPROTEOMICS - CLINICAL APPLICATIONS, Issue 1 2008Tatsuji Nishioka Abstract Asthma is the most common chronic disorder in childhood and asthma exacerbation is an important cause of childhood morbidity and hospitalization. Allergic responses are known to be biased toward T-helper type 2 in asthmatics; however, the pathogenesis of asthma is not simple, and our understanding of the disease mechanism remains incomplete. The aim of the present study was to identify protein expression signatures that reflect acute exacerbation of asthma. Plasma was taken twice from pediatric asthmatic patients, once during asthma exacerbation and once during a stable period. Plasma was also taken from healthy children as a control. The protein profiles of plasma during asthma exacerbation were analyzed by 2-DE and 49 spots were differentially expressed during asthma exacerbation. Thirty-eight of the spots were successfully identified by MALDI-TOF MS. Proteins up- or down-regulated during asthma exacerbation were involved in responses to stress and pathogens, in the complement and coagulation cascades, and in acute-phase responses. Among the differentially expressed proteins, up-regulation of alpha-1-antitrypsin and complement component C7 was confirmed by nephelometry and ELISA. Our present results suggest that protease inhibitors and complement components may be involved in asthma exacerbation, and plasma level of alpha-1-antitrypsin may be a potential biomarker for asthma. [source] Novel complement inhibitor limits severity of experimentally myasthenia gravis,ANNALS OF NEUROLOGY, Issue 1 2009Jindrich Soltys DVM Objective Complement mediated injury of the neuromuscular junction is considered a primary disease mechanism in human myasthenia gravis and animal models of experimentally acquired myasthenia gravis (EAMG). We utilized active and passive models of EAMG to investigate the efficacy of a novel C5 complement inhibitor rEV576, recombinantly produced protein derived from tick saliva, in moderating disease severity. Methods Standardized disease severity assessment, serum complement hemolytic activity, serum cytotoxicity, acetylcholine receptor (AChR) antibody concentration, IgG subclassification, and C9 deposition at the neuromuscular junction were used to assess the effect of complement inhibition on EAMG induced by administration of AChR antibody or immunization with purified AChR. Results Administration of rEV576 in passive transfer EAMG limited disease severity as evidenced by 100% survival rate and a low disease severity score. In active EAMG, rats with severe and mild EAMG were protected from worsening of disease and had limited weight loss. Serum complement activity (CH50) in severe and mild EAMG was reduced to undetectable levels during treatment, and C9 deposition at the neuromuscular junction was reduced. Treatment with rEV576 resulted in reduction of toxicity of serum from severe and mild EAMG rats. Levels of total AChR IgG, and IgG2a antibodies were similar, but unexpectedly, the concentration of complement fixing IgG1 antibodies was lower in a group of rEV576-treated animals, suggesting an effect of rEV576 on cellular immunity. Interpretation Inhibition of complement significantly reduced weakness in two models of EAMG. C5 inhibition could prove to be of significant therapeutic value in human myasthenia gravis. Ann Neurol 2009;65:67,75 [source] Biomarkers for Parkison's disease: Tools to assess Parkinson's disease onset and progression,ANNALS OF NEUROLOGY, Issue S2 2008Kenneth Marek MD Reliable and well-validated biomarkers for PD to identify individuals "at risk" before motor symptoms, accurately diagnose individuals at the threshold of clinical PD, and monitor PD progression throughout its course would dramatically accelerate research into both PD cause and therapeutics. Biomarkers offer the potential to provide a window onto disease mechanism, potentially generating therapeutic targets for disease. In particular, biomarkers enable investigation of the premotor period of PD before typical symptoms are manifest, but while degeneration has already begun. Given the multiple genetic causes for PD already identified, the marked variability in the loss of dopaminergic markers measured by imaging at motor symptom onset and the clear heterogeneity of clinical symptoms in PD onset and clinical progression, it is likely many biomarkers with a focus ranging from clinical symptoms to PD pathobiology to molecular genetic mechanisms will be necessary to fully map PD risk and progression. Biomarkers are also critical in new drug development for PD, both in early validation studies to assess drug dosing and to determine drug penetrance into the brain, and in later efficacy studies to complement PD clinical outcomes. During the past two decades, much progress has been made in identifying and assessing PD biomarkers, but as yet, no fully validated biomarker for PD is currently available. Nonetheless, there is increasing evidence that molecular genetics, focused -omic (proteomic, metabolomic, and transcriptomic) assessment of blood and cerebrospinal fluid, and advanced in vivo brain imaging will provide critical clues to assist in the diagnosis and medical management of PD patients. Ann Neurol 2008;64 (suppl):S111,S121 [source] Etiology of cicatricial alopecias: a basic science point of viewDERMATOLOGIC THERAPY, Issue 4 2008Kevin J. McElwee ABSTRACT: This article presents a short summary of our current knowledge of cicatricial alopecia disease pathogenesis and the hypothetical disease mechanisms that may be involved in scarring alopecia development. Several forms of scarring alopecia likely involve targeted cytotoxic action against hair follicle cells mediated by a folliculocentric inflammation. However, the specific nature of the inflammatory interference in hair follicle growth is open to question. A popular hypothesis of lymphocyte-mediated scarring alopecia development involves autoimmune targeting of hair follicle,specific self-antigens, although there is no direct evidence in support of such a view. Alternative hypotheses focus on defects in sebaceous gland function, destruction of hair follicle stem cells, and interference in the communication between hair follicle mesenchyme and epithelium. Many questions arise from these hypotheses, and addressing them with a systematic research approach may enable significant advances in understanding cicatricial alopecia etiology. [source] Molecular background of EPM1,Unverricht,Lundborg diseaseEPILEPSIA, Issue 4 2008Tarja Joensuu Summary Unverricht,Lundborg disease (EPM1) is an autosomal recessively inherited neurodegenerative disorder and the most common single cause of progressive myoclonus epilepsy worldwide. Mutations in the gene encoding cystatin B (CSTB), a cysteine protease inhibitor, are responsible for the primary defect underlying EPM1. Here, progress toward understanding the molecular mechanisms in EPM1 is reviewed. We summarize the current knowledge about the CSTB gene and mutations as well as the cellular biology of the CSTB protein with emphasis on data emerging from analysis of EPM1 patients. We shed light on the disease mechanisms of EPM1 based on characterization of the CSTB -deficient mouse model. [source] National Institute of Neurological Disorders and Stroke (NINDS): Advances in understanding and treating neuropathy, 24,25 October 2006; Bethesda, MarylandJOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 1 2008Eva L. Feldman Abstract National Institute of Neurological Disorders and Stroke sponsored a meeting to explore the current status of basic and clinical research in peripheral neurobiology and clinical neuropathy. The goal of the workshop was to identify areas where additional research could lead to the development of new therapeutics in the next 5 years. Participants discussed the current understanding of disease mechanisms of axonal and demyelinating neuropathies, existing techniques in research, disease biomarkers, and assessment of neuropathy. Painful neuropathies were discussed at the basic scientific and clinical levels in relation to new insights into etiology and treatment. The meeting concluded with a discussion on therapeutic development in neuropathy and the need for a unified approach to multicenter trials. Short-term goals of the workshop were to form a working group for neuropathy, the Peripheral Neuropathy Study Group, and to translate new scientific findings into therapies and complete clinical trials. [source] Genomics and systems biology , how relevant are the developments to veterinary pharmacology, toxicology and therapeutics?JOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2005R. F. WITKAMP This review discusses some of the recent developments in genomics and its current and future relevance for veterinary pharmacology and toxicology. With the rapid progress made in this field several new approaches in pharmacological and toxicological research have developed and drug discovery and drug development strategies have changed dramatically. In this review, the term genomics is used to encompass the three sub-disciplines transcriptomics, proteomics and metabolomics (or metabonomics) to describe the formation and fate of mRNA, proteins and metabolites, respectively. The current status and methods of the technology and some applications are briefly described. Although the DNA sequencing programmes are receiving considerable attention, the real value of genomics for pharmacology and toxicology is brought by the parallel developments in bio-informatics, bio-statistics and the integration of biology with mathematics and information technology. The ultimate level of integration is now mostly called systems biology, where mRNA, proteins and metabolites are being analysed in parallel, using a complete arsenal of analytical techniques (DNA-array, LC-MS/MS, GC-MS/MS, NMR, etc.). The information thus collected is analysed, integrated, linked to database information and translated to pathways and systems. This approach offers an enormous potential to study disease mechanisms and find new drug targets. Thus far, genomics and systems biology have not been introduced significantly in typical veterinary pharmacological and toxicological research programmes. The high costs and complexity connected to these large projects often form major obstacles for research groups with limited budgets. In other veterinary areas and disciplines, including infectious diseases, animal production and food-safety more examples of application are available. Genomics and bio-informatics provide outstanding opportunities to study pharmacology and toxicology in a more holistic way, taking into account the complexity of biological systems and based on the basic principles of physiology and the concept of homeostasis. Knowledge of biology, in vivo and in vitro models, and comparative pharmacology/toxicology is essential here, creating excellent opportunities for the veterinary trained scientist. [source] Endocannabinoids and liver disease , reviewLIVER INTERNATIONAL, Issue 5 2005Ezra Gabbay Abstract: Aims: Endocannabinoids are endogenous compounds that bind to the same receptors as tetrahydrocannabinol, the active component in marijuana and hashish. They have been found to have many physiological and patho-physiological functions, including mood alteration, control of feeding and appetite, motor and co-ordination activities, analgesia, immune modulation and gut motility. In this review we aim to elucidate current knowledge as to their role in liver physiology and disease. Methods: The major findings published to date concerning endocannabinoids and liver disease are described, and their implications with regard to understanding disease mechanisms, and the development of new treatments is considered. Results: Recently, endocannabinoids have been implicated in the hemodynamic alterations occurring in cirrhosis. These changes appear to be mediated via specific cannabinoid receptors (CB1) on splanchnic and hepatic vascular endothelium. Plasma levels of endocannabinoids also seem to be elevated in hepatitis, and are involved in apoptosis of hepatocytes by a membrane mechanism not related to a specific receptor. Other studies suggest a beneficial role for cannabinoids in reducing the inflammation of experimental hepatitis. In an animal model of acute hepatic failure, both endocannabinoids and the antagonist to the CB1 receptor have been found to have a beneficial effect on neurological and cognitive function. Conclusions: Endocannabinoids appear to be involved in several aspects of acute and chronic liver disease, including vascular changes, modulation of inflammatory process and neurological function, Further research may provide new insights into the pathophysiology of liver disease, as well as a basis for novel treatment modalities. [source] Metabolism of Maillard reaction products by the human gut microbiota , implications for healthMOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue 9 2006Kieran M. Tuohy Abstract The human colonic microbiota imparts metabolic versatility on the colon, interacts at many levels in healthy intestinal and systemic metabolism, and plays protective roles in chronic disease and acute infection. Colonic bacterial metabolism is largely dependant on dietary residues from the upper gut. Carbohydrates, resistant to digestion, drive colonic bacterial fermentation and the resulting end products are considered beneficial. Many colonic species ferment proteins but the end products are not always beneficial and include toxic compounds, such as amines and phenols. Most components of a typical Western diet are heat processed. The Maillard reaction, involving food protein and sugar, is a complex network of reactions occurring during thermal processing. The resultant modified protein resists digestion in the small intestine but is available for colonic bacterial fermentation. Little is known about the fate of the modified protein but some Maillard reaction products (MRP) are biologically active by, e. g. altering bacterial population levels within the colon or, upon absorption, interacting with human disease mechanisms by induction of inflammatory responses. This review presents current understanding of the interactions between MRP and intestinal bacteria. Recent scientific advances offering the possibility of elucidating the consequences of microbe-MRP interactions within the gut are discussed. [source] Translational experimental therapeutics: The translation of laboratory-based discovery into disease-related therapyMOUNT SINAI JOURNAL OF MEDICINE: A JOURNAL OF PERSONALIZED AND TRANSLATIONAL MEDICINE, Issue 1 2007Karl Kieburtz MD Abstract In the past decade, there has been an increasing emphasis on laboratory-based translational research. This has led to significant scientific advances in our understanding of disease mechanisms and in the development of novel approaches to therapy such as gene therapy, RNA interference, and stem cells. However, the translation of these remarkable scientific achievements into new and effective disease-modifying therapies has lagged behind these scientific accomplishments. We use the term "translational experimental therapeutics" to describe the pathway between the discovery of a basic disease mechanism or novel therapeutic approach and its translation into an effective treatment for patients with a specific disease. In this article, we review the components of this pathway, and discuss issues that might impede this process. Only by optimizing this pathway can we realize the full therapeutic potential of current scientific discoveries and translate the astounding advances that have been accomplished in the laboratory into effective treatments for our patients. Mt Sinai J Med 74: 7-14, 2007. Copyright © 2007 Mount Sinai School of Medicine [source] Cerebellar metabolic symmetry in essential tremor studied with 1H magnetic resonance spectroscopic imaging: Implications for disease pathologyMOVEMENT DISORDERS, Issue 6 2004Elan D. Louis MD Abstract The pathological basis for essential tremor (ET) is not known; however, metabolic changes in the cerebellum can be observed in positron emission tomography (PET) and 1H magnetic resonance spectroscopic imaging (MRSI) studies. Tremor is relatively symmetric in ET, suggesting that underlying metabolic changes could be also symmetric. The degree of metabolic asymmetry in the cerebellum, however, has not yet been studied in ET, and knowledge about distribution and laterality of metabolic changes might shed some light on basic disease mechanisms. We measured brain metabolism (N -acetylaspartate[NAA]/creatine [tCR]) to obtain an asymmetry index for cerebellar cortical metabolism ET patients compared with that in controls. This index, a percentage, was calculated as |(value right , value left)|/(value right + value left) × 100. Multislice 1H MRSI data were acquired for 20 patients and 11 controls. In ET patients, mean right and left cerebellar cortical NAA/tCR values were 1.61 ± 0.42 and 1.55 ± 0.38, respectively, compared with 1.81 ± 0.62 and 1.87 ± 0.49 in controls. The difference between right and left cerebellar cortical NAA/tCR was also calculated for each subject. In ET patients, the mean right-left difference was 0.14 ± 0.11, compared with 0.32 ± 0.27 in controls (P = 0.016). The mean cerebellar cortical asymmetry index was low in ET (8.8 ± 6.1%), one-half of that in controls (17.0 ± 13.7%, P = 0.027). These data suggest that pathological lesions in ET patients, which remain elusive, might be distributed similarly in each cerebellar cortex. Postmortem studies are needed to confirm these preliminary imaging results. © 2004 Movement Disorder Society [source] Myasthenia gravis and premature ovarian failureMUSCLE AND NERVE, Issue 2 2004Monique M. Ryan MMed Abstract We describe a patient who developed seropositive myasthenia gravis 16 years after she was diagnosed with autoimmune premature ovarian failure with antibodies to the receptor for follicle-stimulating hormone (FSH). Although thymectomy led to improvement of her myasthenic symptoms, menses did not resume. Such combined seropositivity for antibodies to acetylcholine and ovarian hormone receptors in a patient with myasthenia gravis and premature ovarian failure may reflect common disease mechanisms, although the precise pathogenesis of these disorders remains ill-defined. Muscle Nerve 30: 231,233, 2004 [source] Embryonic stem cells and prospects for their use in regenerative medicine approaches to motor neurone diseaseNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 5 2007Y. A. Christou Human embryonic stem cells are pluripotent cells with the potential to differentiate into any cell type in the presence of appropriate stimulatory factors and environmental cues. Their broad developmental potential has led to valuable insights into the principles of developmental and cell biology and to the proposed use of human embryonic stem cells or their differentiated progeny in regenerative medicine. This review focuses on the prospects for the use of embryonic stem cells in cell-based therapy for motor neurone disease or amyotrophic lateral sclerosis, a progressive neurodegenerative disease that specifically affects upper and lower motor neurones and leads ultimately to death from respiratory failure. Stem cell-derived motor neurones could conceivably be used to replace the degenerated cells, to provide authentic substrates for drug development and screening and for furthering our understanding of disease mechanisms. However, to reliably and accurately culture motor neurones, the complex pathways by which differentiation occurs in vivo must be understood and reiterated in vitro by embryonic stem cells. Here we discuss the need for new therapeutic strategies in the treatment of motor neurone disease, the developmental processes that result in motor neurone formation in vivo, a number of experimental approaches to motor neurone production in vitro and recent progress in the application of stem cells to the treatment and understanding of motor neurone disease. [source] Current Understandings on Complex Regional Pain SyndromePAIN PRACTICE, Issue 2 2009Marissa De Mos MD Abstract The mechanisms underlying complex regional pain syndrome (CRPS) have been increasingly studied over the past decade. Classically, this painful and disabling disorder was considered to emerge from pathology of the central nervous system. However, the involvement of additional peripheral disease mechanisms is likely, and recently these mechanisms have also attracted scientific attention. The present article provides an overview of the current understandings regarding pathology of the autonomic and somatic nervous system in CRPS, as well as the roles of neurogenic inflammation, hypoxia, and the contribution of psychological factors. Potential connections between the separate disease mechanisms will be discussed. Additionally, currently known risk factors for CRPS will be addressed. Insight into risk factors is of relevance as it facilitates early diagnosis and tailored treatment. Moreover, it may provide clues for further unraveling of the pathogenesis and etiology of CRPS. [source] RET receptor signaling: Dysfunction in thyroid cancer and Hirschsprung's diseasePATHOLOGY INTERNATIONAL, Issue 4 2006Naoya Asai Gain-of-function mutations within the receptor tyrosine kinase gene RET cause inherited and non-inherited thyroid cancer. Somatic gene rearrangements of RET have been found in papillary thyroid carcinoma and germline point mutations in multiple endocrine neoplasia (MEN) types 2A and 2B and familial medullary thyroid carcinoma (FMTC). Conversely, loss-of-function mutations are responsible for the development of Hirschsprung's disease, a congenital malformation of the enteric nervous system. Comparison between normal RET signaling activated by the RET ligand glial cell line-derived neurotrophic factor (GDNF) and abnormal RET signaling caused by various mutations has led to a deeper understanding of disease mechanisms. The focus of the present review is on recent progress in the study of RET signaling dysfunction in human diseases. [source] Transcriptosome and serum cytokine profiling of an atypical case of myelodysplastic syndrome with progression to acute myelogenous leukemiaAMERICAN JOURNAL OF HEMATOLOGY, Issue 10 2006Daruka Mahadevan Abstract A Native American-Indian female presenting with anemia and thrombocytosis was diagnosed with myelodysplastic syndrome (MDS, refractory anemia). Over the course of 5 years she developed cytopenias and periods of leukocytosis with normal bone marrow (BM) blast counts, features of an unclassifiable MDS/MPS syndrome. The patient ultimately progressed to acute myelogenous leukemia (AML, FAB M2) and had a normal karyotype throughout her course. The episodes of leukocytosis were associated with infectious complications. Transformation to AML was characterized by a BM blast percentage of 49%. Peripheral blood and BM samples were obtained for serum protein analysis and gene expression profiling (GEP) to elucidate her disease process. An ELISA assay of the serum analyzed ,80 cytokines, which demonstrated that hepatocyte growth factor/scatter factor and insulin-like growth factor binding protein 1 were markedly elevated compared to normal. GEP demonstrated a unique "tumor molecular profile," which included overexpression of oncogenes (HOXA9, N-MYC, KOC1), proliferative genes (PAWR, DLG5, AKR1C3), invasion/metastatic genes (FN1, N-CAM-1, ITGB5), pro-angiogenesis genes (c-Kit), and down regulation of tumor suppressor genes (SUI1, BARD1) and anti-apoptotic genes (PGLYRP, SERPINB2, MPO). Hence, a biomics approach has provided insight into elucidating disease mechanisms, molecular prognostic factors, and discovery of novel targets for therapeutic intervention. Am. J. Hematol., 2006. © 2006 Wiley-Liss, Inc. [source] Proteomics: New insights into rheumatic diseasesPROTEOMICS - CLINICAL APPLICATIONS, Issue 2 2009Emilio Camafeita Abstract Tremendous advances undergone in electrophoresis, chromatography, and MS have led proteomic research to unprecedented achievement over the last decade. Proteomics is presently employed for assessing protein expression levels, for monitoring cellular activities and for determination of biochemical pathways, revolutionizing the way we study disease by opening up the possibility to decipher the pathogenesis of clinical manifestations. Over 200 disorders including osteoarthritis (OA), rheumatoid arthritis (RA), and osteoporosis are considered rheumatic diseases (RDs), which affect the musculoskeletal system (joints and other supporting structures of the body such as muscles, tendons, ligaments, and bones) and are a leading cause of disability among older adults. Despite that an autoimmune origin has been proposed for some RDs like RA, the pathogenesis of most of these diseases is still unclear. Therefore, proteomic research on RDs, notably OA and RA, can help clarify underlying disease mechanisms, develop biomarkers to improve early detection, measure response to treatment, and devise new therapies. Achievements in the field of proteomics research on RDs are summarized in this work. [source] Molecular and cellular themes in inflammation and immunology,THE JOURNAL OF PATHOLOGY, Issue 2 2008CS Herrington Abstract This issue of the Journal of Pathology contains a series of cutting-edge review articles that deal with the broad issue of inflammatory and immunological disease mechanisms. Of necessity, these reviews deal with selected topics but the mixture of articles on specific signalling pathways and mediators with articles addressing individual organ systems provides a broad overview of the field. These contributions provide insight into current areas of debate in inflammation and immunology. In particular, they highlight current interest in the interface between innate and adaptive immunity and present intriguing prospects for future therapeutic developments in a variety of disease areas. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] | |||||||||||||||||||||||||||||||