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 May April March February January 2003 2002 2001

Jun 30,2004 Interferon-γ activation of polymorphonuclear neutrophil function
  As current research illuminates the dynamic interplay between the innate and acquired immune responses, the interaction and communication between these two arms has yet to be fully investigated.Polymorphonuclear neutrophils (PMNs) and interferon-γ (IFN-γ) are known critical components of innate and acquired immunity, respectively.However, recent studies have demonstrated that these two components are not entirely isolated.Treatment of PMNs with IFN-γ elicits a variety of responses depending on stimuli and environmental conditions.These responses include increased oxidative burst, differential gene expression, and induction of antigen presentation.
Jun 29,2004 RNA interference (RNAi) in hematology
  RNA interference (RNAi), an evolutionary highly conserved process of post-transcriptional gene silencing, can be triggered by small interfering RNAs (siRNAs) that mediate sequence-specific mRNA degradation. Since the first reports in 1998, RNAi has rapidly been developed into an effective tool to specifically knock down gene expression in a wide variety of target cells. Accordingly, RNAi is currently used for both systematic functional genomics in several organisms and for specific therapeutic intervention in preclinical models of different diseases characterized by aberrant gene expression.
Jun 28,2004 Stem-Cell Transplantation in Myocardial Infarction
  Myocardial infarction is the leading cause of congestive heart failure and death in the industrialized world. Current therapy is limited in preventing the progression of ventricular remodeling and congestive heart failure. Recent interest has focused on stem cells, which are undifferentiated and pluripotent cells that can proliferate, potentially self-renew, and differentiate into cardiomyocytes. Myocardial regeneration with stem-cell transplantation is a possible treatment option to reverse the deleterious hemodynamic and neurohormonal effects that occur after myocardial infarction and can lead to congestive heart failure.
Jun 27,2004 Role of epigenetic changes in hematological malignancies
  Inactivation of tumor suppressor genes is an important event contributing to the development of neoplasia. In addition to the classic genetic mechanisms of deletion or inactivating point mutations, growth regulatory genes can be functionally inactivated without alterations of the primary sequence by methylation of cytosine residues in the promoter regions of the genes. After introducing epigenetic phenomena in general and the molecular basis of DNA methylation in more detail, this review will present the broad spectrum of alterations in DNA methylation patterns found in hematopoietic malignancies. In addition, the implications for therapy and prognosis will be discussed.
Jun 26,2004 RNA interference
  Over the past decade "RNA interference" has emerged as a natural mechanism for silencing gene expression. This ancient cellular antiviral response can be harnessed to allow specific inhibition of the function of any chosen target genes, including those involved in causing diseases such as cancer, AIDS, and hepatitis. RNA interference is already proving to be an invaluable research tool, allowing much more rapid characterisation of the function of known genes. More importantly, the technology considerably bolsters functional genomics to aid in the identification of novel genes involved in disease processes. But can RNA interference be used as an effective therapeutic strategy?
Jun 25,2004 OXYGEN SENSING BY HIF HYDROXYLASES
  The transcription factor HIF (hypoxia-inducible factor) has a central role in oxygen homeostasis in animals ranging from nematode worms to man. Recent studies have shown that this factor is regulated by an unprecedented signalling mechanism that involves post-translational hydroxylation. This hydroxylation is catalysed by a set of non-haem, Fe2+-dependent enzymes that belong to the 2-oxoglutarate-dependent-oxygenase superfamily. The absolute requirement of these enzymes for molecular oxygen has provided new insights into the way cells sense oxygen.
Jun 24,2004 Clearance of Apoptotic Cells
  The efficient elimination of apoptotic cells is crucial for tissue homeostasis in multicellular organisms. Secreted "find-me," exposed "eat-me," and lacking "don' t-eat-me" signals comprise the central elements of apoptotic cell removal, thus preventing the release of intracellular contents into the surrounding tissue. This is of special importance, as there is growing evidence that the onset of autoimmune disorders can be linked to the inefficient removal of apoptotic cells. This review focuses on the signals displayed by apoptotic cells, the bridging and receptor molecules on the phagocyte, and is intended to present a simplified model of the phagocytic synapse.
Jun 23,2004 Proteoglycans in Atherosclerosis and Restenosis
  The proteoglycan versican is one of several extracellular matrix (ECM) molecules that accumulate in lesions of atherosclerosis and restenosis. Its unique structural features create a highly interactive molecule that binds growth factors, enzymes, lipoproteins, and a variety of other ECM components to influence fundamental events involved in vascular disease. Versican is one of the principal genes that is upregulated after vascular injury and is a prominent component in stented and nonstented restenotic lesions. The synthesis of versican is highly regulated by specific growth factors and cytokines and the principal source of versican is the smooth muscle cell.
Jun 22,2004 Immunological inhibition of carcinogenesis
  The combination of new information provided by fundamental immunology, along with the re.nement of genetic engineering techniques has given scientists the capacity to produce vaccines able to inhibit the growth of most if not every transplantable tumor. However, when faced with already established tumors, vaccines fail to a.ord any signi.cant protection. Many studies are underway which seek to overcome this gloomy situation. However, another possibility is to follow the indications provided by a large quantity of experimental data and to evaluate the possibility of using immunotherapy to prevent the initial stages of tumor growth. Is it possible to prevent an autologous tumor by means of a vaccination performed before tumor onset?
Jun 21,2004 CELLULAR AND MOLECULAR MECHANISMS OF PRESYNAPTIC ASSEMBLY
  The formation of a presynaptic neurotransmitter secretion site involves the transformation of a patch of unspecialized plasma membrane into a complex structure that is highly specialized for sustained, depolarization-evoked synaptic vesicle exocytosis. This transformation is governed by dynamic intracellular and intercellular processes, and by global developmental processes. Recent work has shed light on the cellular processes that are responsible for transporting presynaptic molecules to nascent presynaptic sites and for the subsequent transformation of these sites into functional presynaptic structures. Other studies are providing clues to the identity of molecules that induce and initiate the transformation process.
Jun 20,2004 Endothelial Progenitor Cells
  The formation of new capillaries (angiogenesis) may be of clinical importance in facilitating reperfusion and regeneration of hibernating cardiac tissue after myocardial infarction and in microvascular ischemia. Evidence is accumulating that as part of the response to hypoxia, bone marrow-derived circulating endothelial progenitor cells (CEPs) are mobilized and subsequently differentiate into proper endothelial cells. There are also indications that such CEPs can facilitate endothelial repair and angiogenesis in vivo. It is not clear yet, however, whether these CEPs are essential for these adaptive processes or what the relative contribution of CEP is compared with that of other mononuclear inflammatory cells that are mobilized to areas of ischemia.
Jun 19,2004 The future of gastric cancer prevention
  Despite advances in surgical treatment and chemotherapy, gastric cancer remains a major global health burden. The most recent estimates show that it is the fourth most common cancer and the second most common cause of cancer deaths worldwide. Various etiologic factors have been linked with the disease. It is widely accepted that Helicobacter pylori infection and high salt intake are positively associated with this neoplastic process. Controversial associations have been found with smoking or drinking habits. In contrast, there is convincing evidence that the adequate consumption of fresh fruits and vegetables reduces the risk of gastric cancer. Prevention intervention trials involving antioxidant supplements and anti-H.
Jun 18,2004 Degenerative and regenerative mechanisms governing spinal cord injury
  Spinal cord injury (SCI) is a major cause of disability, and at present, there is no universally accepted treatment. The functional decline following SCI is contributed to both direct mechanical injury and secondary pathophysiological mechanisms that are induced by the initial trauma. These mechanisms initially involve widespread haemorrhage at the site of injury and necrosis of central nervous system (CNS) cellular components. At later stages of injury, the cord is observed to display reactive gliosis. The actions of astrocytes as well as numerous other cells in this response create an environment that is highly nonpermissive to axonal regrowth. Also manifesting important effects is the immune system.
Jun 17,2004 Rho localization in cells and tissues
  Rho family small GTPases regulate cytoskeletal organization. Although their spatiotemporal activities appear to be important for cellular morphogenesis, there has been little characterization of the localization of Rho family GTPases in cells and tissues. Here we show precise localization of Rho subfamily proteins in mammalian cultured cells and tissues through evaluation of anti-Rho antibodies and fixation protocols. Although Rho is not a structural protein but functions as a switching molecule, it often localizes at several distinct domains or structures of cells. In cultured epithelial cells, Rho was highly accumulated at lateral membranes. However, in fibroblastic cells, Rho appeared to be distributed evenly in the cytoplasm.
Jun 16,2004 Towards a standardized human proteome database
  Comparative proteome profiling, performed by two-dimensional polyacrylamide gel electrophoresis or multidimensional protein identification technology, usually relies on the relative comparison of samples of interest with respect to a reference. Currently, no standardized quantitative protein expression database of human cells, facilitating data comparisons between different laboratories, exists. Recently, we have published two-dimensional polyacrylamide gel electrophoresis-based techniques to assess absolute protein data comprising protein amounts, synthesis rates and biological half-lives (Mol. Cell. Proteomics 2002, 1, 528–537).
Jun 15,2004 Genomic variants in exons and introns
  When genome variants are identified in genomic DNA, especially during routine analysis of disease-associated genes, their functional implications might not be immediately evident. Distinguishing between a genomic variant that changes the phenotype and one that does not is a difficult task. An increasing amount of evidence indicates that genomic variants in both coding and non-coding sequences can have unexpected deleterious effects on the splicing of the gene transcript. So how can benign polymorphisms be distinguished from disease-associated splicing mutations?
Jun 14,2004 Vaccines for the prevention of diseases caused by potential bioweapons
  The development of vaccines and implementation of vaccination programs are among the most important medical contributions to humanity. To date, vaccination has reduced morbidity and mortality from infectious diseases more than any other specific medical intervention. The intentional use of bioweapons against civilians (bioterrorism), recently highlighted by events around the world, has fueled interest in the development of vaccines for potential microbial agents of bioterror. This review discusses the microbial agents that are considered to pose the greatest risk to the public, the diseases associated with them, and the vaccines that are available for their prevention.
Jun 13,2004 Cyclooxygenases
  The beneficial actions of nonsteroidal anti-inflammatory drugs (NSAIDs) have been linked to their ability to inhibit inducible COX-2 at sites of inflammation, and their side effects (e.g., gastric damage) to inhibition of constitutive COX-1. Selective inhibitors of COX-2, such as celecoxib, etoricoxib, lumiracoxib, rofecoxib, and valdecoxib have been developed and the greatest recent growth in our knowledge in this area has been come from the clinical use of these compounds. Although clinical data indicate that COX-2 selectivity is associated with a reduction in severe gastrointestinal events, they also reveal there are roles for constitutive COX-2 within tissues such as the brain, kidney, pancreas, intestine, and blood vessels.
Jun 12,2004 Modulation of the Inflammatory Response in Cardiovascular Disease
  There is a growing body of evidence that inflammation might play an important role in the initiation and progression of cardiovascular diseases (CVDs). The designation of CVD as a chronic inflammatory process is further supported by evidence that the risk factors for CVD cause endothelial cells throughout the vascular tree to assume an inflammatory phenotype. These activated endothelial cells characteristically exhibit oxidative stress and increased adhesiveness for circulating leukocytes. Although initial efforts to define the mechanisms underlying the inflammatory phenotype in diseased endothelial cells have focused on the linkage between oxidative stress and adhesion molecule activation/expression, recent work has implicated a variety of additional factors that can modulate the magnitude and/or nature of the inflammatory responses in CVD.
Jun 11,2004 The JAK/STAT Signaling Pathway
  The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway is one of a handful of pleiotropic cascades used to transduce a multitude of signals for development and homeostasis in animals, from humans to flies. In mammals, the JAK/STAT pathway is the principal signaling mechanism for a wide array of cytokines and growth factors. JAK activation stimulates cell proliferation, differentiation, cell migration and apoptosis. These cellular events are critical to hematopoiesis, immune development, mammary gland development and lactation, adipogenesis, sexually dimorphic growth and other processes. Predictably, mutations that reduce JAK/STAT pathway activity affect these processes .
Jun 10,2004 Genetic alteration and gene expression modulation during cancer progression
  Cancer progresses through a series of histopathological stages. Progression is thought to be driven by the accumulation of genetic alterations and consequently gene expression pattern changes. The identification of genes and pathways involved will not only enhance our understanding of the biology of this process, it will also provide new targets for early diagnosis and facilitate treatment design. Genomic approaches have proven to be effective in detecting chromosomal alterations and identifying genes disrupted in cancer. Gene expression profiling has led to the subclassification of tumors. In this article, we will describe the current technologies used in cancer gene discovery, the model systems used to validate the significance of the genes and pathways, and some of the genes and pathways implicated in the progression of preneoplastic and early stage cancer.
Jun 9,2004 Prediction of proteinfunction fromprotein sequence and structure
  The sequence of a genome contains the plans of the possible life of an organism, but implementation of genetic information depends on the functions of the proteins and nucleic acids that it encodes. Many individual proteins of known sequence and structure present challenges to the understanding of their function. In particular, a number of genes responsible for diseases have been identified but their specific functions are unknown. Wholegenome sequencing projects are a major source of proteins of unknown function. Annotation of a genome involves assignment of functions to gene products, in most cases on the basis of amino-acid sequence alone. 3D structure can aid the assignment of function, motivating the challenge of structural genomics projects to make structural information available for novel uncharacterized proteins.
Jun 8,2004 Dual vagal cardiac efferent pathways
  THE ANATOMICAL WORK PERFORMED by Cheng and colleagues (2) presented in this issue of the American Journal of Physiology- Regulatory, Integrative and Comparative Physiology provides evidence for specific innervation patterns arising from select populations of neurons in the medulla oblongata to neurons that are clustered in adjacent regions within a mammalian intrinsic cardiac ganglionated plexus. As such, the techniques depicted in this study provide the anatomical substrate with which one can study how populations of parasympathetic efferent preganglionic neurons located in different medullary regions innervate select populations of cholinergic efferent postganglionic neurons within one or more intrinsic cardiac ganglionated plexus.
Jun 7,2004 Current and Future Challenges in School-Based Prevention
  During the next decade we will see broad dissemination of a growing number of empirically validated school-based prevention programs. The processes of effectiveness research, broad program diffusion, and program integration at the school and community level will become a central focus of research activity. The paper presents six future directions for research in the field of school-based prevention and health promotion. The directions include developing new programs and models, developing standards and accountability systems related to school success, moving from efficacy to effectiveness research, understanding factors influencing program integration, broad dissemination of programs and policies, and the sustainability of programs, policies, and community partnerships.
Jun 6,2004 Ethical Issues in Geriatrics
  Because of demographic trends,it is reasonable to expect that clinicians will care for an increasing number of elderly persons with challenging medical and psychosocial problms.These problems and issues,in turn,may lead to daunting ethical dilemmas.Therefore,clinicians should be familiar with ethical dilemmas commonly encountered when caring for elderly patients.We review some of these dilemmas,including ensuring informed consent and confidentiality,determining decision-making capacity,promoting advance care planning and the use of advance directives,surrogate decision making,withdrawing and withholding interventions,using cardiopulmonary resuscitation and do-not-resuscitate orders,responding to requests for interventions,allocating health care resources, and recommending nursing home care.
Jun 5,2004 Acquired and Inherited Lipodystrophies
  lipodystrophies are clinically heterogeneous acquired or in- herited disorders characterized by the selective loss of adipose tissue. Affected patients are predisposed to insulin resistance and its attendant complications, including diabetes mellitus, dyslipidemia, hepatic steatosis, and acanthosis nigricans. Features of polycystic ovary syndrome - hirsutism, oligoamenorrhea, and polycystic ovaries - may develop in affected women. The mechanisms involved in the pathogenesis of various types of lipodystrophy are listed in Table 1.
Jun 4,2004 Gene Therapy Progress and Prospects
  Targeting tumour suppressor gene pathways is an attractive therapeutic strategy in cancer. Since the first clinical trial took place in 1996, at least 20 other trials have investigated the possibility of restoring p53 function, either alone or in combination with chemotherapy, but with limited success. Other recent clinical trials have sought to harness abnormalities in the p53 pathway to permit tumour-selective replication of adenoviral vectors such as dl1520 (Onyx- 015). Other tumour suppressor genes, such as retinoblastoma (Rb) and PTEN (phosphatase, tensin homologue, deleted on chromosome 10), are the targets for imminent clinical trials, while microarray technologies are revealing multiple new genes that are potential targets for future gene therapy.
Jun 3,2004 Cytokine function of heat shock proteins
  Extensive work in the last 10 years has suggested that heat shock proteins (HSPs) may be potent activators of the innate immune system. It has been reported that Hsp60, Hsp70, Hsp90, and gp96 are capable of inducing the production of proinflammatory cytokines by the monocyte-macrophage system and the activation and maturation of dendritic cells (antigen-presenting cells) in a manner similar to the effects of lipopolysaccharide (LPS) and bacterial lipoprotein, e.g., via CD14/ Toll-like receptor2 (TLR2) and CD14/TLR4 receptor complex-mediated signal transduction pathways. However, recent evidence suggests that the reported cytokine effects of HSPs may be due to the contaminating LPS and LPS-associated molecules.
Jun 2,2004 Planning of clinical trials
  This article focuses on steps of planning clinical trials most relevant to the question the clinician asks and how this question is properly transformed in a design and a protocol. All steps are important for the data quality or the validity of the results. A clinical trial is an experiment aimed at testing an hypothesis regarding the efficacy of a given intervention on an event, symptom or impaired quality of life in patients with a defined condition and a particular profile.As such, it should meet the fundamentals of scientific discovery that guarantee causality between the observed difference and the intervention. All the planning components are thought according to these fundamentals.
Jun 1,2004 Apoptosis and necrosis in liver disease
  Liver cell injury and cell death is a prominent feature in all liver disease processes. During the last 5-10 years, most research activities focused almost exclusively on evaluating apoptotic cell death and the corresponding intracellular signaling pathways. Although this effort led to substantial progress in our understanding of the mechanisms of apoptosis, it also created substantial confusion regarding the predominant mode of cell death and the relevance of apoptosis in a variety of liver disease models, as discussed in this review for acetaminophen and troglitazone hepatotoxicity, obstructive cholestasis and viral hepatitis.

May April March February January 2003 2002 2001