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  • Annual Reviews  (20,354)
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  • 1
    Palo Alto, Calif. : Annual Reviews
    Call number: 04-Zell:210/23
    Pages: xiii, 731 p.
    ISBN: 9780824331238
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    04-Zell:210/23 departmental collection or stack – please contact the library
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  • 2
    Electronic Resource
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Entomology 51 (2006), S. 137-161 
    ISSN: 0066-4170
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology
    Notes: Boreal peat bogs contain distinctive insects in addition to widely distributed generalists, including species restricted to bogs (tyrphobionts) and species characteristic of bogs but not confined to them (tyrphophiles). Bogs raised above the water table form characteristic habitat islands in southern boreal and temperate forest zones. Many bogs have persisted for hundreds and even thousands of years, preserving relict ecosystems related to subarctic biomes. The historical development and nature of individual bogs are reflected by differences among their insects, which are of great biogeographical and ecological interest. The environmental sensitivity of bogs also makes insects valuable as bioindicators. Moreover, few readily accessible bogs remain in a natural state. Given the scientific interest of bog insects and the fact that each relict bog habitat island is unique, further studies of the diversity of bog faunas are merited, and the conservation of these habitats should be strongly supported by entomologists.
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  • 3
    ISSN: 0066-4189
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Notes: We review recent advances in understanding, modeling, and controlling oscillations in the flow past a cavity. The fundamental mechanisms underlying cavity flow oscillations have been known for at least 40 years, but suppressing these oscillations in a reliable and robust way is still a challenge today. Interest in controlling the flow past a cavity is motivated by aerospace applications, but in addition, cavity flows provide an attractive canonical problem for exploring general flow control techniques. The focus is on recent advances in modeling these flows, and in controlling them, using both open-loop and closed-loop techniques. A relatively new perspective is that cavity oscillations may not always be self-sustained, but under some flow conditions may be lightly damped resonances, sustained by external disturbances such as boundary layer turbulence. Areas in which our understanding is incomplete, and which deserve further study, are discussed, in particular the effects of high-frequency open-loop forcing, fundamental limitations of feedback control for a given configuration of sensors and actuators, and the development of a feedback design methodology that respects the limited range of validity of the available dynamical models.
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  • 4
    Electronic Resource
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Medicine 57 (2006), S. 207-221 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Celiac disease is an autoimmune disease that occurs in genetically predisposed individuals as the result of an immune response to gluten. This immune response occurs in both the lamina propria and the epithelium of the small intestine. There is a close link to HLA DQ2 and DQ8, although these HLA genes account for only 40% of the genetic influence. Environmental factors, such as the amount and timing of gluten administration in infancy, as well as breastfeeding, influence the disease. Serologic screening studies that use sensitive and specific antibody tests have revealed the disease to be common, occurring in Đ♯1% of the population. Clinical presentations are diverse and atypical; the majority of patients lack diarrhea. Therapy is a gluten-free diet that requires avoidance of wheat, rye, and barley, although there is potential for other therapies based on our understanding of the pathophysiology of the disease.
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  • 5
    Electronic Resource
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Medicine 57 (2006), S. 403-417 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Umbilical cord blood transplantation (UCBT) is an expanding practice for both pediatric and adult patients. Rapid availability, low risk of infectious disease transmission, lower risk of graft-versus-host disease, and lack of risk for the donor makes UCB an attractive alternative source of hematopoietic stem cells for transplantation. We review the state of the art of pediatric and adult UCBT and important aspects of UCB banking. Current strategies to improve clinical results and expand access to UCBT to a larger number of adult patients are discussed. New approaches to enhance hematopoietic recovery by the use of accessory cells or direct intra-bone marrow injection are also reviewed.
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  • 6
    Electronic Resource
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Medicine 57 (2006), S. 535-551 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Existing treatments for neuropathic pain deliver inadequate pain relief, unacceptable side effects, or both. The unmet medical need for more effective treatment is driving a large volume of research to discover new drugs. Most existing treatments are drugs introduced to treat other pain conditions or other medical conditions, such as antidepressants and anticonvulsants, which were found empirically to be effective for neuropathic pain. Only recently have drug discovery efforts have become mechanistically driven, addressing targets identified by a molecular neurobiological approach to the pathophysiology of neuropathic states.
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  • 7
    Electronic Resource
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Medicine 57 (2006), S. 419-436 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Recent advances have demonstrated that thrombotic thrombocytopenic purpura (TTP), characterized by widespread thrombosis in the arterioles and capillaries, is caused by deficiency of a circulating zinc metalloprotease, ADAMTS13. Two types of TTP are recognized: autoimmune TTP, caused by inhibitory antibodies of ADAMTS13, and hereditary TTP, caused by genetic mutations of ADAMTS13. This article reviews the characteristics and function of ADAMTS13, the mechanism by which ADAMTS13 deficiency may lead to thrombosis, and the causes of ADAMTS13 deficiency. It also discusses how the new knowledge may improve the diagnosis and treatment of this previously mysterious disorder.
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  • 8
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: We review the diagnosis, categorization, and treatment of prostatitis/chronic pelvic pain syndrome based on the National Institutes of Health (NIH) classification. Prostatitis is an extremely common syndrome that afflicts 2%Đ??10% of men. Formerly a purely clinical diagnosis, prostatitis is now classified within a complex series of syndromes (NIH category IĐ??IV prostatitis) that vary widely in clinical presentation and response to treatment. Acute bacterial prostatitis (category I) and chronic bacterial prostatitis (category II) are characterized by uropathogenic infections of the prostate gland that respond well to antimicrobial treatment. In contrast, chronic prostatitis/chronic pelvic pain syndrome (category III), which accounts for 90%Đ??95% of prostatitis cases, is of unknown etiology and is marked by a mixture of pain, urinary, and ejaculatory symptoms with no uniformly effective therapy. Asymptomatic inflammatory prostatitis (category IV) is an incidental finding of unknown clinical significance. This review describes the current status of prostatitis syndromes and explores the future prospects of new diagnostic tools and therapies.
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  • 9
    Electronic Resource
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Medicine 57 (2006), S. 331-347 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: A number of genetic disorders can result in the accumulation of excess iron in the body. These causes of hereditary hemochromatosis include defects in genes encoding HFE, transferrin receptor 2, ferroportin, hepcidin, and hemojuvelin. Hepcidin, with its cognate receptor, ferroportin, has emerged as a central regulator of iron homeostasis; all of the known causes of hemochromatosis appear to prevent this system from functioning normally. The most common form of primary hemochromatosis is that caused by C282Y mutation of the HFE gene. This mutation is most prevalent among Northern Europeans. Although the frequency of the homozygous genotype is approximately 5 per 1000, the disease itself is quite rare because the clinical penetrance of the genotype is very low.
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  • 10
    Electronic Resource
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Medicine 57 (2006), S. 455-471 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: More than three decades of clinical experience in cardiac transplantation resulted in the spread of the procedure worldwide with a wealth of knowledge and advancements. Developments included liberalization of recipient and donor selection criteria, improved surgical techniques, novel immunosuppressive drugs and protocols, new rejection surveillance techniques, and better understanding of the pathophysiology of cardiac allograft vasculopathy to direct interventions for prevention and treatment.
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  • 11
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Medicine 57 (2006), S. 139-154 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Influenza A viral infection causes substantial annual morbidity and mortality worldwide, particularly for infants, the elderly, and the immunocompromised. The virus mainly replicates in the respiratory tract and is spread by respiratory secretions. A growing concern is the recent identification of H5N1 strains of avian influenza A in Asia that were previously thought to infect only wild birds and poultry, but have now infected humans, cats, pigs, and other mammals, often with fatal results, in an ongoing outbreak. A human pandemic with H5N1 virus could potentially be catastrophic because most human populations have negligible antibody-mediated immunity to the H5 surface protein and this viral subtype is highly virulent. Whether an H5N1 influenza pandemic will occur is likely to hinge on whether the viral strains involved in the current outbreak acquire additional mutations that facilitate efficient human-to-human transfer of infection. Although there is no historical precedent for an H5N1 avian strain causing widespread human-to-human transmission, some type of influenza A pandemic is very likely in the near future. The possibility of an H5N1 influenza pandemic has highlighted the many current limitations of treatment with antiviral agents and of vaccine production and immunogenicity. Future vaccine strategies that may include more robust induction of T-cell responses, such as cytotoxic T lymphocytes, may provide better protection than is offered by current vaccines, which rely solely or mainly on antibody neutralization of infection.
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  • 12
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: VELCADE?℗ (bortezomib, Millennium Pharmaceuticals, Inc., Cambridge, MA, and Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Raritan, NJ) is a first-in-class proteasome inhibitor developed specifically for use as an antineoplastic agent. Inhibition of the proteasome results in disruption of homeostatic mechanisms within the cell that can lead to cell death. Bortezomib's first indication, for the treatment of relapsed myeloma in patients who have received at least two prior treatments and progressed on their previous treatment, was based in part on the magnitude of activity demonstrated in phase II trials. Bortezomib is currently indicated for patients who have received at least one prior therapy in the United States and European Union, although patients in the European Union must have already undergone bone marrow transplantation or be unsuitable for the procedure. A phase III trial demonstrated the superiority of bortezomib over high-dose dexamethasone in response rate, time to progression, and survival in patients with myeloma who had relapsed after 1Đ??3 prior therapies. Clinical development is ongoing to investigate its activity as monotherapy and in combination regimens for the treatment of non-Hodgkin's lymphoma, solid tumors, and earlier presentations of myeloma.
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  • 13
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Researchers have made great progress in defining genetic and molecular alterations that contribute to cancer. New therapeutic targets have been identified and targeted therapeutic agents have been developed, but our ability to evaluate potential drugs has not kept pace. Molecular imaging technologies that monitor biological processes and/or measure levels of targeted macromolecules can contribute significantly to preclinical and clinical drug evaluation. This article describes the drug discovery process, economic problems facing drug discovery and development, and successes and failures in this realm. We briefly describe the available molecular imaging tools, with emphasis on positron emission tomography. We discuss biological processes that are altered in tumors and can be measured by molecular imaging; examples include gene expression, signal transduction, tumor cell metabolism, proliferation, apoptosis, hypoxia, and angiogenesis. We conclude with a proposal to integrate molecular imaging into the drug development process.
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  • 14
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Medicine 57 (2006), S. 365-380 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Various disciplines within nephrology investigate the mechanisms by which kidneys fail. Progress in the areas of glomerular hemodynamics, proteinuria, tubular biology, interstitial nephritis, fibroblast formation, and fibrosis have added kernels of information that together support a unified theory of renal progression. Prevention of progression to end-stage disease has largely focused on control of systemic and glomerular hypertension. Current success in delaying a decline in glomerular filtration rate underlines the promise of a more comprehensive approach. New knowledge about the cell biology of progression also suggests that other adjunctive therapies may be possible. We describe the progress and highlight those spheres where new-targeted interventions may arise.
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  • 15
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Advances in radiation oncology have been made on three major fronts: biology, physics, and clinical application. Our biological understanding of how radiation kills cells and how malignant cells avoid damage has identified new targets for therapeutic manipulation. Research in physics has yielded sophisticated methods to direct the deposition of radiation energy in ways that enhance target coverage while minimizing dose to normal structures as much as possible. Intensity-modulated radiation therapy (IMRT) and image-guided radiation therapy represent new paradigms in treatment planning and dose delivery. Clinical management of the cancer patient is multidisciplinary. Increasingly, combinations of radiation and chemotherapy, with or without surgery, are enhancing cure rates, often with preservation of organ function. Taken together, these advances have increased the effectiveness of radiation therapy and promise better treatment results in the future.
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  • 16
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Medicine 57 (2006), S. 49-63 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Prostate cancer is an attractive target for chemoprevention because of its ubiquity, treatment-related morbidity, long latency between premalignant lesions and clinically evident cancer, and defined molecular pathogenesis. The Prostate Cancer Prevention Trial has provided the first firm evidence that this cancer can be prevented by a relatively nontoxic oral agent. Additional agents, many of which are antioxidants with antiandrogenic effects, are being tested (or soon will be) in large clinical trials. The current body of evidence is insufficient to make a routine recommendation of any dietary or nutritional supplement for the prevention of prostate cancer.
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  • 17
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: West Nile virus (WNV) was first detected in North America in 1999 during an outbreak of encephalitis in New York City. Since then the virus has spread across North America and into Canada, Latin America, and the Caribbean. The largest epidemics of neuroinvasive WNV disease ever reported occurred in the United States in 2002 and 2003. This paper reviews new information on the epidemiology and clinical aspects of WNV disease derived from greatly expanded surveillance and research on WNV during the past six years.
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  • 18
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Medicine 57 (2006), S. 381-402 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: The human immune system mounts specific responses to a vast array of antigens. Although this is clearly beneficial in fighting off harmful infections and cancerous cells, the system must be carefully controlled to ensure that normal self-antigens are not targeted. A recently characterized subset of T cells, identified by their cell surface expression of CD4 and CD25, is critical in regulating the function of other immune cells and preventing potentially harmful autoimmune responses. This article reviews what is currently known about these so-called regulatory T cells and discusses the therapeutic potential of these cells to modulate human immune-based diseases.
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  • 19
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The sodium-hydrogen exchanger regulatory factors (NHERF-1 and NHERF-2) are a family of adaptor proteins characterized by the presence of two tandem PDZ protein interaction domains and a C-terminal domain that binds the cytoskeleton proteins ezrin, radixin, moesin, and merlin. The NHERF proteins are highly expressed in the kidney, small intestine, and other organs, where they associate with a number of transporters and ion channels, signaling proteins, and transcription factors. Recent evidence has revealed important associations between the NHERF proteins and several G proteinĐ??coupled receptors such as the ?‚2-adrenergic receptor, the ?”-opioid receptor, and the parathyroid hormone receptor, as well as growth factor tyrosine kinase receptors such as the platelet-derived growth factor receptor and the epidermal growth factor receptor. This review summarizes the emerging data on the biochemical mechanisms, physiologic outcomes, and potential clinical implications of the assembly and disassembly of receptor/NHERF complexes.
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  • 20
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Retinoic acid (RA) is involved in vertebrate morphogenesis, growth, cellular differentiation, and tissue homeostasis. The use of in vitro systems initially led to the identification of nuclear receptor RXR/RAR heterodimers as possible transducers of the RA signal. To unveil the physiological functions of RARs and RXRs, genetic and pharmacological studies have been performed in the mouse. Together, their results demonstrate that (a) RXR/RAR heterodimers in which RXR is either transcriptionally active or silent are involved in the transduction of the RA signal during prenatal development, (b) specific RXRʼ̛/RAR heterodimers are required at many distinct stages during early embryogenesis and organogenesis, (c) the physiological role of RA and its receptors cannot be extrapolated from teratogenesis studies using retinoids in excess. Additional cell typeĐ??restricted and temporally controlled somatic mutagenesis is required to determine the functions of RARs and RXRs during postnatal life.
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  • 21
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The multitude of chemically highly different agonists for 7TM receptors apparently do not share a common binding mode or active site but nevertheless act through induction of a common molecular activation mechanism. A global toggle switch model is proposed for this activation mechanism to reconcile the accumulated biophysical data supporting an outward rigid-body movement of the intracellular segments, as well as the recent data derived from activating metal ion sites and tethered ligands, which suggests an opposite, inward movement of the extracellular segments of the transmembrane helices. According to this model, a vertical see-saw movement of TM-VIĐ??and to some degree TM-VIIĐ??around a pivot corresponding to the highly conserved prolines will occur during receptor activation, which may involve the outer segment of TM-V in an as yet unclear fashion. Small-molecule agonists can stabilize such a proposed active conformation, where the extracellular segments of TM-VI and -VII are bent inward toward TM-III, by acting as molecular glue deep in the main ligand-binding pocket between the helices, whereas larger agonists, peptides, and proteins can stabilize a similar active conformation by acting as Velcro at the extracellular ends of the helices and the connecting loops.
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  • 22
    ISSN: 1553-4006
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Helicobacter pylori is the main cause of peptic ulceration, distal gastric adenocarcinoma, and gastric lymphoma. Only 15% of those colonized develop disease, and pathogenesis depends upon strain virulence, host genetic susceptibility, and environmental cofactors. Virulence factors include the cag pathogenicity island, which induces proinflammatory, pro-proliferative epithelial cell signaling; the cytotoxin VacA, which causes epithelial damage; and an adhesin, BabA. Host genetic polymorphisms that lead to high-level pro-inflammatory cytokine release in response to infection increase cancer risk. Pathogenesis is dependent upon inflammation, a Th-1 acquired immune response and hormonal changes including hypergastrinaemia. Antral-predominant inflammation leads to increased acid production from the uninflamed corpus and predisposes to duodenal ulceration; corpus-predominant gastritis leads to hypochlorhydria and predisposes to gastric ulceration and adenocarcinoma. Falling prevalence of H. pylori in developed countries has led to a falling incidence of associated diseases. However, whether there are disadvantages of an H. pylori-free stomach, for example increased risk of esosphageal adenocarcinoma, remains unclear.
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  • 23
    ISSN: 1553-4006
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Loss of Ca2+ homeostasis, often in the form of cytoplasmic increases, leads to cell injury. Depending upon cell type and the intensity of Ca2+ toxicity, the ensuing pathology can be reversible or irreversible. Although multiple destructive processes are activated by Ca2+, lethal outcomes are determined largely by Ca2+-induced mitochondrial permeability transition. This form of damage is primarily dependent upon mitochondrial Ca2+ accumulation, which is regulated by the mitochondrial membrane potential. Retention of the mitochondrial membrane potential during Ca2+ increases favors mitochondrial Ca2+ uptake and overload, resulting in mitochondrial permeability transition and cell death. In contrast, dissipation of mitochondrial membrane potential reduces mitochondrial Ca2+ uptake, retards mitochondrial permeability transition, and delays death, even in cells with large Ca2+ increases. The rates of mitochondrial membrane potential dissipation and mitochondrial Ca2+ uptake may determine cellular sensitivity to Ca2+ toxicity under pathological conditions, including ischemic injury.
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  • 24
    ISSN: 1553-4006
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Atherosclerosis, the cause of myocardial infarction, stroke, and ischemic gangrene, is an inflammatory disease. The atherosclerotic process is initiated when cholesterol-containing low-density lipoproteins accumulate in the intima and activate the endothelium. Leukocyte adhesion molecules and chemokines promote recruitment of monocytes and T cells. Monocytes differentiate into macrophages and upregulate pattern recognition receptors, including scavenger receptors and toll-like receptors. Scavenger receptors mediate lipoprotein internalization, which leads to foam-cell formation. Toll-like receptors transmit activating signals that lead to the release of cytokines, proteases, and vasoactive molecules. T cells in lesions recognize local antigens and mount T helper-1 responses with secretion of pro-inflammatory cytokines that contribute to local inflammation and growth of the plaque. Intensified inflammatory activation may lead to local proteolysis, plaque rupture, and thrombus formation, which causes ischemia and infarction. Inflammatory markers are already used to monitor the disease process and anti-inflammatory therapy may be useful to control disease activity.
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  • 25
    ISSN: 1553-4006
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Sarcomas form a highly diverse group of rare tumors that are derived from connective tissue. More than 100 different malignant and benign soft tissue neoplasms can be recognized by histologic examination. Few diagnostic markers exist, and the cell of origin for many soft tissue tumors is unknown. The accurate diagnosis of many of these tumors therefore remains a challenge. The study of sarcomas has yielded many insights that can be applied to other neoplasms such as carcinoma. For example, the success of the treatment of gastrointestinal stromal tumor with Imatinib has led to an increased effort to find targeted therapies for other malignancies. Here we describe the known molecular changes in a number of sarcomas and focus on novel scientific approaches that can be expected to lead to improved diagnosis, prognostication, and therapy of sarcoma.
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  • 26
    ISSN: 1553-4006
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: In the past 25 years, a majority of cancer studies have focused on examining functional consequences of activating and/or inactivating mutations in critical genes implicated in cell cycle control. These studies have taught us a great deal about the functions of oncogenes and tumor suppressor genes and the signaling pathways regulating cell proliferation and/or cell death. However, such studies have largely ignored the fact that cancers are heterogeneous cellular entities whose growth is dependent upon reciprocal interactions between genetically altered "initiated" cells and the dynamic microenvironment in which they live. This review highlights the aspects of cancer development that, like organogenesis during embryonic development and tissue repair in adult mammals, are regulated by interactions between epithelial cells, activated stromal cells, and soluble and insoluble components of the extracellular matrix.
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  • 27
    ISSN: 1553-4006
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Among the many viruses that are known to infect the human liver, hepatitis B virus (HBV) and hepatitis C virus (HCV) are unique because of their prodigious capacity to cause persistent infection, cirrhosis, and liver cancer. HBV and HCV are noncytopathic viruses and, thus, immunologically mediated events play an important role in the pathogenesis and outcome of these infections. The adaptive immune response mediates virtually all of the liver disease associated with viral hepatitis. However, it is becoming increasingly clear that antigen-nonspecific inflammatory cells exacerbate cytotoxic T lymphocyte (CTL)-induced immunopathology and that platelets enhance the accumulation of CTLs in the liver. Chronic hepatitis is characterized by an inefficient T cell response unable to completely clear HBV or HCV from the liver, which consequently sustains continuous cycles of low-level cell destruction. Over long periods of time, recurrent immune-mediated liver damage contributes to the development of cirrhosis and hepatocellular carcinoma.
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  • 28
    ISSN: 1553-4006
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Developmental heart disorders are the most common of all human birth defects and occur in nearly one percent of the population. Survivors of congenital heart malformations are an increasing population, and it is becoming clear that genetic mutations that cause developmental anomalies may result in cardiac dysfunction later in life. This review highlights the progress in understanding the underlying molecular basis for cardiac formation and how disruption of the intricate steps of cardiogenesis can lead to congenital heart defects. The lessons learned from examining the early steps of heart formation are essential for informing the prevention of malformations and their long-term consequences, as well as for approaches to guide stem cells into cardiac lineages.
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  • 29
    ISSN: 1553-4006
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Modern techniques of cell and molecular biology have rapidly uncovered the mechanisms underlying inflammatory injury of the lung. This expanding knowledge (which includes an understanding of complement, cell surface receptors, cytokines and chemokines, transcription factors, oxidants, proteinases, and endogenous inhibitors, as well as the role of leukocyte adhesion-promoting molecules) has provided new insights into the inflammatory system in general, as well as in the context of lung injury. In this review, we summarize recent progress in understanding the regulation of lung inflammation by using immunoglobulin G (IgG) immune complexĐ??induced lung injury as a model. These studies have provided information on the role of various inflammatory mediators and their sequence of engagement. Insights into potential interventional approaches for the suppression of inflammatory processes in humans have emerged from those studies.
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  • 30
    ISSN: 1553-4006
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Nonimmune glomerulopathies are an area of significant research. This review discusses the development of focal segmental glomerulosclerosis, with particular attention to the role of the podocyte in the initiation of glomerulosclerosis and the contribution to glomerulosclerosis from capillary hypertension and soluble factors such as transforming growth factor beta, platelet-derived growth factor, vascular endothelial growth factor, and angiotensin. The effects of these factors on endothelial and mesangial cells are also discussed. In addition, we review our current understanding of the slit diaphragm (a specialized cell junction found in the kidney), slit diaphragmĐ??associated proteins (including nephrin, podocin, ʼ̛-actinin-4, CD2-associated protein, and transient receptor potential channel 6), and the role of these proteins in glomerular disease. We also discuss the most recent research on the pathogenesis of collapsing glomerulosclerosis, human immunodeficiency virus associated nephropathy, Denys-Drash, diabetic nephropathy, Alport syndrome, and other diseases related to the interaction between the podocyte and the glomerular basement membrane.
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  • 31
    Electronic Resource
    Palo Alto, Calif. : Annual Reviews
    ISSN: 1553-4006
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Malignant gliomas, the most common type of primary brain tumor, are a spectrum of tumors of varying differentiation and malignancy grades. These tumors may arise from neural stem cells and appear to contain tumor stem cells. Early genetic events differ between astrocytic and oligodendroglial tumors, but all tumors have an initially invasive phenotype, which complicates therapy. Progression-associated genetic alterations are common to different tumor types, targeting growth-promoting and cell cycle control pathways and resulting in focal hypoxia, necrosis, and angiogenesis. Knowledge of malignant glioma genetics has already impacted clinical management of these tumors, and researchers hope that further knowledge of the molecular pathology of malignant gliomas will result in novel therapies.
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  • 32
    ISSN: 1553-4006
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: The association between Epstein-Barr virus (EBV) and a large number of benign and malignant diseases is unique among DNA viruses. Within infected tissues, proteins that are expressed during the normal lytic and latent viral life cycle lead to cellular alterations that contribute to these EBV-associated diseases. Although the early events of EBV infection are poorly understood, increasing knowledge of the viral processes that govern viral latency has shed light upon the potential mechanisms by which EBV infection can lead to cellular transformation. Our current understanding of the role of EBV in the development of Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma, and other EBV-associated diseases is discussed.
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  • 33
    ISSN: 1553-4006
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Prostate cancer displays considerable clinical, morphological, and biological heterogeneity. Classical genetic techniques have provided only limited information about the pathogenesis of prostate cancer progression. Nevertheless, several candidate genes and pathways have been implicated in prostate cancer development. High-throughput techniques have exponentially expanded the number of candidate genes, including some whose role in prostate cancer pathogenesis has been studied. However, the techniques used to study the prostate cancer genome, transcriptome, and proteome generate massive amounts of data that have yet to be integrated and explored. To move beyond candidate gene identification and develop a comprehensive understanding of cancer pathogenesis, integrative approaches need to analyze this data on a global level. This review addresses candidate genes involved in prostate cancer pathogenesis in a biological and clinical context and demonstrates how integrated analysis of high-throughput data augments our understanding of prostate cancer.
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  • 34
    ISSN: 1553-4006
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Neurodegenerative diseases as diverse as Alzheimer's, Parkinson's, and Creutzfeldt-Jakob disease share a common pathogenetic mechanism involving aggregation and deposition of misfolded proteins, which leads to progressive central nervous system disease. Although the type of aggregated protein and the regional and cellular distribution of deposition vary from disease to disease, these disorders may all be linked by similar pathways of protein aggregation with fibril formation and amyloid deposition. This perspective on pathogenesis suggests that a wide variety of neurodegenerative diseases can be grouped mechanistically as brain amyloidoses, an outlook that yields novel insights into potential therapeutic approaches that may be applicable across the broad spectrum of neurodegenerative disease.
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  • 35
    ISSN: 1553-4006
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: The endothelial cells lining vascular and lymphatic vessels are targets of several infectious agents, including viruses and bacteria, that lead to dramatic changes in their functions. Understanding the pathophysiological mechanisms that cause the clinical manifestations of those infections has been advanced through the use of animal models and in vitro systems; however, there are also abundant studies that explore the consequences of endothelial infection in vitro without supporting evidence that endothelial cells are actual in vivo targets of infection in human diseases. This article defines criteria for considering an infection as truly endothelium-targeted and reviews the literature that offers insights into the pathogenesis of human endothelial-target infections.
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  • 36
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    Palo Alto, Calif. : Annual Reviews
    ISSN: 1553-4006
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: I am honored to write the prefatory chapter for the inaugural volume of the Annual Review of Pathology: Mechanisms of Disease. This publishing venture signals that pathology takes its rightful place alongside the other biomedical sciences. I thought it may be of interest to some to delineate how a circuitous path led me into a career in experimental pathology and to give some of the flavor of a past era in experimental approaches. Thus, my title.
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  • 37
    ISSN: 1553-4006
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Parasitic diseases represent major global health problems of immense proportion. Schistosomiasis, malaria, leishmaniasis, Chagas disease, and African sleeping sickness affect hundreds of millions of people worldwide, cause millions of deaths annually, and present an immense social and economic burden. Recent advances in genomic analysis of several of the major global parasites have revealed key factors involved in the pathogenesis of parasite diseases. Among the major virulence factors identified are parasite-derived proteases. This review focuses on the direct role of proteases in disease pathogenesis. Well-characterized examples of the roles proteases play in pathogenesis include their involvement in invasion of the host by parasite migration through tissue barriers, degradation of hemoglobin and other blood proteins, immune evasion, and activation of inflammation.
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  • 38
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    Palo Alto, Calif. : Annual Reviews
    ISSN: 1553-4006
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Kaposi's sarcoma (KS) has long been suspected of having an infectious etiology on the basis of its unusual epidemiology, histopathology, and natural history. Nearly a decade ago, a novel herpesviral genome was discovered in KS biopsies, and since that time strong epidemiologic evidence has accumulated correlating infection with this KS-associated herpesvirus (KSHV, also known as human herpesvirus 8) with the development of the disease. Here we review the evidence linking KSHV infection to KS risk and discuss current notions of how KSHV gene expression promotes the development of this remarkable neoplasm. These studies show that both latent and lytic viral replicative cycles contribute significantlyĐ??but differentlyĐ??to KS development. The studies also highlight mechanistic differences between oncogenesis caused by KSHV and that caused by its distant relative Epstein-Barr virus.
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  • 39
    ISSN: 1553-4006
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Although Gram-negative bacteria have often been implicated in the pathogenesis of severe sepsis and septic shock, how they trigger these often lethal syndromes is uncertain. In particular, the role played by blood-borne bacteria is controversial. This review considers two alternatives. In the first, circulating Gram-negative bacteria induce toxic reactions directly within the vasculature; in the second, the major inflammatory stimulus occurs in local extravascular sites of infection and circulating bacteria contribute little to inducing toxic responses. Evidence for each alternative is found in the literature. Bacteremia and severe sepsis are not so closely linked that the most striking cases can be a model for the rest. Intravascular and extravascular triggers may warrant different approaches to prevention and therapy.
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  • 40
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    Palo Alto, Calif. : Annual Reviews
    ISSN: 1553-4006
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: From histological and biological perspectives, lung cancer is a complex neoplasm. Although the sequential preneoplastic changes have been defined for centrally arising squamous carcinomas of the lung, they have been poorly documented for the other major forms of lung cancers, including small cell lung carcinoma and adenocarcinomas. There are three main morphologic forms of preneoplastic lesions recognized in the lung: squamous dysplasias, atypical adenomatous hyperplasia, and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. However, these lesions account for the development of only a subset of lung cancers. Several studies have provided information regarding the molecular characterization of lung preneoplastic changes, especially for squamous cell carcinoma. These molecular changes have been detected in the histologically normal and abnormal respiratory epithelium of smokers. Two different molecular pathways have been detected in lung adenocarcinoma pathogenesis: smoking-associated activation of RAS signaling, and nonsmoking-associated activation of EGFR signaling; the latter is detected in histologically normal respiratory epithelium.
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  • 41
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Fluid Mechanics 38 (2006), S. 193-224 
    ISSN: 0066-4189
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Notes: What mechanisms of flow control do animals use to enhance hydrodynamic performance? Animals are capable of manipulating flow around the body and appendages both passively and actively. Passive mechanisms rely on structural and morphological components of the body (i.e., humpback whale tubercles, riblets). Active flow control mechanisms use appendage or body musculature to directly generate wake flow structures or stiffen fins against external hydrodynamic loads. Fish can actively control fin curvature, displacement, and area. The vortex wake shed by the tail differs between eel-like fishes and fishes with a discrete narrowing of the body in front of the tail, and three-dimensional effects may play a major role in determining wake structure in most fishes.
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  • 42
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Fluid Mechanics 38 (2006), S. 225-249 
    ISSN: 0066-4189
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Notes: The gas-lift technique comprises the injection of gas bubbles in vertical oil wells to increase production. It is based on a reduction of the tubing gravitational pressure gradient. Several fluid-flow phenomena influencing such vertical gas-liquid flows are discussed. These effects include the radial distribution of void fraction and of gas and liquid velocity, flow regime changes, and system stability problems. Associated consequences for gas-lift performance and related optimization approaches are also discussed.
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  • 43
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Selective loss of body fat is the hallmark of patients with lipodystrophies. Among genetic lipodystrophies, fat loss is observed either from birth, as in congenital generalized lipodystrophy, or later in life, as in familial partial lipodystrophy. The extent of fat loss also varies among subtypes of lipodystrophies. Patients develop hyperinsulinemia, acanthosis nigricans, hypertriglyceridemia, diabetes mellitus, and hepatic steatosis. Defects in several genes, such as those encoding an enzyme (AGPAT2), a nuclear receptor (PPAR??), a nuclear lamina protein (LMNA) and its processing endoprotease (ZMPSTE24), a kinase (AKT2), and a protein of unknown function (BSCL2), have been found in patients with genetic lipodystrophies. Additional loci remain to be discovered. We discuss features of autosomal recessive and dominant types of lipodystrophies and therapeutic interventions available for these patients.
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  • 44
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: The behavioral and neuropsychiatric symptoms of dementia and Alzheimer's disease have become an increasingly important focus of clinical research. These symptoms also pose a tremendous challenge to families and caregivers. The late afternoon/evening exacerbation of behavioral symptoms in dementia has been recognized by clinicians for >60 years. Researchers have utilized a variety of increasingly sophisticated tools to examine the circadian, hormonal, physiological, and epidemiological correlations with sundowning behavior. Although treatment remains largely empirical, an improved understanding of the complex relationships that drive sundowning behavior should lead to more effective therapies in the future.
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  • 45
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Medicine 57 (2006), S. 553-574 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Although used for more than 4000 years for recreational and medicinal purposes, Cannabis and its best-known pharmacologically active constituents, the cannabinoids, became a protagonist in medical research only recently. This revival of interest is explained by the finding in the 1990s of the mechanism of action of the main psychotropic cannabinoid, ??9-tetrahydrocannabinol (THC), which acts through specific membrane receptors, the cannabinoid receptors. The molecular characterization of these receptors allowed the development of synthetic molecules with cannabinoid and noncannabinoid structure and with higher selectivity, metabolic stability, and efficacy than THC, as well as the development of antagonists that have already found pharmaceutical application. The finding of endogenous agonists at these receptors, the endocannabinoids, opened new therapeutic possibilities through the modulation of the activity of cannabinoid receptors by targeting the biochemical mechanisms controlling endocannabinoid tissue levels.
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  • 46
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: In the short time since it became effective for health care organizations, a privacy regulation issued under the Health Insurance Portability and Accountability Act of 1996 (HIPAA) has had a significant adverse impact on the conduct of clinical research in the United States, without a substantial corresponding increase in privacy protection for research participants. Some of the problems associated with HIPAA have been resolved through revisions since the regulation's initial promulgation in December 2000, and other problems can be addressed by better educating health care providers and researchers about its requirements and available alternatives for compliance; however, considerable structural challenges remain. These constitute substantial barriers to research and resulting medical advances. Additional revisions to HIPAA based on the principles and trade-offs reflected in the Common RuleĐ??which responsibly balances an individual's interest in privacy protection with the public interest in gaining knowledge through biomedical researchĐ??can go a long way to remedying remaining flaws in the system.
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  • 47
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Medicine 57 (2006), S. 155-166 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Hepatitis B is a global health problem. Patients with chronic hepatitis B (CHB) carry a significant risk to eventually develop cirrhotic liver disease. Recent therapeutic advances against CHB offer excellent potential for long-term suppression of hepatitis B virus (HBV) replication during antiviral therapy, and occasionally a durable remission off medication. Selection of appropriate patients for antiviral therapy depends on identification of HBV replication and an elevated alanine aminotransferase level or histologic liver injury. Pegylated interferon alpha offers potent immunomodulatory and antiviral activity with the potential for durability, but also with adverse effects and significant cost. The nucleoside or nucleotide analogs, lamivudine, adefovir, and entecavir, suppress HBV replication and are extremely well-tolerated, but long-term or even lifelong therapy is required. Most experience has been gained with lamivudine, but viral resistance occurs frequently. Newer analogs appear to be relatively free of this problem. Approaches using a combination of agents have promise, but have yet to be proven superior to individual drugs alone.
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  • 48
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The serum/glucocorticoid-induced kinase Sgk1 plays an important role in the regulation of epithelial ion transport. This kinase is very rapidly regulated at the transcriptional level as well as via posttranslational modifications involving phosphorylation by the MAP or PI-3 kinase pathways and/or ubiquitylation. Although Sgk1 is a cell survival kinase, its primary role likely concerns the regulation of epithelial ion transport, as suggested by the phenotype of Sgk1-null mice, which display a defect in Na+ homeostasis owing to disturbed renal tubular Na+ handling. In this review we first discuss the molecular, cellular, and regulatory aspects of Sgk1 and its paralogs. We then discuss its roles in the physiology and pathophysiology of epithelial ion transport.
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  • 49
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Superfast muscles of vertebrates power sound production. The fastest, the swimbladder muscle of toadfish, generates mechanical power at frequencies in excess of 200 Hz. To operate at these frequencies, the speed of relaxation has had to increase approximately 50-fold. This increase is accomplished by modifications of three kinetic traits: (a) a fast calcium transient due to extremely high concentration of sarcoplasmic reticulum (SR)-Ca2+ pumps and parvalbumin, (b) fast off-rate of Ca2+ from troponin C due to an alteration in troponin, and (c) fast cross-bridge detachment rate constant (g, 50 times faster than that in rabbit fast-twitch muscle) due to an alteration in myosin. Although these three modifications permit swimbladder muscle to generate mechanical work at high frequencies (where locomotor muscles cannot), it comes with a cost: The high g causes a large reduction in attached force-generating cross-bridges, making the swimbladder incapable of powering low-frequency locomotory movements. Hence the locomotory and sound-producing muscles have mutually exclusive designs.
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  • 50
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 345-374 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Phosphorylation of Ser19 on the 20-kDa regulatory light chain of myosin II (MLC20) by Ca2+/calmodulin-dependent myosin light-chain kinase (MLCK) is essential for initiation of smooth muscle contraction. The initial [Ca2+]i transient is rapidly dissipated and MLCK inactivated, whereas MLC20 and muscle contraction are well maintained. Sustained contraction does not reflect Ca2+ sensitization because complete inhibition of MLC phosphatase activity in the absence of Ca2+ induces smooth muscle contraction. This contraction is suppressed by staurosporine, implying participation of a Ca2+-independent MLCK. Thus, sustained contraction, as with agonist-induced contraction at experimentally fixed Ca2+ concentrations, involves (a) G protein activation, (b) regulated inhibition of MLC phosphatase, and (c) MLC20 phosphorylation via a Ca2+-independent MLCK. The pathways that lead to inhibition of MLC phosphatase by Gq/13-coupled receptors are initiated by sequential activation of Gʼ̛q/ʼ̛13, RhoGEF, and RhoA, and involve Rho kinaseĐ??mediated phosphorylation of the regulatory subunit of MLC phosphatase (MYPT1) and/or PKC-mediated phosphorylation of CPI-17, an endogenous inhibitor of MLC phosphatase. Sustained MLC20 phosphorylation is probably induced by the Ca2+-independent MLCK, ZIP kinase. The pathways initiated by Gi-coupled receptors involve sequential activation of G?‚??i, PI 3-kinase, and the Ca2+-independent MLCK, integrin-linked kinase. The last phosphorylates MLC20 directly and inhibits MLC phosphatase by phosphorylating CPI-17. PKA and PKG, which mediate relaxation, act upstream to desensitize the receptors (VPAC2 and NPR-C), inhibit adenylyl and guanylyl cyclase activities, and stimulate cAMP-specific PDE3 and PDE4 and cGMP-specific PDE5 activities. These kinases also act downstream to inhibit (a) initial contraction by inhibiting Ca2+ mobilization and (b) sustained contraction by inhibiting RhoA and targets downstream of RhoA. This increases MLC phosphatase activity and induces MLC20 dephosphorylation and muscle relaxation.
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  • 51
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The ability of animals to survive food deprivation is clearly of considerable survival value. Unsurprisingly, therefore, all animals exhibit adaptive biochemical and physiological responses to the lack of food. Many animals inhabit environments in which food availability fluctuates or encounters with appropriate food items are rare and unpredictable; these species offer interesting opportunities to study physiological adaptations to fasting and starvation. When deprived of food, animals employ various behavioral, physiological, and structural responses to reduce metabolism, which prolongs the period in which energy reserves can cover metabolism. Such behavioral responses can include a reduction in spontaneous activity and a lowering in body temperature, although in later stages of food deprivation in which starvation commences, activity may increase as food-searching is activated. In most animals, the gastrointestinal tract undergoes marked atrophy when digestive processes are curtailed; this structural response and others seem particularly pronounced in species that normally feed at intermittent intervals. Such animals, however, must be able to restore digestive functions soon after feeding, and these transitions appear to occur at low metabolic costs.
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  • 52
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    Annual Review of Physiology 68 (2006), S. 431-459 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The FXYD proteins are a family of seven homologous single transmembrane segment proteins (FXYD1Đ??7), expressed in a tissue-specific fashion. The FXYD proteins modulate the function of Na,K-ATPase, thus adapting kinetic properties of active Na+ and K+ transport to the specific needs of different cells. Six FXYD proteins ( 1Đ??5, 7 ) are known to interact with Na,K-ATPase and affect its kinetic properties in specific ways. Although effects of FXYD proteins on parameters such as K1/2Na+, K1/2K+, KmATP, and Vmax are modest, usually twofold, these effects may have important long-term consequences for homeostasis of cation balance. In this review we summarize basic features of FXYD proteins and present recent evidence for functional effects, structure-function relations and structural interactions with Na,K-ATPase. We then discuss possible physiological roles, based on in vitro observations and newly available knockout mice models. Finally, we also consider evidence that FXYD proteins affect functioning of other ion transport systems.
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  • 53
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Ion channels are pore-forming transmembrane proteins that allow ions to permeate biological membranes. Pore structure plays a crucial role in determining the ion permeation and selectivity properties of particular channels. In the past few decades, efforts have been undertaken to identify key elements of the pore regions of different classes of ion channels. In this review, we summarize current knowledge about permeation and selectivity of channel proteins from the transient receptor potential (TRP) superfamily. Whereas all TRP channels are permeable for cations, only two TRP channels are impermeable for Ca2+ (TRPM4, TRPM5), and two others are highly Ca2+ permeable (TRPV5, TRPV6). Despite the great advances in the TRP channel field during the past decade, only a limited number of reports have dealt with functional characterization of pore properties, biophysical aspects of cation permeation, or description of pore structures of TRP channels. This review gives an overview of available experimental and theoretical data and discusses the functional impact of pore-structure modifications on TRP channel properties.
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  • 54
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 719-736 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The TRP (transient receptor potential) superfamily of cation channels is present in all eukaryotes, from yeast to mammals. Many TRP channels have been studied in the nematode Caenorhabditis elegans, revealing novel biological functions, regulatory modes, and mechanisms of localization. C. elegans TRPV channels function in olfaction, mechanosensation, osmosensation, and activity-dependent gene regulation. Their activity is regulated by G protein signaling and polyunsaturated fatty acids. C. elegans TRPPs related to human polycystic kidney disease genes are expressed in male-specific neurons. The KLP-6 kinesin directs TRPP channels to cilia, where they may interact with F0/F1 ATPases. A sperm-specific TRPC channel, TRP-3, is required for fertilization. Upon sperm activation, TRP-3 translocates from an intracellular compartment to the plasma membrane to allow store-operated Ca2+ entry. The TRPM channels GON-2 and GTL-2 regulate Mg2+ homeostasis and Mg2+ uptake by intestinal cells; GON-2 is also required for gonad development. The TRPML CUP-5 promotes normal lysosome biogenesis and prevents apoptosis. Dynamic, precise expression of TRP proteins generates a remarkable range of cellular functions.
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  • 55
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The physical removal of viruses and bacteria on the mucociliary escalator is an important aspect of the mammalian lung's innate defense mechanism. The volume of airway surface liquid (ASL) present in the respiratory tract is a critical determinant of both mucus hydration and the rate of mucus clearance from the lung. ASL volume is maintained by the predominantly ciliated epithelium via coordinated regulation of (a) absorption, by the epithelial Na+ channel, and (b) secretion, by the Ca2+ -activated Cl channel (CaCC) and CFTR. This review provides an update on our current understanding of how shear stress regulates ASL volume height in normal and cystic fibrosis (CF) airway epithelia through extracellular ATP- and adenosine (ADO)-mediated pathways that modulate ion transport and ASL volume homeostasis. We also discuss (a) how derangement of the ADO-CFTR pathway renders CF airways vulnerable to viral infections that deplete ASL volume and produce mucus stasis, and (b) potential shear stressĐ??dependent therapies for CF.
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  • 56
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 649-684 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Transient receptor potential (TRP) channels mediate responses in a large variety of signaling mechanisms. Most studies on mammalian TRP channels rely on heterologous expression, but their relevance to in vivo tissues is not entirely clear. In contrast, Drosophila TRP and TRP-like (TRPL) channels allow direct analyses of in vivo function. In Drosophila photoreceptors, activation of TRP and TRPL is mediated via the phosphoinositide cascade, with both Ca2+ and diacylglycerol (DAG) essential for generating the light response. In tissue culture cells, TRPL channels are constitutively active, and lipid second messengers greatly facilitate this activity. Inhibition of phospholipase C (PLC) completely blocks lipid activation of TRPL, suggesting that lipid activation is mediated via PLC. In vivo studies in mutant Drosophila also reveal an acute requirement for lipid-producing enzyme, which may regulate PLC activity. Thus, PLC and its downstream second messengers, Ca2+ and DAG, constitute critical mediators of TRP/TRPL gating in vivo.
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  • 57
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Because of the anatomy, function, and nonregenerative nature of the myocardium, inflammation in this tissue is not well tolerated. Nevertheless, various diseases of the heart are characterized by inflammatory responses involving the effector mechanisms of innate and adaptive (lymphocyte-dependent) immunity. The innate immune response to ischemia-reperfusion injury is, by far, the most common cause of myocardial inflammation. Innate responses may have beneficial influences that preserve myocardial function in the short term but may be maladaptive in chronic states. Adaptive responses in the myocardium occur with infection or loss of tolerance, and lead to myocarditis. Given the narrow margin for benefit of cardiac inflammation, special regulatory mechanisms likely raise the threshold, compared to other tissues, for the induction and persistence of adaptive immune responses. These mechanisms include strong central and peripheral T cell tolerance to heart antigens and induction of anti-inflammatory feedback mechanisms involving cytokines such as interferon-??.
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  • 58
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Liver X receptors (LXRs) and farnesoid X receptor (FXR) are nuclear receptors that function as intracellular sensors for sterols and bile acids, respectively. In response to their ligands, these receptors induce transcriptional responses that maintain a balanced, finely tuned regulation of cholesterol and bile acid metabolism. LXRs also permit the efficient storage of carbohydrate- and fat-derived energy, whereas FXR activation results in an overall decrease in triglyceride levels and modulation of glucose metabolism. The elegant, dual interplay between these two receptor systems suggests that they coevolved to constitute a highly sensitive and efficient system for the maintenance of total body fat and cholesterol homeostasis. Emerging evidence suggests that the tissue-specific action of these receptors is also crucial for the proper function of the cardiovascular, immune, reproductive, endocrine pancreas, renal, and central nervous systems. Together, LXRs and FXR represent potential therapeutic targets for the treatment and prevention of numerous metabolic and lipid-related diseases.
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  • 59
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 29-49 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Many forms of pediatric and adult heart disease result from a deficiency in cardiomyocyte number. Through repopulation of the heart with new cardiomyocytes (that is, induction of regenerative cardiac growth), cardiac disease potentially can be reversed, provided that the newly formed myocytes structurally and functionally integrate in the preexisting myocardium. A number of approaches have been utilized to effect regenerative growth of the myocardium in experimental animals. These include interventions aimed at enhancing the ability of cardiomyocytes to proliferate in response to cardiac injury, as well as transplantation of cardiomyocytes or myogenic stem cells into diseased hearts. Here we review efforts to induce myocardial regeneration. We also provide a critical review of techniques currently used to assess cardiac regeneration and functional integration of de novo cardiomyocytes.
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  • 60
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 507-541 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Gas exchange, the primary function of the lung, can come about only with the application of physical forces on the macroscale and their transmission to the scale of small airway, small blood vessel, and alveolus, where they serve to distend and stabilize structures that would otherwise collapse. The pathway for force transmission then continues down to the level of cell, nucleus, and molecule; moreover, to lesser or greater degrees most cell types that are resident in the lung have the ability to generate contractile forces. At these smallest scales, physical forces serve to distend the cytoskeleton, drive cytoskeletal remodeling, expose cryptic binding domains, and ultimately modulate reaction rates and gene expression. Importantly, evidence has now accumulated suggesting that multiscale phenomena span these scales and govern integrative lung behavior.
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  • 61
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 563-583 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Airways are embedded in the mechanically dynamic environment of the lung. In utero, this mechanical environment is defined largely by fluid secretion into the developing airway lumen. Clinical, whole lung, and cellular studies demonstrate pivotal roles for mechanical distention in airway morphogenesis and cellular behavior during lung development. In the adult lung, the mechanical environment is defined by a dynamic balance of surface, tissue, and muscle forces. Diseases of the airways modulate both the mechanical stresses to which the airways are exposed as well as the structure and mechanical behavior of the airways. For instance, in asthma, activation of airway smooth muscle abruptly changes the airway size and stress state within the airway wall; asthma also results in profound remodeling of the airway wall. Data now demonstrate that airway epithelial cells, smooth muscle cells, and fibroblasts respond to their mechanical environment. A prominent role has been identified for the epithelium in transducing mechanical stresses, and in both the fetal and mature airways, epithelial cells interact with mesenchymal cells to coordinate remodeling of tissue architecture in response to the mechanical environment.
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  • 62
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    Annual Review of Physiology 68 (2006), S. 123-158 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The insulin resistance syndrome refers to a constellation of findings, including glucose intolerance, obesity, dyslipidemia, and hypertension, that promote the development of type 2 diabetes, cardiovascular disease, cancer, and other disorders. Defining the pathophysiological links between insulin resistance, the insulin resistance syndrome, and its sequelae is critical to understanding and treating these disorders. Over the past decade, two approaches have provided important insights into how changes in insulin signaling produce the spectrum of phenotypes associated with insulin resistance. First, studies using tissue-specific knockouts or tissue-specific reconstitution of the insulin receptor in vivo in mice have enabled us to deconstruct the insulin resistance syndromes by dissecting the contributions of different tissues to the insulin-resistant state. Second, in vivo and in vitro studies of the complex network of insulin signaling have provided insight into how insulin resistance can develop in some pathways whereas insulin sensitivity is maintained in others. These data, taken together, give us a framework for understanding the relationship between insulin resistance and the insulin resistance syndromes.
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  • 63
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: In the gastrointestinal tract, phasic contractions are caused by electrical activity termed slow waves. Slow waves are generated and actively propagated by interstitial cells of Cajal (ICC). The initiation of pacemaker activity in the ICC is caused by release of Ca2+ from inositol 1,4,5-trisphosphate (IP3) receptorĐ??operated stores, uptake of Ca2+ into mitochondria, and the development of unitary currents. Summation of unitary currents causes depolarization and activation of a dihydropyridine-resistant Ca2+ conductance that entrains pacemaker activity in a network of ICC, resulting in the active propagation of slow waves. Slow wave frequency is regulated by a variety of physiological agonists and conditions, and shifts in pacemaker dominance can occur in response to both neural and nonneural inputs. Loss of ICC in many human motility disorders suggests exciting new hypotheses for the etiology of these disorders.
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  • 64
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Communication between endothelial cells and cardiomyocytes regulates not only early cardiac development but also adult cardiomyocyte function, including the contractile state. In the normal mammalian myocardium, each cardiomyocyte is surrounded by an intricate network of capillaries and is next to endothelial cells. Cardiomyocytes depend on endothelial cells not only for oxygenated blood supply but also for local protective signals that promote cardiomyocyte organization and survival. While endothelial cells direct cardiomyocytes, cardiomyocytes reciprocally secrete factors that impact endothelial cell function. Understanding how endothelial cells communicate with cardiomyocytes will be critical for cardiac regeneration, in which the ultimate goal is not simply to improve systolic function transiently but to establish new myocardium that is both structurally and functionally normal in the long term.
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  • 65
    Electronic Resource
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 619-647 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The aim of this review is to provide a basic framework for understanding the function of mammalian transient receptor potential (TRP) channels, particularly as they have been elucidated in heterologous expression systems. Mammalian TRP channel proteins form six-transmembrane (6-TM) cation-permeable channels that may be grouped into six subfamilies on the basis of amino acid sequence homology (TRPC, TRPV, TRPM, TRPA, TRPP, and TRPML). Selected functional properties of TRP channels from each subfamily are summarized in this review. Although a single defining characteristic of TRP channel function has not yet emerged, TRP channels may be generally described as calcium-permeable cation channels with polymodal activation properties. By integrating multiple concomitant stimuli and coupling their activity to downstream cellular signal amplification via calcium permeation and membrane depolarization, TRP channels appear well adapted to function in cellular sensation. Our review of recent literature implicating TRP channels in neuronal growth cone steering suggests that TRPs may function more widely in cellular guidance and chemotaxis. The TRP channel gene family and its nomenclature, the encoded proteins and alternatively spliced variants, and the rapidly expanding pharmacology of TRP channels are summarized in online supplemental material.
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  • 66
    Electronic Resource
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 403-429 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Tight junctions form continuous intercellular contacts controlling solute movement through the paracellular pathway across epithelia. Paracellular barriers vary among epithelia in electrical resistance and behave as if they are lined with pores that have charge and size selectivity. Recent evidence shows that claudins, a large family (at least 24 members) of intercellular adhesion molecules, form the seal and its variable pore-like properties. This evidence comes from the study of claudins expressed in cultured epithelial cell models, genetically altered mice, and human mutants. We review information on the structure, function, and transcriptional and posttranslational regulation of the claudin family as well as of their evolutionarily distant relatives called the PMP22/EMP/MP20/claudin, or pfam00822, superfamily.
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  • 67
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Although there have been important advances in diagnostic modalities and therapeutic strategies for congenital heart defects (CHD), these malformations still lead to significant morbidity and mortality in the human population. Over the past 10 years, characterization of the genetic causes of CHD has begun to elucidate some of the molecular causes of these defects. Linkage analysis and candidate-gene approaches have been used to identify gene mutations that are associated with both familial and sporadic cases of CHD. Complementation of the human studies with developmental studies in mouse models provides information for the roles of these genes in normal development as well as indications for disease pathogenesis. Biochemical analysis of these gene mutations has provided further insight into the molecular effects of these genetic mutations. Here we review genetic, developmental, and biochemical studies of six cardiac transcription factors that have been identified as genetic causes for CHD in humans.
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  • 68
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: This commentary presents a series of examples of "impossible experimental problems" that we have encountered over the years in addressing various challenging questions in physiology. We aim to show how stimulating the challenges of physiology can be and demonstrate how our naive invocation of methods from disparate fields of science and engineering has led to delightful resolutions of physiological challenges that were utterly new to this intrepid interdisciplinary researcher.
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  • 69
    Electronic Resource
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 189-213 
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The proteasome, a multicatalytic proteinase complex, is responsible for the majority of intracellular protein degradation. Pharmacologic inhibitors of the proteasome possess in vitro and in vivo antitumor activity, and bortezomib, the first such agent to undergo clinical testing, has significant efficacy against multiple myeloma and non-Hodgkin lymphoma (NHL). Preclinical studies demonstrate that proteasome inhibition potentiates the activity of other cancer therapeutics, in part by downregulating chemoresistance pathways. Early clinical studies of bortezomib-based combinations, showing encouraging activity, support this observation. Molecular characterization of resistance to proteasome inhibitors has revealed novel therapeutic targets for sensitizing malignancies to these agents, such as the heat shock pathway. Below, we review the pharmacologic, preclinical, and clinical data that have paved the way for the use of proteasome inhibitors for cancer therapy; outline strategies aimed at enhancing the efficacy of proteasome inhibitors; and review other potential targets in the ubiquitin proteasome pathway for the treatment of cancer.
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  • 70
    Electronic Resource
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 411-449 
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Many biological functions of heme oxygenase (HO), such as cytoprotection against oxidative stress, vasodilation, neurotransmission in the central or peripheral nervous systems, and anti-inflammatory, anti-apoptotic, or anti-proliferative potential, have been attributed to its enzymatic byproduct carbon monoxide (CO), although roles for biliverdin/bilirubin and iron have also been proposed. In addition to these well-characterized effects, recent findings reveal that HO-derived CO may act as an oxygen sensor and circadian modulator of heme biosynthesis. In lymphocytes, CO may participate in regulatory T cell function. A number of the known signaling effects of CO depend on stimulation of soluble guanylate cyclase and/or activation of mitogen-activated protein kinases (MAPK). Furthermore, modulation of caveolin-1 status may serve as an essential component of certain aspects of CO action, such as growth control. In this review, we summarize recent findings of the beneficial or detrimental effects of endogenous CO with an emphasis on the signaling pathways and downstream targets that trigger the action of this gas.
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  • 71
    Electronic Resource
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 101-122 
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: CB1 and CB2 cannabinoid receptors are the primary targets of endogenous cannabinoids (endocannabinoids). These G proteinĐ??coupled receptors play an important role in many processes, including metabolic regulation, craving, pain, anxiety, bone growth, and immune function. Cannabinoid receptors can be engaged directly by agonists or antagonists, or indirectly by manipulating endocannabinoid metabolism. In the past several years, it has become apparent from preclinical studies that therapies either directly or indirectly influencing cannabinoid receptors might be clinically useful. This review considers the components of the endocannabinoid system and discusses some of the most promising endocannabinoid-based therapies.
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  • 72
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The roles of proteases in cancer are now known to be much broader than simply degradation of extracellular matrix during tumor invasion and metastasis. Furthermore, proteases from tumor-associated cells (e.g., fibroblasts, inflammatory cells, endothelial cells) as well as tumor cells are recognized to contribute to pathways critical to neoplastic progression. Although elevated expression (transcripts and proteins) of proteases, and in some cases protease inhibitors, has been documented in many tumors, techniques to assess functional roles for proteases require that we measure protease activity and inhibition of that activity rather than levels of proteases, activators, and inhibitors. Novel techniques for functional imaging of protease activity, both in vitro and in vivo, are being developed as are imaging probes that will allow us to determine protease activity and in some cases to discriminate among protease activities. These should be useful clinically as surrogate endpoints for therapies that alter protease activities.
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  • 73
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Inflammation and infection have long been known to downregulate the activity and expression of cytochrome P450 (CYP) enzymes involved in hepatic drug clearance. This can result in elevated plasma drug levels and increased adverse effects. Recent information on regulation of human CYP enzymes is presented, as are new developments in our understanding of the mechanisms of regulation. Experiments to study the effects of modulating CYP activities on the inflammatory response have yielded possible insights into the physiological consequences, if not the purpose, of the downregulation. Regulation of hepatic flavin monooxygenases, UDP-glucuronosyltransferases, sulfotransferases, glutathione S-transferases, as well as of hepatic transporters during the inflammatory response, exhibits similarities and differences with regulation of CYPs.
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