bluuebunny/crossref_metadata_2025 huggingface dataset:
Lateral Gene Transfer and the Origins of Prokaryotic Groups
Authors: Boucher Yan , Douady Christophe J. , Papke R. Thane , Walsh David A. , Boudreau Mary Ellen R. , Nesbø Camilla L. , Case Rebecca J. , Doolittle W. Ford
Published: January 2004

▪ Abstract  Lateral gene transfer (LGT) is now known to be a major force in the evolution of prokaryotic genomes. To date, most analyses have focused on either (a) verifying phylogenies of individual genes thought to have been transferred, or (b) estimating the fraction of individual genomes likely to have been introduced by transfer. Neither approach does justice to the ability of LGT to effect massive and complex transformations in basic biology. In some cases, such transformation will be manifested as the patchy distribution of a seemingly fundamental property (such as aerobiosis or nitrogen fixation) among the members of a group classically defined by the sharing of other properties (metabolic, morphological, or molecular, such as small subunit ribosomal RNA sequence). In other cases, the lineage of recipients so transformed may be seen to comprise a new group of high taxonomic rank (“class” or even “phylum”). Here we review evidence for an important role of LGT in the evolution of photosynthesis, aerobic respiration, nitrogen fixation, sulfate reduction, methylotrophy, isoprenoid biosynthesis, quorum sensing, flotation (gas vesicles), thermophily, and halophily. Sometimes transfer of complex gene clusters may have been involved, whereas other times separate exchanges of many genes must be invoked.
Cell Polarity and the Cytoskeleton in theCaenorhabditis ElegansZygote
Authors: Schneider Stephan Q. , Bowerman Bruce
Published: January 2004

▪ Abstract  The anterior-posterior axis of the Caenorhabditis elegans zygote forms shortly after fertilization when the sperm pronucleus and its associated centrosomal asters provide a cue that establishes the anterior-posterior (AP) body axis. In response to this cue, the microfilament cytoskeleton polarizes the distribution of a group of widely conserved, cortically localized regulators called the PAR proteins, which are required for the first mitotic division to be asymmetric. These asymmetries include a posterior displacement of the first mitotic spindle and the differential segregation of cell-fate determinants to the anterior and posterior daughters produced by the first cleavage of the zygote. Here we review recent advances in our understanding of the mechanisms that polarize the one-cell zygote to generate an AP axis of asymmetry.
RecA-Dependent Recovery of Arrested DNA Replication Forks
Authors: Courcelle Justin , Hanawalt Philip C.
Published: January 2004

▪ Abstract  DNA damage encountered during the cellular process of chromosomal replication can disrupt the replication machinery and result in mutagenesis or lethality. The RecA protein of Escherichia coli is essential for survival in this situation: It maintains the integrity of the arrested replication fork and signals the upregulation of over 40 gene products, of which most are required to restore the genomic template and to facilitate the resumption of processive replication. Although RecA was originally discovered as a gene product that was required to change the genetic information during sexual cell cycles, over three decades of research have revealed that it is also the key enzyme required to maintain the genetic information when DNA damage is encountered during replication in asexual cell cycles. In this review, we examine the significant experimental approaches that have led to our current understanding of the RecA-mediated processes that restore replication following encounters with DNA damage.
Recognition and Response in the Plant Immune System
Authors: Nimchuk Zachary , Eulgem Thomas , Holt III Ben F. , Dangl Jeffery L.
Published: January 2004

▪ Abstract  Molecular communication between plants and potential pathogens determines the ultimate outcome of their interaction. The directed delivery of microbial molecules into and around the host cell, and the subsequent perception of these by the invaded plant tissue (or lack thereof), determines the difference between disease and disease resistance. In theory, any foreign molecule produced by an invading pathogen could act as an elicitor of the broad physiological and transcriptional re-programming indicative of a plant defense response. The diversity of elicitors recognized by plants seems to support this hypothesis. Additionally, these elicitors are often virulence factors from the pathogen recognized by the host. This recognition, though genetically as simple as a ligand-receptor interaction, may require additional host proteins that are the nominal targets of virulence factor action. Transduction of recognition probably requires regulated protein degradation and results in massive changes in cellular homeostasis, including a programmed cell death known as the hypersensitive response that indicates a successful, if perhaps over-zealous, disease resistance response.
A Cyanobacterial Circadian Timing Mechanism
Authors: Ditty J.L. , Williams S.B. , Golden S.S.
Published: January 2004

▪ Abstract  Cyanobacteria such as Synechococcus elongatus PCC 7942 exhibit 24-h rhythms of gene expression that are controlled by an endogenous circadian clock that is mechanistically distinct from those described for diverse eukaryotes. Genetic and biochemical experiments over the past decade have identified key components of the circadian oscillator, input pathways that synchronize the clock with the daily environment, and output pathways that relay temporal information to downstream genes. The mechanism of the cyanobacterial circadian clock that is emerging is based principally on the assembly and disassembly of a large complex at whose heart are the proteins KaiA, KaiB, and KaiC. Signal transduction pathways that feed into and out of the clock employ protein domains that are similar to those in two-component regulatory systems of bacteria.
Transmission Ratio Distortion in Mice
Authors: Lyon Mary F.
Published: January 2004

▪ Abstract  The most studied example of transmission ratio distortion (TRD) in mice is that of the t-complex. This is a variant region of Chromosome 17 which exists as a polymorphism in wild mice. Males heterozygous for a t-haplotype and a normal Chr 17 transmit the t-haplotype to >50% of their young, up to 99%. Homozygous males are sterile. The TRD produced by the t-complex is due to the action of three or more distorter genes (Tcd) on a responder gene (Tcr). t-Haplotypes are maintained intact by crossover suppression induced by four neighboring inversions, the Tcd and Tcr loci lying in different inversions. Sperm formation is normal in t/t males, but sperm function is impaired through gross defects in sperm motility. The responder gene has been identified as a fusion gene formed from a sperm motility kinase and a ribosomal S6 kinase. Three candidate distorter genes have also been identified as genes coding for dynein chains, and thus possibly involved in sperm flagellar function.
Structure, Diversity, and Evolution of Protein Toxins from Spore-Forming Entomopathogenic Bacteria
Authors: de Maagd Ruud A. , Bravo Alejandra , Berry Colin , Crickmore Neil , Schnepf H. Ernest
Published: January 2004

▪ Abstract  Gram-positive spore-forming entomopathogenic bacteria can utilize a large variety of protein toxins to help them invade, infect, and finally kill their hosts, through their action on the insect midgut. These toxins belong to a number of homology groups containing a diversity of protein structures and modes of action. In many cases, the toxins consist of unique folds or novel combinations of domains having known protein folds. Some of the toxins display a similar structure and mode of action to certain toxins of mammalian pathogens, suggesting a common evolutionary origin. Most of these toxins are produced in large amounts during sporulation and have the remarkable feature that they are localized in parasporal crystals. Localization of multiple toxin-encoding genes on plasmids together with mobilizable elements enables bacteria to shuffle their armory of toxins. Recombination between toxin genes and sequence divergence has resulted in a wide range of host specificities.
Regulation of Cell Cycles in Drosophila Development: Intrinsic and Extrinsic Cues
Authors: Lee Laura A. , Orr-Weaver Terry L.
Published: January 2004

▪ Abstract  An intriguing aspect of cell cycle regulation is how cell growth and division are coordinated with developmental signals to produce properly patterned organisms of the appropriate size. Using the foundation laid by a detailed understanding of the regulators that intrinsically control progression through the cell cycle, links between developmental signals and the cell cycle are being elucidated. Considerable progress has been made using Drosophila melanogaster, both in identifying new cell cycle regulators that respond to developmental cues and in defining the impact of extrinsic signals on homologs of mammalian oncogenes and tumor suppressors. In this review, we discuss each cell cycle phase, highlighting differences between archetypal and variant cell cycles employed for specific developmental strategies. We emphasize the interplay between developmental signals and cell cycle transitions. Developmental control of checkpoints, cell cycle exit, and cell growth are also addressed.
Natural Selection and the Evolution of Genome Imprinting
Authors: de la Casa-Esperón Elena , Sapienza Carmen
Published: January 2004

▪ Abstract  Sexual reproduction results from the fusion of gametes in which the chromatin configuration of maternal and paternal chromosomes is distinct at fertilization. Although many of the differences are erased during successive cellular divisions and chromatin modifications, some are retained in both somatic and germline cells. These epigenetic modifications can confer different characteristics on maternal and paternal chromosomes and such differences can be selected during any process that has the ability to distinguish between homologues. The end result of these selective forces are parental origin effects, writ large. The range of effects observed, including transcriptional imprinting and effects on chromosome segregation and heterochromatization, reflects the diversity of selective forces in operation. However, a closer look at these effects suggests that parental origin–dependent differences in chromatin structure might be subject to some common forces and that these forces may explain many of the “nontranscriptional” parental origin effects observed in mammals.
Unusual Life Style of Giant Chlorella Viruses
Authors: Van Etten James L.
Published: January 2004

▪ Abstract  Paramecium bursaria chlorella virus (PBCV-1) is the prototype of a family of large, icosahedral, plaque-forming, dsDNA viruses that replicate in certain unicellular, eukaryotic chlorella-like green algae. Its 330-kb genome contains ∼373 protein-encoding genes and 11 tRNA genes. The predicted gene products of ∼50% of these genes resemble proteins of known function, including many that are unexpected for a virus, e.g., ornithine decarboxylase, hyaluronan synthase, GDP-D-mannose 4,6 dehydratase, and a potassium ion channel protein. In addition to their large genome size, the chlorella viruses have other features that distinguish them from most viruses. These features include: (a) The viruses encode multiple DNA methyltransferases and DNA site-specific endonucleases. (b) The viruses encode at least some, if not all, of the enzymes required to glycosylate their proteins. (c) PBCV-1 has at least three types of introns, a self-splicing intron in a transcription factor-like gene, a spliceosomal processed intron in its DNA polymerase gene, and a small intron in one of its tRNA genes. (d) Many chlorella virus-encoded proteins are either the smallest or among the smallest proteins of their class. (e) Accumulating evidence indicates that the chlorella viruses have a very long evolutionary history.
Retrotransposons Provide an Evolutionarily Robust Non-Telomerase Mechanism to Maintain Telomeres
Authors: Pardue Mary-Lou , DeBaryshe P.G.
Published: January 2004

▪ Abstract  Telomere molecular biology is far more complex than originally thought. Understanding biological systems is aided by study of evolutionary variants, and Drosophila telomeres are remarkable variants. Drosophila lack telomerase and the arrays of simple repeats generated by telomerase in almost all other organisms; instead, Drosophila telomeres are long tandem arrays of two non-LTR retrotransposons, HeT-A and TART. These are the first transposable elements found to have a bona fide role in cell structure, revealing an unexpected link between telomeres and what is generally considered to be parasitic DNA. In addition to providing insight into the cellular functions performed by telomeres, analysis of HeT-A and TART is providing insight into the evolution of chromosomes, retrotransposons, and retroviruses. Recent studies show that retrotransposon telomeres constitute a robust system for maintaining chromosome ends. These telomeres are now known to predate the separation of extant Drosophila species, allowing ample time for elements and hosts to coevolve interesting mechanisms.
Human Papillomavirus Vaccines and Prevention of Cervical Cancer
Authors: Jansen Kathrin U. , Shaw Alan R.
Published: January 2004

Cervical cancer and precancerous cervical lesions constitute a major problem in women's health. Every year 470,000 cases of cervical cancer are diagnosed worldwide, and about half the women afflicted will die. In the United States alone, ∼14,000 cases of cervical cancer are diagnosed each year despite the availability of screening and access to high-quality gynecological care. With the confirmation that cervical cancer is caused by an infectious agent, human papillomavirus, the possibility of fighting this disease with either prophylactic or therapeutic vaccination arose. This review describes advances in vaccine development and very promising first results for prophylactic vaccination against cervical cancer.
Beta-Cell Replacement for Type I Diabetes
Authors: Stock Peter G. , Bluestone Jeffrey A.
Published: January 2004

The ability to achieve insulin independence with either solid-organ pancreas or islet transplantation has increased the number of patients seeking beta-cell replacement as an alternative to insulin therapy. Despite dramatic improvements in the ability to achieve insulin independence following solid-organ pancreas transplantation, the secondary complications of long-standing diabetes are frequently irreversible by the time surgical intervention is justified based on the risk of this procedure. Pancreatic islet transplantation provides a safer and less invasive alternative for beta-cell replacement that could be justified earlier in the course of diabetes to prevent the development of secondary complications. Recent advances in the technology of islet isolation, as well as the ability to prevent the alloimmune and recurrent autoimmune response following islet transplantation with immunosuppressive regimens that are not toxic to beta cells, have rekindled an interest in this field. Widespread application of islet transplantation will depend on further improvements in selective immunosuppression, development of immunologic tolerance, and finding new sources of beta cells.
Opportunities for Control of Meningococcal Disease in the United States
Authors: Raghunathan Pratima L. , Bernhardt Scott A. , Rosenstein Nancy E.
Published: January 2004

The United States currently has relatively low rates of meningococcal disease caused by Neisseria meningitidis. Serogroups Y, C, and B are most common. Although most cases are sporadic, a minority are associated with outbreaks. Pediatric populations have disproportionately higher rates of disease, but nearly two thirds of all cases occur in persons aged 15 years and older. The major challenge to control of domestic meningococcal disease is the absence of a vaccine to prevent sporadic cases spanning many age groups. The quadrivalent A/C/Y/W-135 meningococcal polysaccharide vaccine is licensed in the United States, but because of its limited efficacy in children under two years of age, it is recommended for high-risk groups and outbreak response rather than routine childhood immunization. New conjugate meningococcal vaccines have successfully reduced endemic disease in the United Kingdom, and similar vaccines promise to have a dramatic impact on the burden of meningococcal disease in the United States.
Lead Poisoning
Authors: Needleman Herbert
Published: January 2004

Understanding of lead toxicity has advanced substantially over the past three decades, and focus has shifted from high-dose effects in clinically symptomatic individuals to the consequences of exposure at lower doses that cause no symptoms, particularly in children and fetuses. The availability of more sensitive analytic methods has made it possible to measure lead at much lower concentrations. This advance, along with more refined epidemiological techniques and better outcome measures, has lowered the least observable effect level until it approaches zero. As a consequence, the segment of the population who are diagnosed with exposure to toxic levels has expanded. At the same time, environmental efforts, most importantly the removal of lead from gasoline, have dramatically reduced the amount of lead in the biosphere. The remaining major source of lead is older housing stock. Although the cost of lead paint abatement is measured in billions of dollars, the monetized benefits of such a Herculean task have been shown to far outweigh the costs.
Implementing A Research Agenda for Complementary and Alternative Medicine
Authors: Berman Jonathan D. , Straus Stephen E.
Published: January 2004

Complementary and alternative medicine (CAM) consists of diverse clinical interventions that are practiced because of their popularity rather than the prior demonstration of safety and efficacy required for conventional agents. CAM therapies can be grouped into five categories: biologically based therapies, manipulative and body-based interventions, mind-body interventions, “energy” therapies, and alternative medical systems. The present evidence that individual CAM interventions are efficacious is largely anecdotal, but hundreds of small trials have yielded positive results. For a few modalities, existing data are either very encouraging or else sufficient to conclude that they are ineffective. CAM interventions are presumed to be safe, yet they may not be, particularly in the case of botanical agents with inherent toxicities, significant drug interactions, or potent adulterants. The public health questions regarding CAM can only be addressed through a research agenda that defines which interventions have favorable therapeutic indices. Implementation of this agenda involves adequate characterization and standardization of the product or practice, with rigorous investigation to demonstrate its safety, mechanism of action, and efficacy.
Molecular Neurobiology of Drug Addiction
Authors: Chao Jennifer , Nestler Eric J.
Published: January 2004

Addiction can be viewed as a form of drug-induced neural plasticity. One of the best-established molecular mechanisms of addiction is upregulation of the cAMP second messenger pathway, which occurs in many neuronal cell types in response to chronic administration of opiates or other drugs of abuse. This upregulation and the resulting activation of the transcription factor CREB appear to mediate aspects of tolerance and dependence. In contrast, induction of another transcription factor, termed ΔFosB, exerts the opposite effect and may contribute to sensitized responses to drug exposure. Knowledge of these mechanisms could lead to more effective treatments for addictive disorders.
Clinical Management of Tuberculosis in the Context of HIV Infection
Authors: de Jong Bouke C. , Israelski Dennis M. , Corbett Elizabeth L. , Small Peter M.
Published: January 2004

Globally, the HIV and tuberculosis epidemics are stoking each other, creating a public health crisis of enormous proportions. At the level of individuals, contemporaneous infection with M. tuberculosis and HIV poses great challenges to clinical management. This chapter provides an overview of active and latent tuberculosis treatment in HIV-infected and -uninfected individuals. The discussion focuses on medication issues, including interactions between antitubercular drugs, antiretroviral drugs, and medicines used for opportunistic infections and treatment in the face of comorbidities. Clinical questions specific to coinfection are discussed, including duration and timing initiation of therapy and immune reconstitution. Most of the data presented were generated in industrialized settings and are presented to assist patient management in such settings. However, given the disproportionate amount of TB/HIV in less-developed nations and the increasing availability of antiretroviral therapy in resource-limited settings, the issues presented will become increasingly relevant globally.
New Approaches to Hemodialysis
Authors: Pierratos Andreas
Published: January 2004

Treatment of end-stage renal disease with dialysis is characterized by high mortality rate, low quality of life, and high cost. Recent randomized controlled studies showed that increasing the dialysis dose above the currently recommended levels in thrice-weekly hemodialysis does not decrease the patient mortality rate. Short daily hemodialysis or daily home nocturnal hemodialysis are promising alternatives. Both improve quality of life and control blood pressure and anemia; nocturnal hemodialysis additionally controls serum phosphates without phosphate binders, allows a free diet, and corrects sleep apnea. Although the direct cost of daily hemodialysis is higher than that of conventional hemodialysis, the cost of total care, especially when delivered at home, seems to be lower. Further confirmation of these results is important. Restructuring of the dialysis reimbursement system is necessary to make the use of daily hemodialysis possible. Hemofiltration techniques, sorbents, and the renal tubular assist device may also help change the current grim statistics.
Mechanisms of Pulmonary Fibrosis
Authors: Thannickal Victor J. , Toews Galen B. , White Eric S. , Lynch III Joseph P. , Martinez Fernando J.
Published: January 2004

Tissue injury evokes highly conserved, tightly regulated inflammatory responses and less well-understood host repair responses. Both inflammation and repair involve the recruitment, activation, apoptosis, and eventual clearance of key effector cells. In this review, we propose the concept of pulmonary fibrosis as a dysregulated repair process that is perpetually “turned on” even though classical inflammatory pathways may be dampened or “switched off.” Significant regional heterogeneity, with varied histopathological patterns of inflammation and fibrosis, has been observed in individual patients with idiopathic pulmonary fibrosis. We discuss environmental factors and host response factors, such as genetic susceptibility and age, that may influence these varied manifestations. Better understanding of the mechanisms of lung repair, which include alveolar reepithelialization, myofibroblast differentiation/activation, and apoptosis, should offer more effective therapeutic options for progressive pulmonary fibrosis.
Management of Infections in the Neutropenic Patient
Authors: Rolston Kenneth V.I.
Published: January 2004

Neutropenic patients continue to be at increased risk for developing serious infections despite substantial advances in supportive care. Epidemiologic shifts occur periodically and need to be detected early because they influence prophylactic, empiric, and specific therapy strategies. Although effective in preventing bacterial and some fungal infections, prophylaxis must be used with caution because it is associated with the emergence of resistance. The choices for empiric therapy include combination regimens and monotherapy. Specific choices depend on local factors (epidemiology, susceptibility/resistance patterns, availability). Various treatment settings (hospital-based, early discharge, outpatient) are also available, and the choice depends on the patient's risk category. Early diagnosis and treatment of many fungal and viral infections remains suboptimal. Infection control and prevention are important strategies, especially with the emergence of multidrug-resistant organisms.
Emerging Infectious Threats to the Blood Supply
Authors: Dodd Roger Y. , Leiby David A.
Published: January 2004

During the past 15 years, it has become clear that new agents and new strains of existing agents continue to emerge worldwide as protagonists of infectious disease. These emerging agents pose threats not only to the general human population but also to recipients of blood transfusions. Indeed, the modern era of blood safety perhaps began with the recognition of HIV as an emerging agent transmissible by blood transfusion. Today, emerging infectious agents that pose a threat to the blood supply are not limited to viruses, but include bacterial, protozoan, and prion agents. Preventing the transmission of these new agents by blood transfusion is often problematic, as the available tools may be inadequate. It is certain, however, that new agents will continue to emerge as threats to blood safety and these agents are likely to require novel approaches to prevent their transmission.
Inherited Diseases Involving G Proteins and G Protein–Coupled Receptors
Authors: Spiegel Allen M. , Weinstein Lee S.
Published: January 2004

Heterotrimeric G proteins couple seven-transmembrane receptors for diverse extracellular signals to effectors that generate intracellular signals altering cell function. Mutations in the gene encoding the α subunit of the G protein–coupling receptors to stimulation of adenylyl cyclase cause developmental abnormalities of bone, as well as hormone resistance (pseudohypoparathyroidism caused by loss-of-function mutations) and hormone hypersecretion (McCune-Albright syndrome caused by gain-of-function mutations). Loss- and gain-of-function mutations in genes encoding G protein–coupled receptors (GPCRs) have been identified as the cause of an increasing number of retinal, endocrine, metabolic, and developmental disorders. GPCRs comprise an evolutionarily conserved gene superfamily ( 1 ). By coupling to heterotrimeric G proteins, GPCRs transduce a wide variety of extracellular signals including monoamine, amino acid, and nucleoside neurotransmitters, as well as photons, chemical odorants, divalent cations, hormones, lipids, peptides and proteins. Following a brief overview of G protein–coupled signal transduction, we review the growing body of evidence that mutations in genes encoding GPCRs and G proteins are an important cause of human disease.
Rituximab: Expanding Role in Therapy for Lymphomas and Autoimmune Diseases
Authors: Rastetter William , Molina Arturo , White Christine A.
Published: January 2004

Rituximab (Rituxan®) is a human-mouse chimeric monoclonal antibody that targets the B-cell CD20 antigen and causes rapid and specific B-cell depletion. Rituximab was approved in the United States in 1997 to treat low-grade or follicular, relapsed or refractory, CD20-positive B-cell non-Hodgkin's lymphoma (NHL). Since then, further clinical experience with rituximab has been incorporated into the prescribing information, which now stipulates an extended eight-week schedule, treatment of patients with refractory or relapsed bulky disease measuring >10 cm, and retreatment of patients who responded to rituximab previously. In 1998, the European Union approved rituximab (MabThera®) to treat stage III/IV, follicular, chemotherapy-resistant, or relapsed NHL. Recently, the European Union also approved the use of rituximab in combination with standard chemotherapy for aggressive NHL. Many clinical trials have evaluated rituximab, alone or with other therapies, in indolent and aggressive NHL as well as other B-cell lymphoproliferative disorders. New studies are evaluating rituximab's role in first-line therapy, maintenance therapy, and stem-cell transplantation procedures. The use of rituximab against autoimmune disorders, such as rheumatoid arthritis, immune thrombocytopenic purpura, autoimmune hemolytic anemia, systemic lupus erythematosus, and multiple sclerosis, is also under investigation.
Progress in Antisense Technology
Authors: Crooke Stanley T.
Published: January 2004

Antisense technology exploits oligonucleotide analogs to bind to target RNAs via Watson-Crick hybridization. Once bound, the antisense agent either disables or induces the degradation of the target RNA. Antisense agents can also alter splicing. During the past decade, much has been learned about the basic mechanisms of antisense, the medicinal chemistry, and the pharmacologic, pharmacokinetic, and toxicologic properties of antisense molecules. Antisense technology has proven valuable in gene functionalization and target validation. With one drug marketed, Vitravene™, and approximately 20 antisense drugs in clinical development, it appears that antisense drugs may prove important in the treatment of a wide range of diseases.
HIV–Associated Lipodystrophy: Pathogenesis, Prognosis, Treatment, and Controversies
Authors: Koutkia Polyxeni , Grinspoon Steven
Published: January 2004

Potent antiretroviral agents markedly suppress HIV and have dramatically improved the clinical course, prognosis, and survival of HIV-infected patients. Unfortunately, highly active antiretroviral therapy is often compromised by metabolic complications, including insulin resistance, dyslipidemia, and fat redistribution. Together these changes have been termed the HIV-lipodystrophy syndrome, which is estimated to affect a majority of patients treated with potent combination antiretroviral therapy. Routine testing of fasting glucose is recommended for all HIV-infected patients, particularly those who are obese, have a family history of diabetes mellitus, or are receiving protease inhibitor therapy. Preliminary investigations have demonstrated the potential utility of insulin-sensitizing agents and lipid-lowering therapies to ameliorate these metabolic disturbances. Patients with HIV infection who demonstrate fat redistribution and develop hyperinsulinemia and dyslipidemia may be at increased risk of cardiovascular disease. However, the long-term effects on cardiovascular disease have not yet been determined.
Left Ventricular Diastolic Dysfunction and Diastolic Heart Failure
Authors: Gaasch William H. , Zile Michael R.
Published: January 2004

Thirty to fifty percent of patients presenting with signs and symptoms of heart failure have a normal left ventricular (LV) systolic ejection fraction. The clinical examination cannot distinguish these patients (diastolic heart failure) from those with a depressed ejection fraction (systolic heart failure), but echocardiography can. The management of diastolic heart failure has two major objectives. The first is to reverse the consequences of diastolic dysfunction (e.g., venous congestion), and the second is to eliminate or reduce the factors responsible for diastolic dysfunction (e.g., myocardial hypertrophy, fibrosis, and ischemia).
The erbB Family: Targets for Therapeutic Development Against Cancer and Therapeutic Strategies Using Monoclonal Antibodies and Tyrosine Kinase Inhibitors
Authors: Rowinsky Eric K.
Published: January 2004

The overexpression and aberrant function of members of the erbB family of receptors, particularly erbB1 (also known as epidermal growth factor receptor), and its ligands in many human cancers have provided a rationale for targeting this signaling network with novel approaches. erbB1 is a selective target for inhibiting cancers because its activation often confers a proliferative advantage. Activation of the erbB1 tyrosine kinase provides signals that drive dysregulated proliferation, invasion, metastasis, angiogenesis, and cell survival, and its inhibition has potential in both the treatment and prevention of these malignancies. Based on the structure and function of erbB1, two therapeutic strategies have been developed. The first uses human monoclonal antibodies (MAbs) generated against the receptor's ligand-binding extracellular domain. These MAbs block binding of receptor-activating ligands, and, in some cases, can induce receptor endocytosis and downregulation. The second uses small molecules that compete with adenosine triphosphate (ATP) for binding to the receptor's kinase pocket, thereby blocking receptor activation and the transduction of postreceptor signals. Early clinical studies suggest that both approaches are well tolerated and can induce clinical activity in many common malignancies.
Botulinum Toxin and Other New Approaches to Migraine Therapy
Authors: Ashkenazi Avi , Silberstein Stephen D.
Published: January 2004

The number of migraine treatments and our understanding of migraine pathophysiology are both increasing. Newer treatments focus on migraine prevention. Botulinum toxin (BTX) is a potent neurotoxin used primarily to treat diseases associated with increased muscle activity. Recently, BTX was found to have antinociceptive effects that are probably independent of its muscle-relaxant action. Clinical trials support the efficacy of BTX type A (and possibly also type B) in the treatment of migraine. The anticonvulsant topiramate was recently shown to be effective for migraine prevention. At the low doses used for this indication, cognitive side effects are not a major concern. Another new approach to migraine prevention is angiotensin type 1 (AT1) receptor blockade. The high tolerability of the AT1 receptor blocker candesartan warrants further studies to assess its role in migraine prevention.
Nonmyeloablative Allogeneic Immunotherapy for Solid Tumors
Authors: Childs Richard W. , Barrett John
Published: January 2004

Over the past decade, considerable advances have been made in the field of allogeneic hematopoietic stem cell transplantation. Recognition that transplanted donor immune cells can cure patients with leukemia has led to the development of nonmyeloablative or “low-intensity” conditioning regimens, which have expanded the application of allogeneic transplantation to a growing number of hematological malignancies. The improved safety and preliminary success of this transplant approach have justified applying allogeneic immunotherapy to patients with treatment-refractory solid tumors.
Serum Proteomics in Cancer Diagnosis and Management
Authors: Rosenblatt Kevin P. , Bryant-Greenwood Peter , Killian J. Keith , Mehta Arpita , Geho David , Espina Virginia , Petricoin Emanuel F. , Liotta Lance A.
Published: January 2004

Mass spectrometry–based diagnostics has the potential to revolutionize molecular medicine. Using modern mass-spectrometer technologies, clinical tests can be developed that are practical, robust, accurate, and inexpensive. Serum proteomic pattern profiling couples mass spectrometry with adaptive artificial-intelligence–based bioinformatics, which can now be employed to detect pathological states reflected in the serum proteome. With this approach, rapid and cost-effective tests with exquisite clinical sensitivity and specificity are emerging. These tools may dramatically change how disease is detected, monitored, and managed.
Drug-Eluting Stents
Authors: Woods T. Cooper , Marks Andrew R.
Published: January 2004

Advances in catheter and stent design have made stent implantation the standard coronary angioplasty procedure. Unfortunately, in-stent restenosis continues to plague this procedure, with the optimum binary restenosis rates reaching ∼10% to 20%. In the past few years, it has become clear that in-stent restenosis is largely due to the migration and proliferation of vascular smooth muscle cells to form a neointima. To address this issue, stents coated with drug-delivery vehicles have been developed to deliver antiproliferative therapeutics. Two drugs, rapamycin and taxol, have been the lead compounds for testing the idea of a drug-eluting stent. These drugs have been successful largely because of the solid mechanistic understanding of their effects and extensive preclinical examination. The result of these years of work is that the rapamycin-coated stent entered the US market in April of 2003, and the taxol-coated stent appears poised to follow soon.
The Impact of Minimally Invasive Surgical Techniques
Authors: Darzi Ara , Munz Yaron
Published: January 2004

The use of minimally invasive techniques (MIT) in patient care is well documented in ancient history; however, it was not until the 1990s that advancements in technology enabled surgeons to realize the true potential of this approach. The minimally invasive approach has revolutionized surgical care, significantly reducing postoperative pain, recovery time, and hospital stays with marked improvements in cosmetic outcome and overall cost-effectiveness. It is now used around the world and in all major fields of surgery, compelling changes in training programs in order to assure quality control and patient safety. The bond between surgeons practicing minimally invasive surgery (MIS) and the high-tech industry is of utmost importance to future developments. Surgical robotic systems represent the most technologically advanced product of this collaboration, and their potential application in MIS shows much promise. As technology advances, additional developments in MIT are likely.
Cochlear Implantation for the Treatment of Deafness
Authors: Copeland Benjamin J. , Pillsbury Harold C.
Published: January 2004

Cochlear implants have dramatically changed the treatment and prognosis for patients with profound sensorineural hearing loss. Deaf adults and children can be successfully (re)integrated into the hearing world through a multidisciplinary approach involving otolaryngologists, audiologists, and speech/language pathologists. As the technology of the cochlear prosthesis advances, the candidacy for these devices continues to broaden. This review addresses the basic technology, candidacy criteria, and important issues in the fields of adult and pediatric cochlear implantation. Cost utility and future directions in the treatment of the profoundly hearing impaired are discussed.
The Integration of Pharmacokinetics and Pharmacodynamics: Understanding Dose-Response
Authors: Abdel-Rahman Susan M. , Kauffman Ralph E.
Published: January 2004

Pharmacokinetic (PK) and pharmacodynamic (PD) studies have proven to be powerful and instructive tools, particularly in elucidating important aspects of human pharmacology. Nevertheless, they remain imperfect tools in that they only allow researchers to indirectly extrapolate, through computational modeling, the dynamic processes of drug action. Furthermore, neither tool alone provides a complete nor necessarily relevant picture of drug action. This review explores the utility and applications of PK and PD in the study of drugs, provides examples of lessons learned from their application to studies of human pharmacology, points out some of their limitations, and advances the thesis that these tools ideally should be employed together in an integrated approach. As we continue to apply these tools across the continuum of age and disease, they provide a powerful means to enhance our understanding of drug action, drug interactions, and intrinsic host factors that influence pharmacologic response.
CRF and CRF Receptors: Role in Stress Responsivity and Other Behaviors
Authors: Bale Tracy L. , Vale Wylie W.
Published: January 2004

Since corticotropin-releasing factor (CRF) was first characterized, a growing family of ligands and receptors has evolved. The mammalian family members include CRF, urocortinI (UcnI), UcnII, and UcnIII, along with two receptors, CRFR1 and CRFR2, and a CRF binding protein. These family members differ in their tissue distribution and pharmacology. Studies have provided evidence supporting an important role of this family in regulation of the endocrine and behavioral responses to stress. Although CRF appears to play a stimulatory role in stress responsivity through activation of CRFR1, specific actions of UcnII and UcnIII on CRFR2 may be important for dampening stress sensitivity. As the only ligand with high affinity for both receptors, UcnI's role may be promiscuous. Regulation of the relative contribution of the two CRF receptors to brain CRF pathways may be essential in coordinating physiological responses to stress. The development of disorders related to heightened stress sensitivity and dysregulation of stress-coping mechanisms appears to involve regulatory mechanisms of CRF family members.
DARPP-32: An Integrator of Neurotransmission
Authors: Svenningsson Per , Nishi Akinori , Fisone Gilberto , Girault Jean-Antoine , Nairn Angus C. , Greengard Paul
Published: January 2004

Dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa (DARPP-32), was identified initially as a major target for dopamine and protein kinase A (PKA) in striatum. However, recent advances now indicate that regulation of the state of DARPP-32 phosphorylation provides a mechanism for integrating information arriving at dopaminoceptive neurons, in multiple brain regions, via a variety of neurotransmitters, neuromodulators, neuropeptides, and steroid hormones. Activation of PKA or PKG stimulates DARPP-32 phosphorylation at Thr34 and thereby converts DARPP-32 into a potent inhibitor of protein phosphatase-1 (PP-1). DARPP-32 is also phosphorylated at Thr75 by Cdk5 and this converts DARPP-32 into an inhibitor of PKA. Thus, DARPP-32 has the unique property of being a dual-function protein, acting either as an inhibitor of PP-1 or of PKA. The state of phosphorylation of DARPP-32 at Thr34 depends on the phosphorylation state of two serine residues, Ser102 and Ser137, which are phosphorylated by CK2 and CK1, respectively. By virtue of its ability to modulate the activity of PP-1 and PKA, DARPP-32 is critically involved in regulating electrophysiological, transcriptional, and behavioral responses to physiological and pharmacological stimuli, including antidepressants, neuroleptics, and drugs of abuse.
The Identification of Ligands at Orphan G-Protein Coupled Receptors
Authors: Wise Alan , Jupe Steven C. , Rees Stephen
Published: January 2004

The completion of the human genome sequencing project has identified approximately 720 genes that belong to the G-protein coupled receptor (GPCR) superfamily. Approximately half of these genes are thought to encode sensory receptors. Of the remaining 360 receptors, the natural ligand has been identified for approximately 210 receptors, leaving 150 so-called orphan GPCRs with no known ligand or function. The identification of ligands active at orphan GPCRs has been achieved through the development of a number of experimental approaches, including the screening of putative small molecule and peptide ligands, reverse pharmacology, and the use of bioinformatics to predict candidate ligands. In this review, we discuss the methodologies developed for the identification of ligands at orphan GPCRs and include examples of their successful application.
Developmental Neuropathology of Environmental Agents
Authors: Costa Lucio G. , Aschner Michael , Vitalone Annabella , Syversen Tore , Soldin Offie Porat
Published: January 2004

The developing central nervous system (CNS) is more vulnerable to injury than the adult one. Although a great deal of research has been devoted to subtle effects of developmental exposure, such as neurobehavioral changes, this review instead focuses on a number of chemicals that have been shown, in several experimental models as well as humans, to cause morphological changes in the developing nervous system. Chemicals that are discussed include methylmercury (MeHg), lead (Pb), antiepileptic drugs, and ethanol. Additionally, the issue of silent neurotoxicity, i.e., persistent morphological and/or biochemical injury that remains clinically unapparent until later in life, is discussed.
Analysis of GABAA Receptor Function and Dissection of the Pharmacology of Benzodiazepines and General Anesthetics Through Mouse Genetics
Authors: Rudolph Uwe , Möhler Hanns
Published: January 2004

GABAA receptors are molecular substrates for the regulation of vigilance, anxiety, muscle tension, epileptogenic activity, and memory functions, and the enhancement of GABAA receptor-mediated fast synaptic inhibition is the basis for the pharmacotherapy of various neurological and psychiatric disorders. Two kinds of GABAA receptor-targeted mutant mice have been generated: (a) knockout mice that lack individual GABAA receptor subunits (α1, α5, α6, β2, β3, γ2, δ, and ρ1) and (b) knockin mice that carry point mutations affecting the action of modulatory drugs [α1(H101R), α2(H101R), α3(H126R), α5(H105R), and β3(N265M)]. Whereas the knockout mice have provided information primarily with respect to the regulation of subunit gene transcription, receptor assembly, and some physiological functions of individual receptor subtypes, the point-mutated knockin mice in which specific GABAA receptor subtypes are insensitive to diazepam or some general anesthetics have revealed the specific contribution of individual receptor subtypes to the pharmacological spectrum of diazepam and general anesthetics.
ErbB Receptors: Directing Key Signaling Networks Throughout Life
Authors: Holbro Thomas , Hynes Nancy E.
Published: January 2004

The epidermal growth factor (EGF)-related peptides bind the ErbB receptors, inducing the formation of different homo- and heterodimers. Receptor dimerization promotes activation of the intrinsic kinase, leading to phosphorylation of specific tyrosines located in the ErbB's cytoplasmic region. These phosphorylated residues serve as docking sites for a variety of signaling molecules whose recruitment stimulates intracellular signaling cascades, which ultimately control diverse genetic programs. Particular ligand-receptor complexes have essential roles in embryonic development as well as in the adult. Finally, ErbB receptors are being pursued as therapeutic targets because aberrant ErbB activity has been observed in many human cancers. In this review, we discuss these data in more detail, illustrating the importance of tightly regulated ErbB signaling throughout life.
Sex Differences in Pharmacokinetics and Pharmacodynamics
Authors: Gandhi Monica , Aweeka Francesca , Greenblatt Ruth M. , Blaschke Terrence F.
Published: January 2004

The importance of reviewing and studying sex-based differences in pharmacologic parameters is demonstrated by the increasing data on gender variation in drug efficacy and toxicity profiles. Sex-based differences in the four major factors that contribute to interindividual pharmacokinetic variability—bioavailability, distribution, metabolism, and elimination—are theorized to stem from variations between men and women in factors such as body weight, plasma volume, gastric emptying time, plasma protein levels, cytochrome P450 activity, drug transporter function, and excretion activity. Sex-determined variations in pharmacodynamics have traditionally been more difficult to study, but a number of recent studies have explored these differences. This review examines the biologic basis of differences in pharmacokinetics and pharmacodynamics between the sexes and summarizes studies that have addressed these differences. As an example, sex-based variation in the efficacy and toxicity of antiretroviral therapy in human immunodeficiency virus (HIV)-infected patients is explored more thoroughly to illustrate some of the factors underlying sex-based differences in drug therapy.