Use In Clinical Medicine Research Articles

Recent developments and future strategies for immunotherapy of insect venom allergy

Hymenoptera venom allergy may cause life-threatening, sometimes even fatal, allergic reactions and thus may be associated with a serious reduction in the quality of life. Venom immunotherapy is effective in the majority of patients with this allergy. Treatment failures do however occur and immunotherapy may cause frequent systemic allergic side effects, especially in honeybee venom-allergic patients. New strategies to improve safety and efficacy of this treatment are therefore of general interest. Among these new strategies are premedication with antihistamines: this definitely reduces side effects and based on recent in-vitro experiments and one clinical controlled study may even improve efficacy by modulating the T-cell response through interference with histamine receptors on these cells. Furthermore, during recent years the cDNA of most major allergens of bee and vespid venoms has been cloned and these allergens have been expressed in recombinant form. This allows for the preparation of patient-tailored extracts, with or without reduction of their allergenicity, for example by using unrefolded or point-mutated recombinant allergens. Yet another approach is the use of non IgE binding peptide fragments of the allergen with preserved T-cell epitopes for immunotherapy. Such preparations of bee venom phospholipase A2 have been used successfully in pilot studies. Finally, DNA vaccination with phospholipase A2 sequence plasmids has proved effective in one experimental study in sensitized mice. A number of new strategies for venom immunotherapy, mostly based on genetic engineering, have been described and we await their use in clinical medicine.

A website for blood pressure measuring devices: dableducational.com.

Consumers are faced with an ever-increasing array of blood pressure measuring devices, whether for use in clinical areas or for use by individuals anxious to measure their own blood pressure. Validation protocols that allow for independent evaluation of blood pressure measuring devices are available, and some of the devices on the market have been evaluated according to these protocols. The results of such evaluations have been published periodically in medical journals. However, such surveys are not readily available to the public and to health care authorities with responsibility for purchasing blood pressure measuring equipment for use in clinical medicine, and because of the necessarily lengthy publication process they are no longer up-to-date at the time of publication. Moreover, the results of published validation studies are often flawed because of protocol violations and the conclusions may not be valid. These considerations have been the stimulus for the establishment of an independent non-profit website, which will provide quarterly updates on the accuracy and performance of blood pressure measuring devices on the market as well as an expert assessment of the validation procedures on which recommendations are based. The ethos of the website is primarily educational and it is hoped that it will serve as a forum for the provision of much-needed information that will ultimately improve the management of hypertension. The website is due to be launched shortly and this paper outlines the general principles that have governed its establishment and the facilities that it will provide.

Gene therapy to target dendritic cells from blood to lymph nodes.

Peripheral lymph nodes (PLN) are strategic microenvironments where antigen-presenting dendritic cells (DC), loaded with environmental antigens, and naive lymphocytes meet to initiate immune responses. The unique capacity of DC to induce primary immune responses has led to their use in clinical medicine; however, delivering DC to lymph nodes is problematic. Intravenously injected DC cannot access to PLN, while DC injected into tissue migrate inefficiently through lymphatics to PLN. We achieved DC targeting to T-cell areas of PLN by endowing DC with a novel receptor for peripheral node addressin (PNAd), an adhesion molecule present on the lymph node venular endothelium. This novel receptor is a chimeric E/L-selectin (ELS) that, we have previously shown, binds to PNAd. DC were genetically modified by retroviral transduction to express ELS. ELS expression was targeted to tips of microvilli, and mediated rolling of DC on PNAd both in vivo and in vitro. Such genetically engineered DC could extravasate directly from blood through the lymph node endothelium as opposed to nontransduced DC. This study provides evidence that the trafficking of DC can be modified using gene transfer technologies. More efficient delivery of DC to PLN should assist the development of improved vaccination strategies.

Antibiotic resistance: who is winning the war? Introductory remarks.

The evolutionary response of bacteria, fungi, viruses, and parasites to the selective pressure exerted by antimicrobial agents is the emergence of populations that resist the action of the antimicrobial. The emergence and dissemination of such resistance in a variety of these pathogens is a growing public health concern. In response, the scientific community developed an action plan to address this public health issue. Antimicrobial, antifungal, and antiviral drug development for the treatment of diseases caused by resistant pathogens is one component of this strategy. In addition, due to the targeting of specific drugs against resistant pathogens, we may more readily accept a given drugs toxicity profile for the added therapeutic benefit. This symposium provides a discussion of the modes of action and mechanisms of resistance to antimicrobial agents, and the use of surveillance systems to help understand the nature and magnitude of resistance. The goal is to help guide antimicrobial drug product development and use. Specific toxicity issues are presented that should be considered in phase 1 development of antimicrobial drug products for use in clinical medicine and veterinary medicine. Finally, the national and global strategies developed by federal agencies in the Public Health Action Plan to Combat Antimicrobial Resistance are outlined.

Genetics of gastrointestinal and hepatobiliary disorders: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition.

Genetics of gastrointestinal and hepatobiliary disorders: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition.

The pharmacokinetics and cardiovascular effects of a single intravenous dose of protamine in normal volunteers.

Despite its long use in clinical medicine, protamine concentrations and pharmacokinetics in humans have not been reported. The occasional reoccurrence of anticoagulation after protamine reversal of heparin led us to hypothesize that protamine plasma concentrations decrease rapidly. We developed a method for the measurement of protamine in plasma. Eighteen fit volunteers gave their consent to receive 0.5 mg/kg protamine sulfate administered IV by an infusion pump over 10 min. Heart rate, mean arterial blood pressure, and cardiac output, all measured noninvasively, were recorded and blood samples obtained during and after protamine infusion. Blood plasma was subjected to solid-phase extraction and high-performance liquid chromatography. The administration of protamine was associated with no significant changes in heart rate, mean arterial blood pressure, or cardiac output. Plasma protamine concentrations decreased rapidly, becoming nondetectable within approximately 20 min. Protamine elimination differed significantly between men and women: men had significantly larger areas under the concentration versus time curve. Model-independent pharmacokinetic analysis revealed median (range) values as follows: volume of distribution at steady state, 12.3 (6.9--63.1) L; clearance, 2.2 (1.1--12.1) L/min; and t1/2, 7.4 (5.9--9.3) min. Concentration versus time plots revealed an atypical pattern inconsistent with usual exponential models. The Schwartz-Bayesian criterion identified a one-compartment Michaelis-Menten model and a two-compartment exponential model with irreversible binding as performing better than conventional one- or two-compartmental exponential models; however, performance errors were large with both Michaelis-Menten and exponential models. All models described rapid decreases in protamine blood concentrations. We developed a method for measurement of protamine in human blood. In volunteers, protamine concentrations decreased rapidly after administration. The rapid disappearance of protamine from the circulation, as defined by a median half-life of 7.4 min, could contribute to cases of "heparin rebound" after initial adequate reversal of heparin.

Angiotensin-converting enzyme inhibitors: Are there credible mechanisms for beneficial effects in diabetic neuropathy?

Publisher Summary This chapter discusses that there is no treatment for diabetic neuropathy, and this lack of an effective therapy derives from three principal factors: (1) the complex etiology of the condition, (2) imperfect animal modeling and failure to accurately translate experimental findings to the clinical arena, and (3) imperfect drug candidates and flawed clinical trial design. Retrospective rationalization offers plausible explanations for the spectacular failures has been witnessed in clinical trials of human diabetic neuropathy. They include inappropriate selection of patients according to neuropathic severity, drug toxicity, inadequate drug potency, inappropriate measures of therapeutic efficacy, and inadequately short periods of study aimed to rapidly reverse a process, which has taken many years to develop. Angiotensin-converting enzyme (ACE) inhibitors have surpassed all predictions for their widespread use in clinical medicine. Initially deemed useful only in a select group of patients with renovascular hypertension, they constitute the panacea for the treatment of diabetes and its complications, ischemic heart and cerebrovascular disease, and nephropathy from a variety of causes. The pharmacology of ACE inhibition is complex and provides for a number of major interactions with pathogenetically relevant pathways resulting in human diabetic neuropathy.

Applications of meta-analysis in pathology practice.

Meta-analysis is the structured and systematic integration of information from different studies of a given problem. It has been widely used to integrate findings of randomized controlled trials (RCTs) investigating the efficacy of therapeutic interventions, but its use in pathology has lagged behind its use in clinical medicine. The purpose of this review is to present pathologists with the necessary background for reading and evaluating published reports of metaanalyses. The concepts and methods of meta-analyses of RCTs are presented, followed by a discussion of how these concepts and methods potentially can be applied to studies of diagnostic test accuracy. Three differences between RCTs and studies of diagnostic test accuracy are identified, and 4 possible obstacles to the use of meta-analysis in pathology are discussed. Despite these specific difficulties in the meta-analysis of diagnostic test data, meta-analysis can (and should) be used to produce valid summary estimates of the diagnostic accuracy of laboratory tests across all available studies.

Mechanisms of changes in basal metabolism during ageing.

A considerable number of physiological functions are known to show a gradual decline with increasing age. However, the effects of ageing differ widely between organ systems. It is believed that basal metabolic rate (BMR) falls dramatically with age. These observations, largely based on cross-sectional surveys, are discussed in light of our present understanding of the biology of ageing. This paper reviews both the longitudinal and cross-sectional studies of BMR and presents evidence that the fall in BMR with ageing may be less dramatic than previously perceived. Indeed, some subjects may show an increase in BMR with ageing. The mechanism of changes in BMR during ageing will be discussed. Organ weight changes appear to have a profound impact on BMR. The use of BMR to predict total energy expenditure in the 'old elderly' (>75 y) is unlikely to be of any practical use due to wide intra- and inter-individual variation in BMR. This wide intra- and inter-individual variation in BMR is due to illness, disease and other metabolic disorders seen in the elderly. Finally, the importance of measuring BMR in elderly populations for its use in clinical medicine will be discussed.

Mining variations in genes of innate and phagocytic immunity: current status and future prospects.

The large number of sequence variations in human genes reflects the diversity of human populations and the response to prior environmental and pathogen challenges. Currently, major efforts are under way to identify and catalog single-nucleotide polymorphisms for use in genetic studies designed to explore the contribution of common variants to both disease susceptibility and interindividual differences in outcomes. So far, the most productive approach has been to search with candidate genes for which there is a scientific rationale (eg, prior data on the biologic implications of one or more variant alleles). Recently, there has been an explosion in the number of genetic association studies seeking to correlate one or more well-defined outcomes with variant alleles. These studies provide a foundation for identifying and applying genetic risk factors to clinical medicine. However, a number of challenges must be met before widespread use in clinical medicine can be undertaken. These include more efficient bioinformatics, basic insights into the significance of the variant alleles, ethical issues, and the availability of cost-effective, high-throughput platforms for genotype analysis.

High Speed Digital Circuits for Medical Communication; the MINCS-UH Project

In Japan, a high speed, bidirectional digital satellite communication system called Medical Information Network by Communications Satellite for University Hospitals is currently available in 30 national universities, and many programs, including clinical conferences, lectures and tutorials, have been broadcasted. Its characteristics are: (1) a state-of-the-art digital high-definition television system, (2) excellent security protection using digital encryption (3) bidirectional communications using two satellite circuits simultaneously, and (4) easy operability. High-quality motion images, and security protection mechanisms are essential for use in clinical medicine.

Interpretation of repeated tuberculin tests. Boosting, conversion, and reversion.

The tuberculin skin test is one of the few tests developed in the 19th century that is still in present use in clinical medicine. The first tuberculin test material was prepared by Robert Koch (1); its use for detection of tuberculosis (TB) infection was first described in 1907 by von Pirquet (2). Given such a long history of use, it may seem surprising that aspects of interpretation of this test remain controversial. However, this reflects changes in the populations affected with tuberculosis and their relative frequency of true positive tests from TB infection, and false-positive tests associated with bacillus Calmette-Guerin (BCG) vaccination, or nontuberculous mycobacteria, as well as the recent human immunodeficiency virus (HIV) epidemic. Particular problems have arisen with use of repeated tuberculin tests to detect new infection in high-risk populations such as initially tuberculin-negative contacts of active cases, and workers with occupational exposure. This has revealed that tuberculin reactions may decrease in size (reversion) or increase in size because of: ( 1 ) random variability from differences in administration, reading, or biologic response; ( 2 ) immunologic recall of preexisting delayed type hypersensitivity to mycobacterial antigens (boosting); or ( 3 ) new infection (conversion). This review has been undertaken to provide information regarding factors causing changes in the size of repeated tuberculin reactions.

Traditional and High Potency Probiotic Preparations for Oral Bacteriotherapy

Current research continues to improve the treatment options available to clinicians for oral bacteriotherapy. Recently, a greater understanding of the role of endogenous digestive microflora has generated renewed interest in the potential of oral bacteriotherapy for the management of a wide spectrum of gastrointestinal and systemic disorders. Several treatment strategies for oral bacteriotherapy have already entered clinical trials and it is hoped that some of these strategies will become widely available in the near future. This review summarises the current status of oral probiotic preparations for bacteriotherapy and discusses any obstacles to their successful clinical development. Newer probiotic preparations include high potency preparations that are greatly enriched in lactic acid bacteria, both in terms of bacterial concentrations and the number of bacterial strains. These preparations have a greater potential for clinical effectiveness than traditional preparations and are entering clinical evaluation especially in patients with inflammatory bowel disease and pouchitis, irritable bowel syndrome, or cryptosporidiosis. The pitfalls of previous clinical investigations of traditional probiotic preparations and the perils of future clinical trials with high potency preparations are discussed in the context of unmet needs and realistic expectations of success. Although considerable progress has been made in oral bacteriotherapy, focused efforts by basic scientists and clinical investigators and continued support from pharmaceutical companies is required to successfully develop probiotics for use in clinical medicine. Newer high potency probiotic preparations appear to have a great advantage over traditional preparations and should be the area of most active biomedical research in the field.

Sodium valproate, an anticonvulsant drug, stimulates human immunodeficiency virus type 1 replication independently of glutathione levels.

Since modulation of the glutathione (GSH) level has been implicated in the regulation of human immunodeficiency virus (HIV) transcription and expression, we have undertaken an analysis of the effect of sodium valproate (VPA) on HIV-1 replication. VPA, which is an anti-epileptic drug in widespread use in clinical medicine, has been shown to depress the activity of GSH reductase, an enzyme required for maintaining high cellular levels of reduced GSH. The effect of this drug on HIV-1 replication has been studied in primary infected cells, i.e. peripheral blood mononuclear cells (PBMC) and monocyte/macrophages, in the CEM-SS cell line, and in chronically infected stimulated and non-stimulated U1 cells. We have shown that VPA markedly enhanced viral replication in all infected cells tested. Virus production was induced in U1 cells by VPA treatment and the stimulatory effects of tumour necrosis factor-alpha, interleukin-6 and granulocyte/macrophage colony-stimulating factor were augmented. The LTR-driven gene expression in Jurkat T cells was increased. However, the elevated viral production did not correlate with the effect of VPA on the intracellular GSH level. Thus, VPA stimulated in vitro HIV-1 replication in acutely and chronically infected cells and enhanced LTR-driven gene expression. These effects were observed for concentrations that are reached in the plasma of VPA-treated patients. Therefore, although the clinical significance of these data remains to be demonstrated, these results should be considered in the choice of an anticonvulsant drug in HIV-infected individuals.

633 New drug development at the end of the second millenium

A limited number of cancer patients can be cured with currently available chemotherapy. Therefore, the search for and subsequent development of more effective and selective agents for cancer remains one of the major challenges in medicine today. Over the last decade our knowledge on the molecular basis of cellular processes like proliferation, differentiation, and apoptosis and their importance in cancer biology and treatment has increased dramatically. Also specific pathways of neoplastic transformation and processes involved in tumour vascularization have been elucidated. Key proteins involved in such processes are currently investigated as possible targets for therapeutic intervention. Among these the E2F transcription factor family, the cyclin dependent kinases, the tumour suppressor gene P53, the enzyme telomerase and others have attracted enormous interest recently. This is illustrated by the rapid growth of mechanism based screens. The availability of large chemicalor natural product collections recently extended by combinatorial libraries and the presence of advanced technology allow high throughput screening of several thousands of compounds per week. Nevertheless, in vitro and in vivo models exhibiting presence or absence of such mechanisms will remain necessary to demonstrate activity at cellular and tumour level. Moreover, by studying drug activity in relation to the level of expression of different targets in tumour cell line panels, the advantages of both random and mechanism based approaches can be combined. Despite several advantages, the human tumour xenograft model in immunodeficient mice or comparable models cannot be used for such first line testing, because of the high costs and relatively large quantities of drug required. By performing limited "rodent only" toxicological research on potential anticancer agents and careful planning of subsequent steps of the drug development process significant unnecessary time loss up to several years between the discovery of a new drug and its ultimate use in clinical medicine can be avoided. This will certainly lead to an even more rapid clinical evaluation of exciting new concepts in the coming years. Several examples of new drugs already under clinical trial will be presented.

Flauoprotein structure and mechanism 2. Monoamine oxidases: old friends hold many surprises.

The two forms of monoamine oxidase (MAO), A and B, continue to be of major interest to biochemists, pharmacologists, neurologists, and gerontologists. Despite intensive study for more than half a century, unexpected and unique properties of these enzymes continue to come to light. Recent studies have centered on their kinetic mechanism, their unique predilection for substrates related to the neurotoxic tertiary amine MPTP, and their putative role in aging and in the etiology of neurodegenerative diseases. New and potent inhibitors of MAO A and MAO B continue to be developed because of their potential use in clinical medicine. Some are effective in the picomolar range but MAO B from different mammalian species shows remarkable differences in sensitivity to these agents.

Expertensysteme in der Medizin: Einsatzmöglichkeiten in der Anästhesie

The euphoric assumption that powerful computers fed with sophisticated software programmes may serve as a substitute for human knowledge and decision making has been replaced by a more realistic concept of how computers may help in collecting data and their interpretation on the basis of human knowledge and experience. The computer is now used as a dedicated tool to support man in overtaking cumbersome and monotonous processes and tedious calculations. Running 24 hours a day, a specific feature of the computer is that depending on unequivocal software programmes it does neither forget or alter commands and information. Computer programmes imitating human thinking and information processing are called expert or knowledge based systems. These are especially useful when multiple possible combinations of data make a given task very complex. This review presents several systems used in different medical disciplines to describe fundamental ideas, different problem-solving methods, techniques and possible working fields including anaesthesia. It is made clear why computers have found widespread use in all administrative areas. In contrast, no system comparable in potency has been developed for use in clinical medicine in spite of 25 years of research in expert systems. This review starts with a definition of expert knowledge and the appropriate transformation of this knowledge to the computer. In addition, a general survey about the structure of expert systems and a state of the art in some current problem solving methods is given. Additional aspects and restrictions including technical, psychological and legal problems which seem to be unimportant from the outside but are essential for the development of expert systems are presented.

Thrombolytic Therapy: A Comprehensive Review of Its Use in Clinical Medicine. Part II

The second part of this comprehensive review of thrombolytic therapy in clnical medicien focuses on its use in a wide renge of thrombotic disorders, including pulmonary embolism, deep venous thrombosis, arterial thrombocmbolism, catheter-related thrombosis, arterial thrombocmbolism, catheter-relted thrombosis, and prosthetic valve occlusion. New experimental applications in the management of unstable angina and cerebrovascular disease are also discussed.

Thrombolytic Therapy: A Comprehensive Review of its Use in Clinical Medicine—Part I

In the first part of this comprehensive review of thrombolytic therapy in clinical medicine, we begin with a brief history of fibrinolysis, followed by a review of the components of die endogenous fibrinolytic system and the currently available plasminogen activators. An in-depth examination of thrombolysis in treatment of acute myocardial infarction follows, Including recommendations for management based on available clinical trial data. New developments in thrombolytic therapy are also discussed.

The Future of the Quinolones

This review attempts to predict the future of the newer fluoroquinolones by examining what we have learned about this class of compounds during the past decade, as well as what we are currently learning from research and developmental efforts. The molecular mechanism of action of these compounds provides the potential for use in clinical medicine in areas other than their role as antibacterial agents. The newer fluoroquinolones that are currently available and those that have been introduced into the pipeline are categorised by their current stage of development. Also listed are those compounds that have been withdrawn from further investigation. Office practice physicians consider the oral fluoroquinolones to be very effective therapeutic agents for many of their patients. Thus, the future of the fluoroquinolones looks promising because of their unique mechanism of action, the possibility of developing novel and improved compounds in this class, and the acceptance of these compounds as effective therapeutic agents by clinicians.