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At least 271 records · Page 15Linked to original sources
PubMed2004

Etanercept: a clinical review of current and emerging indications.

The recent development of inhibitors of TNF-alpha has provided the opportunity for a more targeted and highly effective approach to the treatment of chronic inflammatory illnesses such as rheumatoid arthritis. Since the initial approval of etanercept as a treatment for rheumatoid arthritis, additional indications, including psoriatic arthritis, juvenile rheumatoid arthritis and ankylosing spondylitis, have also received FDA approval. More than 220,000 patients have been treated with etanercept so far. This review summarises the body of knowledge accumulated so far on etanercept (Enbrel) since it entered the market 5 years ago.

Arthritis, Rheumatoid↗
PubMed2002

Antigen-based immune modulation: DNA vectors and beyond.

The ultimate goal for autoimmune immunotherapy is to achieve a specific downregulation or modification of autoaggressive immune responses while leaving in place the normal repertoire, capable of mediating antimicrobial responses. A multitude of preclinical studies, particularly during the last 15 years, raised hopes that self-antigens could be used to achieve the goal of specific immune modulation. Difficulties associated with the translation of this concept to the clinic revealed inherent limitations of antigen-based immune modulation. To increase the efficiency of antigen-dependent immune modulation, researchers started to investigate novel vectors for antigen delivery. Plasmid vectors, as opposed to protein antigens or peptides, have the ability to trigger prolonged production of limited amounts of antigen in the periphery. However, one complicating factor may be the inherent "danger" signal stimulated by the nature of the unmethylated CpG motifs on bacterial plasmid. Currently, various approaches are being explored to improve the efficacy of response while ameliorating the safety concerns of plasmids as immunotherapeutic tools. This manuscript offers a perspective on such efforts and outlines how the knowledge accumulated in the process will help scientists advance to the next generation of immunotherapeutics.

Adjuvants, Immunologic↗
PubMed2005

Current status and future prospects for a vaccine against American trypanosomiasis.

The clinically relevant pathognomonic consequences of human infection by Trypanosoma cruzi are dilation and hypertrophy of the left ventricle walls and thinning of the apex. The major complications and debilitating evolutionary outcomes of chronic infection include ventricular fibrillation, thromboembolism and congestive heart failure. American trypanosomiasis (Chagas disease) poses serious public healthcare and budgetary concerns. The currently available drugs, although effective against acute infection, are highly toxic and ineffective in arresting or attenuating clinical disease symptoms in chronic patients. The development of an efficacious prophylactic vaccine faces many challenges, and progress is slow, despite several years of effort. Studies in animal models and human patients have revealed the pathogenic mechanisms during disease progression, pathology of disease and features of protective immunity. Accordingly, several antigens, antigen-delivery vehicles and adjuvants have been tested in animal models, and some efforts have been successful in controlling infection and disease. This review will summarize the accumulated knowledge about the parasite and disease, as well as pathogenesis and protective immunity. The authors will discuss the efforts to date, and the challenges faced in achieving an efficient prophylactic vaccine against human American trypanosomiasis, and present the future perspectives.

Animals↗
PubMed2000

[The most frequent neurologic disturbances. A contribution to the definition of topics for the programmatic content to the program of neurology in medical graduation].

INTRODUCTION: Knowledge accumulation is overfilling the thematic content of medical graduation. Medical Schools must be alert to define a minimal content related with the most frequent disturbs. We intent to suggest topics for the minimal content, to the program of Neurology in medical graduation. METHOD: 1. To identify the places where young doctors are working outside the School Hospital (SH): we analysed the answers of the letters sent to 6415 resident - doctors (RD) in São Paulo's State and we made personal interview with 201 RD. 2. To verify the most frequent neuropsychiatric disturbs (ND) in the population: we made the analysis of the patient's diagnostic records in emergency room of three institutions: Municipal of Taubaté-SP, Municipal of São José dos Campos-SP and Faculty of Medicine of São Paulo Santa Casa de Misericórdia. RESULTS: 1. The RD are young and, outside the SH, they work in other emergency services. 2. The most frequent diagnosis in institutions were listed: alcoholism, cerebrovascular disease, coma, cranial trauma, dementia, dizziness, epilepsy, facial paralysis, faint, headache, hemiplegia or paraplegia, meningitis, others paralysis, periferical neuropathy and psychiatric disorders. CONCLUSIONS: Those diagnostics most frequent are relevant topics of the programmatic content to the program of Neurology in medical graduation.

Brazil↗
PubMedDate not supplied

Histoplasmin reaction. Comparison of a polysaccharide antigen to the filtrate antigen.

This work was planned by taking into account all the knowledge accumulated from the immunological study of paracoccidioidomycosis. It aimed at comparing a polysaccharide antigen from Histoplasma capsulatum to a classic histoplasmin with the help of intradermal tests of delayed type of hypersensitivity. Tests were applied to 115 individuals in Santo Amaro, a town in the State of São Paulo. Positive results using classic histoplasmin were obtained in 46.0% cases whereas positive results using the polysaccharide antigen at its highest concentration were obtained in 51.30% cases. The major conclusion in this investigation is that it is possible to use the polysaccharide antigen as histoplasmin instead of the filtrate antigen.

Adolescent↗
PubMedDate not supplied

Determination and control of schistosomiasis.

The subject of this conference reflects the scientific community's interest in seeking to understand the complex causal web whose various social, economic, and biological components interact in the production and reproduction of schistosomiasis and its control in relation to community participation. From the onset, the author stresses the impossibility of dealing separately with community participation, as if social components were just one more "weapon" in the arsenal for schistosomiasis control. This study begins with a brief historical review of the 71 years of control activities with this endemic disease, stressing the enormous efforts and huge expenditures in this field vis-à-vis the limited results, despite the extraordinary technological development of specific, classical control inputs such as new treatment drugs and molluscicides. The article then discusses the various strategies used in control programs, emphasizing ideological consistencies and contradictions. Interactions at the macro and micro levels are discussed, as are the determinants and risk factors involved in producing the disease's endemicity. Unequal occupation of space leaves the segregated portion of the population exposed to extremely favorable conditions for transmission of the disease. This raises the issue of how to control an endemic disease which is so closely linked to the way of life imposed on the population. The study challenges the classical control model and suggests an alternative model now undergoing medium-term investigation in the States of Espirito Santo, and Pernambuco, Brazil. The author concludes that we do not need new strategies, but a new control model, contrary to the prevailing classical model in both concept and practice. From the conceptual point of view, the new model mentioned above is different from others in that schistosomiasis control is seen from a social perspective stressing the population's accumulated knowledge in addition to the building of shared knowledge.(ABSTRACT TRUNCATED AT 250 WORDS)

Community Participation↗
PubMed2003

[Measures developed by the public health system to prevent accidents and violence in children and adolescents in Fortaleza, Ceará, Brazil].

This article deals with measures developed by the public health system to prevent accidents and violence in children in Fortaleza, Ceará State, Brazil. The program resulted from the need perceived by the authors in light of statistics on mortality from external causes in childhood and adolescence and the fact that there was apparently no preventive action being taken by the public health system. We conducted a questionnaire-based survey of health administrators in the six Regional Executive Secretariats (SERs) corresponding to the geographic districts in which the health system is divided in Fortaleza. According to the survey, existing preventive measures are limited in time and space, and there is no overall policy in this direction; the current measures are organized as health education campaigns focused on prevention of alcohol and drug abuse, violence, household accidents, and juvenile delinquency. SER-I was the only health district that had established partnerships with other sectors in developing such activities. We conclude that the public health system's agenda in Fortaleza needs to incorporate the prevention of childhood and adolescent accidents and violence, taking an inter-sectoral approach and joining efforts in order for the knowledge accumulated on such health problems to be transformed into effective action

Accident Prevention↗
PubMed1995

Implications of behavioral pharmacology research for applied behavior analyses: JEAB's special issue celebrating the contributions of Joseph V. Brady (March 1994).

We review four articles from JEAB's March 1994 issue celebrating the contributions of Joseph V. Brady. These articles have implications for studying private events and for studying multiple operants. We suggest that regularly including self-reports about private events in behavioral pharmacological research has resulted in an accumulated knowledge that has facilitated examination of interesting relations among self-reports, environmental factors, and other observable behaviors. Methodological lessons that behavioral pharmacologists have learned regarding the study of multiple operants are also relayed. We provide examples of how these lessons could be useful to applied behavior analysts studying nonpharmacological issues.

Adult↗
PubMed2004

Plumbism reinvented: childhood lead poisoning in France, 1985-1990.

Although the history of childhood lead poisoning started a century ago in the United States, the first French cases were identified in 1985. Instead of merely adopting knowledge accumulated for decades, the public health professionals and activists involved had to reestablish, against incredulity from medical authorities and resistance from policymakers, all the evidence: that children were the main group concerned; that cases were not isolated but part of an epidemic; that wall paint in old, dilapidated apartments was the source of contamination; and that poor housing conditions, and not cultural practices, were responsible for the high incidence in African families. This "reinvention" illustrates more general sociological phenomena: discontinuities in medical history, strength of culturalist prejudices toward immigrants, resistance to socioeconomic interpretations of disease, and struggles between different perspectives in public health. The history shows that public health is the product of intellectual and political struggles to impose visions of the world.

Child↗
PubMed1998

Evaluation of the carcinogenic potential of pharmaceuticals. Opportunities arising from the International Conference on Harmonisation.

The evaluation of the carcinogenic potential of pharmaceuticals is currently undergoing dramatic changes. For the past 25 years the regulatory expectation for agents intended for long term use has been that lifespan studies (usually lasting 2 years) in 2 rodent species be conducted. These studies take at least 3 years to plan, execute and interpret, and use over 1200 animals. It is now recognised that the quality of the information obtained from these studies is unreliable for prediction of carcinogenic risk to humans. Over the past 4 years, the International Conference on Harmonisation (ICH) has recommended changes in approaches to assessing the carcinogenic potential of pharmaceuticals. In future, only one long term rodent study will be routinely required (usually in rats), provided this is complemented with a short or medium term test in one of the emerging new models for carcinogenicity, such as transgenic mice or newborn mice. However, the relevance of these new models to human cancer and their use in risk assessment is still largely unknown and this situation must be kept under review as knowledge accumulates. A long term study in a second rodent species is still an option. Dose selection has also been improved inasmuch as there are now several alternatives to the use of the maximum tolerated dose (MTD). In the past, the use of the MTD, when the normal homeostasis of the test animals is disturbed, has been considered one of the major problems with the rodent carcinogenicity bioassay. However, one of the alternative end-points to the use of the MTD, i.e. the comparison of plasma concentrations in rodents and humans, must be viewed with caution. While this may contribute to limiting the high dose level for agents of very low toxicity, the concept should not be interpreted as signifying that plasma concentrations provide a sound basis for comparing the carcinogenic activity of agents in different species. Recognition of the 4 properties (genotoxicity, immunosuppression, steroid hormonal activity and long term tissue damage), at least one of which is associated with each of the pharmaceuticals known to be carcinogenic to humans, should focus more attention on a search for these properties in patients. Absence of these properties at clinically relevant dose levels indicates that a pharmaceutical is highly unlikely to be carcinogenic to humans.

Animals↗
PubMed1998

Are there potential non-lipid-lowering uses of statins?

Recent clinical trials have demonstrated beyond doubt that statins are effective in the prevention of acute coronary events. Critical analysis of these studies suggests that the benefits of statin therapy cannot be fully explained on the basis of reductions in plasma cholesterol levels. Accumulating knowledge of the actions of these drugs shows that they may prevent several processes that eventually lead to plaque rupture and the development of occlusive thrombosis, the basis of acute coronary events. Hence, statins may correct endothelial dysfunction (thus protecting against ischaemic injury), stabilise existing plaques and modify the coagulation pathway, thereby reducing the likelihood of a sudden vascular event. At a cellular level, these drugs inhibit the synthesis not just of cholesterol, but of other compounds important in cell proliferation. Antiproliferative effects have been demonstrated in vitro and may broaden the applications of statins to the treatment of noncardiovascular diseases. Finally, preliminary clinical studies indicate that as a result of immunosuppressive actions, statins may reduce the incidence of rejection following organ transplantation.

Animals↗
PubMed2003

Giardiasis: recent progress in chemotherapy and drug development.

Giardiasis is a protozoal disease infecting 200 million people throughout the world. Giardiasis is widespread primarily in developing countries. Infections are correlated with poor hygienic conditions, poor water quality control, and overcrowding. There are very few therapeutics currently available, and drug development to treat giardiasis is hampered mainly by socioeconomic obstacles. This article presents the history of antigiardial chemotherapy and current state of therapeutic availability along with the future prospectus of development of antigiardial agents. In addition to accumulated knowledge about the previous and current antigiardial drugs, advanced technologies including computer-aided drug design and combinatorial synthetic chemistry, as well as high throughput screening techniques, accelerate understanding of the disease and further research toward a suitable antigiardial agent.

Animals↗
PubMed2005

Autonomic neural functions in space.

Autonomic neural functions are important to regulate vital functions in the living body. There are different methods to evaluate indirectly and directly autonomic, sympathetic and parasympathetic, neural functions of human body. Among various methods, microneurography is a technique to evaluate directly sympathetic neural functions in humans. Using this technique sympathetic neural traffic leading to skeletal muscles (muscle sympathetic nerve activity; MSNA) can be recorded from human peripheral nerves in situ. MSNA plays essentially important roles to maintain blood pressure homeostasis against gravity. Orthostatic intolerance is an important problem as an autonomic dysfunction encountered after exposure of human beings to microgravity. There exist at least two different types of sympathetic neural responses, low and high responders to orthostatic stress in orthostatic hypotension seen in neurological disorders. To answer the question if post-spaceflight orthostatic intolerance is induced by low or high MSNA responses to orthostatic stress, MSNA was microneurographically recorded for the first time before, during and after spaceflight in 1998 under Neurolab international research project. The same activity has been recorded during and/or after ground-based short- and long-term simulations of microgravity. MSNA was rather enhanced on the 12(th) and 13(th) day of spaceflight and just after landing day. Postflight MSNA response to head-up tilt was well preserved in astronauts who were orthostatically well tolerant. MSNA was suppressed during short-term simulation of microgravity less than 2 hours but was enhanced after long-term simulation of microgravity more than 3 days. Orthostatic intolerance after exposure to long-term simulation of microgravity was associated with reduced MSNA response to orthostatic stress with impaired baroreflex functions. These findings obtained from MSNA recordings in subjects exposed to space as well as short- and long-term simulations of microgravity indicate that sympathetic neural control is lowered when exposed to short-term microgravity but becomes enhanced after exposure to long-term microgravity. A lack of enhanced sympathetic neural response to orthostatic stress may induce orthostatic intolerance. Based on these findings effective countermeasures should be developed to prevent autonomic dysfunctions induced by exposure to microgravity. These include development of prescription and devices of physical exercise, electrical and magnetic nerve stimulations, body vibration, elastic bandage and stocking, lower body negative pressure, artificial gravity, medical drugs, and combinations of them. These countermeasures will be beneficial to prevent autonomic dysfunctions related to gravitational stress such encountered in bedridden subjects as orthostatic hypotension, atrophy of antigravity muscles and so on. This is particularly important in the present aged-society with many bedridden elderly people. The knowledge accumulated from studies on autonomic neural functions in space should be very useful to establish effective countermeasures and preventive methods for gravity-dependent autonomic dysfunctions.

Aging↗
PubMed2004

Regulation of endothelial cell death and its role in angiogenesis and vascular regression.

In multicellular organisms, apoptosis, also known as programmed cell death, is an important physiological response to eliminate unnecessary, excess, or harmful cells. Apoptosis occurs during embryonic development and is important in maintaining homeostasis during adulthood. Apoptosis also plays critical roles in angiogenesis and vessel regression. During these processes, activation of the apoptotic signaling pathway in endothelial cells mediates cell death. Several molecules, including growth factors and cytokines, produced by endothelial cells and other cells, regulate endothelial cell survival and apoptosis. Understanding the regulation of apoptosis is of great importance for determining the physiological role of endothelial cells and for developing novel therapeutic strategies. This review highlights the rapidly accumulating knowledge regarding endothelial cell death and provides insight into the molecular mechanisms regulating apoptosis and survival of endothelial cells.

Animals↗
PubMed2005

Molecular and genetic characteristics of hereditary autoinflammatory diseases.

Autoinflammatory diseases are defined as recurrent "unprovoked" inflammatory events which do not produce high-titer autoantibodies or antigen-specific T cells. There are currently eight hereditary forms of these diseases: Familial Mediterranean fever (FMF), hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), chronic infantile neurologic cutaneous articular (CINCA) syndrome or neonatal-onset multisystem inflammatory disease (NOMID), pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) and Blau syndrome. Apart from FMF (which has a prevalence of about 0.1 percent among non-Ashkenazi Jews, Armenians, Turks and Arabs), they are very rare disorders. FMF and HIDS are autosomal recessive diseases, all the other members of the family are autosomal and dominantly transmitted. Their common clinical features are recurrent and usually short attacks of synovitis and various skin eruptions; abdominal pain and fever are also frequently observed. The genes of all of these diseases have been discovered and, with the exception of HIDS, it was found that the proteins they encode share certain domains taking part in innate immunity and apoptosis. Thus it was evident that hereditary autoinflammatory diseases may help us understand better a number of important and prevalent pathologic events. We have reviewed the recent and rapidly accumulating knowledge on the molecular aspects of these disorders.

Familial Mediterranean Fever↗
PubMed2004

Monoclonal antibodies in cancer therapy.

The recent approval of cetuximab and bevacizumab by FDA for the treatment of metastatic colorectal cancer witnesses the investments of biotech companies in the development of monoclonal antibodies (Mabs) as cancer therapeutics. Several analyses point to the growth of the market for these drugs, and forecast an even higher expansion of sales following completion of several clinical trials, both of approved Mabs tested for other cancers, and of new Mabs aimed at different tumor antigens. Not unsurprisingly, the latest additions to the number of therapeutic Mabs belong to the classes of chimeric and humanized antibodies. A great effort has been made in the last years to overcome the intrinsic limitations of the technology used to produce monoclonal antibodies. The knowledge accumulated in the search of newer ways of production of recombinant therapeutic proteins is reflected by the number of fully human Mabs in the pipeline. Moreover, a thorough understanding of the cellular and molecular events underlying the activity of cancer-aimed antibodies allows the optimisation of these drugs for the treatment of high incidence solid tumors.

Antibodies, Monoclonal↗
PubMed2004

Catabolism of caffeine in plants and microorganisms.

Caffeine has been found in tissues of several plants. Because of its stimulating effect on the central nervous system, a great number of reports have been published on its content in beverages and foodstuffs. However, a much more restricted number of reports have dealt specifically with caffeine metabolism in plants. This review presents, in chronological manner, the contribution of these reports to the vast knowledge accumulated on caffeine catabolism in plants and microorganisms over the last 40 years. In plants, the accumulated data indicate the operation of a main catabolic pathway: caffeine --> theophylline --> 3-methylxantine --> xanthine --> uric acid --> allantoin --> allantoic acid --> glyoxylic acid + urea --> NH3 + CO2. Some studies have shown that, depending on the plant species, other minor routes may operate with the formation of theobromine and 7-methylxantine, which are salvaged for caffeine formation since they also appear in the biosynthetic pathway. A specific group of coffee known as liberio-excelsioides has the ability to convert caffeine to the corresponding methyluric acid, which is methylated to other uric acid derivatives. In bacteria caffeine is either degraded to theobromine or paraxanthine. Both dimethylxanthines are demethylated to 7-methylxantine which in turn is demethylated to xanthine and then enters the catabolic pathway of purines. In bacteria, theobromine, paraxanthine and 7-methylxantine may also be oxidized to their corresponding methyluric acids.

Bacteria↗
PubMed2003

The cadherin superfamily in neural development: diversity, function and interaction with other molecules.

Cell-cell interactions are crucial steps for the development of the highly complex nervous system. A variety of cell-cell adhesion molecules of the cadherin superfamily have been found to be expressed in the developing nervous system. Recently it was proposed classic cadherins are involved in various aspects of neural development such as regionalization, brain nucleus formation, neurite outgrowth, target recognition and synaptogenesis. Classic cadherins preferentially bind to the same cadherin subtype ("homophilic adhesion"), and this binding specificity can provide an "adhesive code" that can account for various aspects of neural morphogenesis. In addition, novel members of the cadherin superfamily are also involved in various steps of neural development. The function of these cadherins molecules is orchestrated in the cellular context by a complex network of signaling pathways such as the small GTPase pathway. Here, we will review the molecular properties of the cadherin superfamily and their coordinated roles in the formation of the nervous system along with the accumulated knowledge in non-neuronal systems.

Animals↗