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Combination therapy in rheumatoid arthritis: the animal model perspective.

Attempts to improve antirheumatic agent efficacy have resulted in exploration of treatment protocols with combinations of 2 or more agents. Hypothetically, an ideal combination therapy would have greater efficacy and less toxicity than any of its component agents used individually. However, even a limited number of available drugs can produce a daunting number of possible combination protocols, each requiring clinical evaluation. Intelligent selection of combination protocols, based on a firm understanding of each agent's specific mechanism(s) of action, may help identify potentially useful regimens. Autoimmune animal models of inflammatory synovitis provide a unique opportunity to study the etiology, pathophysiology, and treatment of rheumatoid arthritis (RA). Induction of chronic inflammatory synovitis in susceptible inbred strains can allow for in vivo study under reproducible controlled conditions, using experimental protocols not possible in humans. Although animal models can only approximate human rheumatic disease in its complete form, they are nonetheless important for developing new therapeutic strategies. We review the 3 most common animal models of RA, the streptococcal cell wall, adjuvant, and collagen arthritis rat models. Surprisingly, few published studies evaluate combination therapy in RA animal models. We discuss these investigations, which use interventions aimed at angiogenesis, microtubule function, and immune regulation, as examples of animal models to assess and develop effective therapeutic combinations of antirheumatic agents.

Animals↗

Aspirin and other nonsteroidal anti-inflammatory agents in the prevention of colorectal cancer.

Chemoprevention refers to the use of specific natural or synthetic chemical agents to reverse, suppress, or prevent the progression to invasive cancer. The ideal chemopreventive agent is safe and nontoxic over the long term. It should be easy to take and demonstrated to be effective in randomized trials in humans. Aspirin and NSAIDs meet many of the criteria for an ideal agent. The literature on aspirin and NSAIDs makes it clear that these agents can prevent colorectal cancer and precursor adenomas. That does not mean that we should make general recommendations for their use. First, we do not know the proper dose or duration. More important, these medications are accompanied by adverse effects that can be considerable. Indeed, the Medical Letter, an authoritative, unbiased publication on drugs and therapeutics, concluded that "for primary prevention in low-risk patients, more studies are required to establish whether the beneficial effect of aspirin is great enough to compensate for the possible increased risk of hemorrhagic stroke." These recommendations were directed at the use of these medications for prevention of myocardial infarction, but the same conclusions apply to colorectal cancer: although aspirin may prevent the disease, it may increase the risk of hemorrhagic strokes or cause other adverse effects. We must accurately balance the benefits and risks of these drugs, based on the results of ongoing randomized studies, before recommending aspirin for prevention of colorectal cancer. Is there anything that we can recommend to our patients for prevention of colorectal cancer? Based on observational epidemiologic studies, it is clear that individuals who consume a diet high in vegetables and natural fibers and low in fat have a reduced risk of colon cancer and polyps. Optimal nutrient intakes for the prevention of cancer might be more readily achieved via food fortification or supplementation, but this requires more research. Regular physical exercise and maintenance of normal body weight are also protective. Until the results of definitive studies of chemopreventive agents are available, we can recommend that our patients eat a sensible diet, exercise, and avoid obesity. Such an approach should protect them from cardiovascular disease, an even deadlier condition than colorectal cancer. In the future, we need randomized prevention trials that, for logistic reasons, may need to focus on the occurrence and progression of colorectal adenomas rather than carcinoma itself. Studies that test more than one compound at a time, using factorial designs, will be more efficient. We will need better information about duration and dose, adverse side effects, molecular mechanisms, and cellular sites of NSAID activity. Ultimately, we will need to know more about the biology and molecular biology of colorectal cancer and its precursors. That information will, perhaps, permit us to design agents to interrupt the pathway to cancer and to use intermediate markers more intelligently.

Adenocarcinoma↗

Medical affective computing: medical informatics meets affective computing.

"The need to cope with a changing and partly unpredictable world makes it very likely that any intelligent system with multiple motives and limited powers will have emotions." [1] From advisory systems that understand emotional attitudes toward medical outcomes, to wearable computers that compensate for communication disability, to computer simulations of emotions and their disorders, the research agendas of medical informatics and affective computing--how and why to create computers that detect, convey, and even have emotions--increasingly overlap. Some psychiatric and neurological researchers state their theories in terms of actual or hypothetical computer programs. Adaptive intelligent systems will increasingly rely on emotions to compensate for their own conflicting goals and limited resources--emotional reactions about which psychiatrists and neurologists have special insights. DEP2 (Depression Emulation Program 2) is a computer simulation of adaptive depression--learning from explainable patterns of failure in autobiographical memory--that simulates many depressive behaviors. In the terminology of fault-tolerant computing, adaptive depression involves fault detection (triggered by failure), fault location (strategic retreat and failure diagnosis), and fault recovery (return to on-line operation). DEP2 relies on subsystems whose structures and behaviors are based on popular hypotheses about left and right brain hemispheric function during depression and emotion. DEP2 and its predecessors, DEP and DEPlanner, are relevant to psychiatric and neurological informatics, and to the design of adaptive autonomous robots and software agents.

Adaptation, Psychological↗

Intelligent systems in the context of surrounding environment.

We investigate the behavioral patterns of a population of agents, each controlled by a simple biologically motivated neural network model, when they are set in competition against each other in the minority model of Challet and Zhang. We explore the effects of changing agent characteristics, demonstrating that crowding behavior takes place among agents of similar memory, and show how this allows unique "rogue" agents with higher memory values to take advantage of a majority population. We also show that agents' analytic capability is largely determined by the size of the intermediary layer of neurons. In the context of these results, we discuss the general nature of natural and artificial intelligence systems, and suggest intelligence only exists in the context of the surrounding environment (embodiment).

Artificial Intelligence↗

scBaseCount: An AI agent-curated, standardized, auto-updated single-cell data repository.

Single-cell RNA sequencing has transformed cell biology by enabling precise transcriptomic measurements of individual cells. The Sequence Read Archive (SRA) is the largest public repository of sequencing reads, yet much of it remains underutilized due to unstandardized metadata. Here, we introduce scBaseCount, a database that leverages an AI agent to automate discovery and metadata extraction and standardize data processing. Built by mining all 10x Genomics datasets, scBaseCount is the largest public repository of single-cell gene expression data, comprising over 502 million cells across 27 organisms and 75 tissues. It offers an unbiased view of the data landscape within the SRA and enables the training of more performant computational models through access to broader phenotypic diversity. Uniform processing enables measurement of both intronic and exonic reads and non-coding gene expression and improves alignment across experiments. Moreover, scBaseCount provides a blueprint for how AI can be leveraged to autonomously curate biological data repositories.

Single-Cell Analysis↗

Medication monitoring in the workplace: toward improving our system of epidemiologic intelligence.

There is a great deal we do not know about the safety of pharmaceutical agents, especially regarding their safe use in the workplace. Economic and scientific imperatives can lead to a new drug's approval and marketing even though testing is limited; therefore, much of the knowledge about drug toxicities must be developed in the postapproval period, through pharmacoepidemiologic methods. The system of epidemiologic intelligence depends on spontaneous, voluntary reports of adverse drug reactions and, as applied to the work force, it is fraught with problems of ascertainment, accountability, and application. Structured epidemiologic studies of these issues have been difficult to perform because of high costs, long time frames, and methodologic problems and biases. Nevertheless, large automated data bases, with the right input, hold great promise for making it easier to accumulate and analyze the data necessary for monitoring drug safety in the workplace.

Drug Evaluation↗

Computational and molecular modeling evaluation of the structural basis for tubulin polymerization inhibition by colchicine site agents.

The computer-automated structure evaluation programs MultiCASE and CASE were used to perform a quantitative structure-activity relationship study on tubulin polymerization inhibitors. A learning set of 536 chemicals (202 active. 27 marginal, and 307 inactive), built using IC50 values for inhibition of tubulin polymerization or mitosis from this and previous studies, was used for artificial intelligence self-teaching. The algorithms successfully predicted the activity of agents in the learning set with > 90% accuracy. Seventeen MultiCASE and twelve CASE (mostly included in the MultiCASE set) biophores (substructures significantly correlated with activity) were identified with a probability > 0.95. Here we present the biophores of podophyllotoxins, colchicinoids, and certain combretastatins, each examined for structure-activity relationships. For the podophyllotoxins and colchicinoids in the learning set, the correlations between observed and predicted potencies were > 0.85. The algorithms recognized the importance of several known site, electronic, and steric effects in the two classes. A predictive QSAR (R2 = 0.98) was developed for combretastain A-2 and dihydrocombretastatin analogues. The MultiCASE/CASE analyzes were used in combination with molecular models to study relative orientations of colchicine, podophyllotoxin, combretastatin A-4, and steganacin at the colchicine site. This resulted in a new hypothesis, consistent with extensive published experimental data, in which the C-ring and part of the B-ring of colchicine overlap with the A- and B-rings of podophyllotoxin. Consequently, the trimethoxyphenyl rings of colchicine and podophyllotoxin occupied different regions of space, each pointing out from a hydrophobic 'core' occupied by the overlapping biophores. The molecular model of the highly potent combretastatin A-4 could fit into the model binding site in at least three different ways. The developed QSARs were used to identify the potent microtubule stabilizer discodermolide. Its identification, in concert with recently reported findings, suggest potential overlap in the colchicine and paclitaxel binding sites on tubulin.

Antineoplastic Agents, Phytogenic↗

Molecular mimicry and the role of B lymphocytes in the processing of autoantigens.

The immune system has evolved several mechanisms that provide lymphocytes with the intelligence to ignore self proteins while attacking foreign pathogenic agents. Notably, B and T lymphocytes that encounter self antigen at either the inappropriate levels or affinity are usually instructed to perish or become anergized. However, the presence of autoimmune disease suggests that the induction of self tolerance is not foolproof. In fact, autoreactive cells are now found to be normal inhabitants of the B and T lymphocyte repertoire. This review examines how foreign peptides which resemble self proteins can elicit autoimmunity that is amplified to many sites on a target autoantigen. In particular, B lymphocytes initiated by foreign molecular mimics can process and present self peptides in the shaping of autoimmune T cell responses.

Animals↗

Antipyretic Therapy's future.

There is little doubt that clinicians will continue to seek new and, one hopes, more intelligent ways to suppress fever. In the process, new agents will be developed, new uses will be identified for existing antipyretic agents, new measures will be designed to maximize the benefits of antipyretic therapy while minimizing its adverse effects, and a concerted effort will be made to define more clearly and to promote appropriate indications for such therapy.

Analgesics, Non-Narcotic↗

Absence of synergistic effects of CNS treatments on neuropsychologic test performance among children.

Three hypotheses are proposed to account for neurobehavioral impairments following treatment with cranial radiation therapy (CRT) and intrathecal (IT) chemotherapy: CNS treatments exert a synergistic effect (A x B), an additive effect (A + B), or a single-agent effect (A or B). Eighty-five long-term survivors of non-CNS cancers aged 6 to 16 years were classified into groups on the basis of CNS treatments: CRT-IT (n = 25), CRT-No IT (n = 11), No CRT-IT (n = 24), and No CRT-No IT (n = 25). Study I findings did not provide support for synergistic mechanisms; nonorthogonal analysis of variance showed interaction effects (CRT x IT) restricted to tactile-perceptual speed. However, main effects were significant for a single agent (CRT) across a wide range of measures. General intelligence, academic achievement, verbal knowledge and reasoning, and perceptual-motor abilities were found to be significantly lower among CRT-treated groups. Study II findings provided additional support for the role of CRT; Pearson correlations within the CRT-No IT group indicated significant negative associations between CRT dose estimates for cortical regions and perceptual-motor abilities.

Adolescent↗

Formulary decisions and health economics.

Because of increasing concerns about health care costs, physicians must consider the cost-effectiveness of a treatment strategy, as well as its efficacy and safety. The question of whether the greater expense of a newer drug is justified over the cost of a generic drug deserves a comprehensive evaluation. The determination of effectiveness and tolerability of the newer antipsychotics should be expanded to include quality-of-life issues, reintegration of the patient into the community, resource utilization, and medical costs. There are clear indications that patients who take atypical antipsychotics utilize fewer medical resources than patients who take typical antipsychotics; however, the positive outcomes of the newer drugs must be translated into cost benefits if formularies are to be intelligently controlled.

Antipsychotic Agents↗

A multi-agent architecture for teaching dermatology.

This work proposes the integration of computer-aided instruction systems in the curricula of medical education, and describes an intelligent tutoring system used for teaching Dermatology. The Dermatology Tutor uses a self-organized society of autonomous software agents which have different capabilities or roles. The society contains tutor, medical and information agents which participate in the tutoring process and collaborate through deliberation in order to achieve a tutoring task. The agents are built according to a BDI architecture, which implements the mental attitudes of beliefs (B), desires (D) and intentions (I). Each medical agent is a specialist in a medical field, while a tutoring agent, which implements a widely accepted dermatology teaching process, coordinates the overall operation of the system. Depending on the subject that is to be taught during any session, the tutoring agent forms teams of medical agents, which in turn use search agents to retrieve information. Although the presented multi-agent architecture is dedicated to teaching dermatology (since the tutor agent is specialized in Dermatology), it can be extended to other domains also with the incorporation of other tutor agents.

Computer Systems↗

Anthropic agency: a multiagent system for physiological processes.

Multiagent systems are powerful and flexible tools for modelling and regulating complex phenomena. In fact, a way to manage the complexity of a phenomenon is to decompose it in such a way that each agent embeds the control model for a portion of the phenomenon. In this perspective, the cooperative interaction among the agents results in the controller for the whole phenomenon. Since the portions in which the phenomenon is decomposed may overlap, the actions the single agents undertake to regulate these portions may conflict; hence a balanced negotiation is required. A class of complex phenomena that present several difficulties in their satisfactory modelling and controlling is the class of physiological processes. The purpose of this paper is to introduce a general multiagent architecture, called anthropic agency, for the modelling and the regulation of complex physiological phenomena.

Animals↗

The role of the clinical laboratory in managing chemical or biological terrorism.

BACKGROUND: Domestic and international acts of terrorism using chemicals and pathogens as weapons have recently attracted much attention because of several hoaxes and real incidents. Clinical laboratories, especially those affiliated with major trauma centers, should be prepared to respond rapidly by providing diagnostic tests for the detection and identification of specific agents, so that specific therapy and victim management can be initiated in a timely manner. As first-line responders, clinical laboratory personnel should become familiar with the various chemical or biological agents and be active participants in their local defense programs. APPROACH: We review the selected agents previously considered or used in chemical and biological warfare, outline their poisonous and pathogenic effects, describe techniques used in their identification, address some of the logistical and technical difficulties in maintaining such tests in clinical laboratories, and comment on some of the analytical issues, such as specimen handling and personal protective equipment. CONTENT: The chemical agents discussed include nerve, blistering, and pulmonary agents and cyanides. Biological agents, including anthrax and smallpox, are also discussed as examples for organisms with potential use in bioterrorism. Available therapies for each agent are outlined to assist clinical laboratory personnel in making intelligent decisions regarding implementation of diagnostic tests as a part of a comprehensive defense program. SUMMARY: As the civilian medical community prepares for biological and chemical terrorist attacks, improvement in the capabilities of clinical laboratories is essential in supporting counterterrorism programs designed to respond to such attacks. Accurate assessment of resources in clinical laboratories is important because it will provide local authorities with an alternative resource for immediate diagnostic analysis. It is, therefore, recommended that clinical laboratories identify their current resources and the extent of support they can provide, and inform the authorities of their state of readiness.

Animals↗

Cerebrospinal fluid monoamines in Prader-Willi syndrome.

BACKGROUND: The behavioral phenotype of Prader-Willi syndrome (PWS) suggests hypothalamic dysfunction and altered neurotransmitter regulation. The purpose of this study was to examine whether there was any difference in the concentrations of monoamine metabolites in the cerebrospinal fluid (CSF) in PWS and non-PWS comparison cases. METHODS: The concentration of monoamine metabolites in CSF was determined in 13 children and adolescents with PWS diagnosed on clinical and genetic criteria. The concentrations were compared with those from 56 comparison cases in healthy and other contrast groups. RESULTS: The concentrations of dopamine and particularly serotonin metabolites were increased in the PWS group. The differences were most prominent for 5-hydroxyindoleacetic acid. The increased concentrations were found in all PWS cases independently of age, body mass index, and level of mental retardation. CONCLUSIONS: The findings implicate dysfunction of the serotonergic system and possibly also of the dopamine system in PWS individuals, and might help inform future psychopharmacologic studies.

Adolescent↗