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PubMed1978

[Neuroleptic disinhibitory agents].

The concept of "disinhibition" appeared in 1956 (Broussolle and Dubor) with a study of the activity of prochlorpémazine in chronic schizophrenia. Each chemical group of neuroleptics includes at least one or two disinhibitory compounds. This activity intervenes upon the affective and intellectual life without necessarily the usual extra-pyramidal akathisia side-effects. Psycho- and sociotherapy are strongly adviced with disinhibitory effect.

Affect↗
PubMed1979

Lead poisoning without encephalopathy. Effect of early diagnosis on neurologic and psychologic salvage.

Medical and psychological status of 166 patients previously treated for lead poisoning and of 22 sibling controls were evaluated. Maximum blood lead levels ranged from 40 to 471 microgram/dL. Eighteen patients had definite symptoms, 32 had questionable symptoms, and 116 were asymptomatic. No patients developed seizures, other neurological sequelae, or abnormal nerve conduction velocity. No statistically significant relationship was found between blood lead concentration (PbB) and subsequent intellectual function. The mean IQ of the patient cohort was 87, approximately at the 50th percentile for inner-city schoolchildren in Chicago. Detection prior to encephalopathy and prompt detoxification were effective in preventing or minimizing sequelae despite high PbBs.

Brain Diseases↗
PubMed1996

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↗
PubMed1996

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↗
PubMed2026

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↗
PubMed1990

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↗
PubMed1996

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↗
PubMed1991

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↗
PubMed1998

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↗
PubMedDate not supplied

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↗
PubMed1998

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↗