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PubMed2004

Human-centric intelligent systems for exploration and knowledge discovery.

This speculative article discusses research and development relating to computational intelligence (CI) technologies comprising powerful machine-based search and exploration techniques that can generate, extract, process and present high-quality information from complex, poorly understood biotechnology domains. The integration and capture of user experiential knowledge within such CI systems in order to support and stimulate knowledge discovery and increase scientific and technological understanding is of particular interest. The manner in which appropriate user interaction can overcome problems relating to poor problem representation within systems utilising evolutionary computation (EC), machine-learning and software agent technologies is investigated. The objective is the development of user-centric intelligent systems that support an improving knowledge-base founded upon gradual problem re-definition and reformulation. Such an approach can overcome initial lack of understanding and associated uncertainty.

Artificial Intelligence↗
PubMedDate not supplied

Toxicogenomics, drug discovery, and the pathologist.

The field of toxicogenomics, which currently focuses on the application of large-scale differential gene expression (DGE) data to toxicology, is starting to influence drug discovery and development in the pharmaceutical industry. Toxicological pathologists, who play key roles in the development of therapeutic agents, have much to contribute to DGE studies, especially in the experimental design and interpretation phases. The intelligent application of DGE to drug discovery can reveal the potential for both desired (therapeutic) and undesired (toxic) responses. The pathologist's understanding of anatomic, physiologic, biochemical, immune, and other underlying factors that drive mechanisms of tissue responses to noxious agents turns a bewildering array of gene expression data into focused research programs. The latter process is critical for the successful application of DGE to toxicology. Pattern recognition is a useful first step, but mechanistically based DGE interpretation is where the long-term future of these new technologies lies. Pathologists trained to carry out such interpretations will become important members of the research teams needed to successfully apply these technologies to drug discovery and safety assessment. As a pathologist using DGE, you will need to learn to read DGE data in the same way you learned to read glass slides, patiently and with a desire to learn and, later, to teach. In return, you will gain a greater depth of understanding of cell and tissue function, both in health and disease.

Animals↗
PubMed1979

Impaired performance and sedation after a single dose of lorazepam.

In a double-blind cross-over study using normal student volunteers, the effects of 1 and 2.5 mg lorazepam on self-rated mood and bodily symptoms, as well as performance in a number of tests were assessed. Both doses significantly increased self ratings of physical and mental sedation, the effects being more marked 4 h after drug administration than after 1 h. Lorazepam impaired simple reaction time, verbal learning, number cancellation, symbol copying and performance in the digit-symbol substitution test. The impairments were greater with the 2.5 mg dose and were more marked 4 h after drug administration than after 1 h.

Adult↗
PubMed2001

An MRI study of midbrain morphology in patients with schizophrenia: relationship to psychosis, neuroleptics, and cerebellar neural circuitry.

BACKGROUND: The midbrain contains the perikarya of all the dopamine neurons in the human brain. Although other neurochemicals may well be involved, dopamine dysregulation is central in the pathophysiology of psychosis. Despite this, few imaging studies have evaluated the morphology of the midbrain. METHODS: Using high-resolution magnetic resonance imaging, morphology of three posterior fossa and brain stem structures were measured: midbrain, pons, and medulla. The patient sample consisted of 50 men with schizophrenia, matched by gender and age to 50 healthy control subjects. RESULTS: Patients had significantly smaller midbrain measures compared with control subjects. There were no differences between groups in measures of pons or medulla. Furthermore, midbrain size was significantly and inversely correlated with positive symptoms and cumulative neuroleptic exposure, but not with negative or disorganized symptoms. After controlling for the effect of cumulative neuroleptic exposure, the relationship between midbrain morphology and positive symptoms remained significant. CONCLUSIONS: Midbrain morphology of patients with schizophrenia is abnormal, being smaller in patients compared with control subjects. Although this appears to be specifically related to psychotic symptoms, there is also a robust medication effect, with greater exposure to neuroleptics being associated with greater morphologic abnormality. We discuss the role of dopaminergic dysregulation and possible neural circuit involvement.

Adult↗
PubMed2004

Psychological and cognitive function: predictors of adherence with cholesterol lowering treatment.

BACKGROUND: Failure to adhere to medication regimes is a significant problem in clinical and research settings yet reliable, consistent identification of key psychosocial predictors remains elusive. Studies of mood and personality related to adherence show mixed results-compliance and objectively measured cognitive function are intuitively related but empirical support is lacking. PURPOSE: This study is a secondary analysis to examine the relations between adherence with a medication regime for lowering serum cholesterol and several domains of psychological and cognitive functioning. METHODS: Participants in the initial study completed a measure of personality and a battery of neuropsychological measures at baseline; anxiety and depression were measured at baseline and at 4-week intervals. Medication adherence was tracked with electronic cap monitors for 24 weeks. RESULTS: Only 23% of the sample was fully adherent to medication regimes at least 80% of the time over the 6-month study period. Conscientiousness, according to the Five Factor Theory of Personality, and estimated IQ remained robust predictors of adherence in hierarchical regression analyses. Depression and anxiety, mental flexibility, and visuospatial-constructional ability were less robust but statistically significant (p <.05) correlates of adherence. CONCLUSIONS: Although results of this analysis explain only a portion of the variance in adherence, they demonstrate the importance of trait psychological and cognitive factors in adherence research.

Adult↗
PubMed2002

Threats in bioterrorism. I: CDC category A agents.

Although once considered unlikely, bioterrorism is now a reality in the United States since the anthrax cases began appearing in the fall of 2001. Intelligence sources indicate there are many countries and terrorist organizations that either possess biological weapons or are attempting to procure them. In the future it is likely that we will experience additional acts of bioterrorism. The CDC category A agents represent our greatest challenge because they have the potential to cause grave harm to the medical and public health systems of a given population. Thus, it is imperative that plans be developed now to deal with the consequences of an intentional release of any one or more of these pathogens.

Anthrax↗
PubMed2025

Vasoactive Agent Therapy in Septic Shock: From Monotherapy Battles to Tailored Hemodynamic Optimization.

Hemodynamic stabilization and preservation of organ perfusion are central elements in the management of septic shock. This is achieved by fluid resuscitation and by administration of vasoactive agents to secure a time window for definitive cause-directed therapy. Guided by the Surviving Sepsis Campaign, the optimization of vasoactive agent strategies, namely protective hemodynamic management, has become a central focus. Tracing key research over the past 25 years reveals a paradigm shift in vasopressor therapy, from empiricism to goal-directed strategy. This evolution has deepened our understanding of the benefit-risk profile of vasoactive agents and fostered a new conceptual framework regarding organ perfusion and protection. Under this framework, management strategies have advanced from the mere pursuit of hemodynamic parameters to care bundles that integrate the monitoring of organ perfusion, microcirculation, and oxygen metabolism. These advances have optimized agent selection, established safe dosing ranges, and ultimately promoted the widespread adoption of combined and multimodal therapy concepts. This review delineates this transformative journey, synthesizing evidence on the reappraisal of traditional agents and exploring "de-catecholaminization" strategies, thereby aiming to broaden the therapeutic landscape. The integration of artificial intelligence and genomic medicine is expected to further advance personalized management strategies for septic shock.

Humans↗
PubMed2001

Measuring the effectiveness of antiretroviral agents.

Considerable progress has been made recently in developing effective antiretroviral combination therapy that can suppress viral replication and delay disease progression in individuals infected with HIV. A range of up to 15 approved antiretroviral agents is now available, which target two different viral enzymes, while several agents are in clinical development. The rapid development and approval of antiretroviral agents, driven by the urgency of clinical need as well as the complexity of possible combinations, has precluded the extensive comparative clinical testing of regimens, which is necessary to establish the relative efficacy of various different agents. The lack of an appropriate animal model for HIV disease also increases reliance on in vitro measures. Several different in vitro and in vivo parameters have been defined in an attempt to quantify the effectiveness of antiretroviral agents, most importantly the 50% inhibitory and effective concentrations (IC50 and EC50). However, the clinical relevance of these measures is uncertain. Additionally, considerable variation exists in the usage of the terms 'IC50' and 'EC50' in recent publications in the literature. These issues pose interpretation problems to clinicians seeking information on the relative clinical efficacy of the agents. In this brief review, we attempt to clarify the different measures available and their potential utility for clinical decision-making, focusing particularly on the example of HIV protease inhibitors. There are many different quantifiable parameters that give information regarding the effectiveness of an antiviral drug. These include: inhibition of the viral target enzyme (inhibition constant, Ki); selectivity for viral versus host enzymes; inhibition of viral replication in cell culture (IC50); ratio of efficacy to cytotoxicity in vitro (therapeutic index); inhibition of viral replication or symptoms in an appropriate animal model of the disease (EC50); and the effect on surrogate markers, such as viral load or CD4 cell count, after administration to humans (in vivo EC50). Each of these different parameters gives valid information about the properties of an antiretroviral agent, which can help to build up a picture of its potential clinical utility relative to other drugs. However, to gain meaningful results, it is important to apply this information intelligently, understanding the limitations of each parameter.

Anti-HIV Agents↗
PubMed1996

[Prospective study on intelligence quotient of 28 hepatic lenticular degeneration patients with treatment combining traditional Chinese and Western medicine].

Intelligence quotient (IQ) of 28 hepatic lenticular degeneration (HLD) patients was analysed with Wechsler Adult Intelligence Scale-revised by China (WAIS-RC) before and after two months treatment by the HLD-Relief decoction supplemented with copper-clearing drug, and the result was compared with that of 30 healthy persons for control. The results showed that the Vocable IQ (VIQ), Performance IQ(PIQ) and Full IQ(FIQ) of HLD patients were markedly lower than that of control (P < 0.005), especially in visual space disorder, which indicated that the copper ion depositing in patient's brain not only damaged neuronic motorial functions but also produced a marked effect on the patient's intelligence. After treatment, the total intelligential level including VIQ, PIQ and FIQ has been raised, particularly in PIQ in which all scores were obviously increased (P < 0.001). It was also showed that the damage of intelligence in HLD patient became more serious as the course of disease was prolonged and the early treatment facilitated the IQ level to approach the normal criterion. It indicated that the treatment with combined therapy is effective to the intelligence and extrapyramidal symptoms in HLD patients.

Adolescent↗
PubMed1963

CHILDHOOD PSYCHOSIS OR MENTAL RETARDATION: A DIAGNOSTIC DILEMMA. I. PSYCHIATRIC AND PSYCHOLOGICAL ASPECTS.

A relatively large percentage of children seen at a mental retardation clinic demonstrated psychotic symptoms. The entire group with psychotic manifestations, 62 in all, were reviewed in order to clarify the diagnosis of childhood psychosis or mental retardation. The 1961 British criteria for childhood psychosis were used and are advocated by the authors. Childhood psychosis was the primary diagnosis in 38 cases, and psychosis secondary to brain damage in 24 cases. Onset of the condition under the age of three years and a poor prognosis for social recovery were characteristic of the entire group.Obvious emotional disorder was present in 21 mothers and 14 fathers. There was a continuum in terms of number of psychotic symptoms, level of intelligence and presence of organic signs. It is concluded that there is an overlap between the entities of childhood psychosis and mental retardation.

Adolescent↗
PubMed2003

ALX 111: ALX1-11, parathyroid hormone (1-84) - NPS Allelix, PREOS, PTH, recombinant human parathyroid hormone, rhPTH (1-84).

ALX 111 [parathyroid hormone (1-84) - NPS Allelix, recombinant human parathyroid hormone, rhPTH (1-84), PREOS] is a full-length, recombinant human parathyroid hormone. It has potential as an anti-osteoporotic agent, due to its properties as a bone formation stimulant. This profile has been selected from R&D Insight, a pharmaceutical intelligence database produced by Adis International Ltd. It has been recommended that ALX 111 should be given for 1 to 2 years and may be given in combination with an antiresorptive agent, such as estrogen or a bisphosphonate. In December 1999, Allelix Biopharmaceuticals merged with NPS Pharmaceuticals. This combined company is operating as NPS Pharmaceuticals in the US and as NPS Allelix in Canada. The merger has enabled a phase III study of ALX 111 to begin in the US, Europe and South America. NPS harmaceuticals has signed an agreement with Bio-Imaging Technologies, which will provide all image handling and analysis for this trial. Until 1994, Allelix Biopharmaceuticals and Glaxo in Canada were involved in a joint venture to investigate the efficacy of ALX 111 in osteoporosis. Allelix was subsequently, until September 1998, collaborating with Astra of Sweden in developing ALX 111. Astra had acquired exclusive worldwide rights to ALX 111 and was responsible for development of the agent. However, Astra returned all rights to ALX 111 to Allelix as a result of its merger with Zeneca to form AstraZeneca. In December 1999, Allelix Biopharmaceuticals merged with NPS Pharmaceuticals. This combined company is operating as NPS Pharmaceuticals in the US and as NPS Allelix in Canada. The merger has enabled a phase III study of ALX 111 to begin in the US, Europe and South America. The phase III trial of ALX 111 for the treatment of osteoporosis has completed patient enrolment, and phase II trials have been completed in Canada and the Netherlands. The 18-month, phase III, multicentre, placebo-controlled trial (Treatment of Osteoporosis with Parathyroid Hormone; TOP) has been designed to assess the bone-building and fracture-reducing potential of the drug, and over 2600 postmenopausal women with osteoporosis who have not received previous drug therapy for osteoporosis have been enrolled. Treatment will be completed in September 2003, but more than 75% of patients enrolled in the TOP study have chosen to enrol in an Open Label Extension Study (OLES), which allows for a total treatment period of up to 24 months. NPS Pharmaceuticals has signed an agreement with Bio-Imaging Technologies, which will provide all image handling and analysis for this trial. In September 2002, NPS Pharmaceuticals announced that it has met its patient enrolment target (n > 150) for its POWER (PTH for Osteoporotic Women on Estrogen Replacement) study; a 24-month phase III trial initiated in Europe in November 2001. In this trial, women with osteoporosis receive SC injections of ALX 111 or placebo, in combination with their existing hormone replacement therapies, to test the bone building potential of the drug. In addition to the POWER study, a clinical trial sponsored by the National Institutes of Health (NIH) is being conducted to evaluate the potential of ALX 111 to build bone in combination with another osteoporosis medication. The 'PaTH' study (PTH/alendronate) is designed to assess the effect of various combinations and sequential uses of ALX 111 and Merck's Fosamax, a drug for slowing the loss of bone due to osteoporosis. The PaTH study, initiated in May 2000 and scheduled to conclude in September 2003, involved 238 patients with postmenopausal osteoporosis. It is thought that alendronic acid and ALX 111, when administered in combination, may act in an additive manner to treat osteoporosis because they act in different ways; alendronic acid acts to inhibit resorption and ALX 111 speeds up bone formation and resorption, with a net increase in formation. Results of this study are still being analysed but preliminary results appear to be positive. The effect of ALX 111 on bone cell cultures underare still being analysed but preliminary results appear to be positive. The effect of ALX 111 on bone cell cultures under conditions of microgravity was tested in orbit on the Space Shuttle Columbia, which was launched on 16 January 2003 but did not survive re-entry. This study was one in a series of studies known as 'OSTEO' and had been prepared by researchers from NPS Pharmaceuticals using Millenium Biologix' OSTEO Mini-Lab System. Under space flight conditions, astronauts experience a loss in bone density at a rate up to ten times faster than that of earth-bound patients with osteoporosis, and it was hoped that this study would indicate the mechanism of action of ALX 111 at cellular and genetic levels. The results of these studies were represented by the samples of human bone cells, which were lost during the re-entry tragedy.

Bone Density↗
PubMed1975

[The future of estrogen substitution in the menopause. Psychological and sociological aspects (author's transl)].

The future of estrogen substitution (ES) in the menopause was examined in 425 patients in our clinic from the psychological and sociological aspects. Of the women questioned, one fourth would not consider estrogen substitution from the menopause onwards another fourth would only accept this for one year, one quarter for up to six years and the remaining quarter for longer than six years. The reasons for this decision were sought. The positive attitude towards estrogen substitution was seen to depend on age, education level, intelligence, knowledge of sexual hormones, experience with the pill, history of abortion, parity and personality factors.

Abortion, Spontaneous↗
PubMed2004

The effects of levodopa on word intelligibility in Parkinson's disease.

Dysarthria is a common manifestation in patients with idiopathic Parkinson's disease. This study investigated the effects of levodopa on intelligibility in patients with Parkinson's disease. Ten participants were tested during on- and off-states using the Yorkston and Beukelman intelligibility test (1980). Intelligibility as scored by a panel of speech therapists was significantly improved in the on-condition. No correlation was found, however, between intelligibility and overall severity of the disease or severity of the motor problems. EDUCATIONAL OUTCOMES: As a result of this activity the participant will be able to discuss the effects of levodopa on intelligibility in patients with Parkinson's disease.

Aged↗
PubMed2004

Toward understanding the ionization of biomarkers from micrometer particles by bio-aerosol mass spectrometry.

The appearance of informative signals in the mass spectra of laser-ablated bio-aerosol particles depends on the effective ionization probabilities (EIP) of individual components during the laser ionization process. This study investigates how bio-aerosol chemical composition governs the EIP values of specific components and the overall features of the spectra from the bio-aerosol mass spectrometry (BAMS). EIP values were determined for a series of amino acid, dipicolinic acid, and peptide aerosol particles to determine what chemical features aid in ionization. The spectra of individual amino acids and dipicolinic acid, as well as mixtures, were examined for extent of fragmentation and the presence of molecular ion dimers, which are indicative of ionization conditions. Standard mixtures yielded information with respect to the significance of secondary ion plume reactions on observed spectra. A greater understanding of how these parameters affect EIP and spectra characteristics of bio-aerosols will aid in the intelligent selection of viable future biomarkers for the identification of bio-terrorism agents.

Aerosols↗