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PubMed1992

Postural stability, tardive dyskinesia and developmental disability.

The postural stability of four adult populations was examined through force platform methods. The four groups were classified as: (1) developmentally disabled (severely and profoundly mentally retarded) with tardive dyskinesia; (2) developmentally disabled but with no history of neuroleptic medication; (3) tardive dyskinetic but of normal intelligence; and (4) a normal and healthy control group. Postural conditions included standing still with arms at side, standing still with one arm or both arms parallel to the ground, and standing still while swinging both arms in the sagittal plane. The findings showed that both tardive dyskinetic and/or developmentally disabled groups exhibited greater sway and variability in centre of pressure motion in contrast to the control group. The developmentally disabled with tardive dyskinesia group also exhibited a strong tendency to produce a different form to the postural sway strategy in that they produced rhythmical centre of pressure motions during stance that were, to some degree, task dependent. The findings show that the combined effects of developmental disability and tardive dyskinesia produce qualitatively and quantitatively different features in postural stability patterns. The data suggest that postural stability measures may be a useful index to assess tardive dyskinesia.

Antipsychotic Agents↗

PubMed2005

Novolizer: how does it fit into inhalation therapy?

Inhalation therapy is the preferred route of administration of anti-asthmatic drugs to the lungs. However, the vast majority of patients cannot use their inhalers correctly, particularly pressurised metered dose inhalers (pMDIs). The actual proportion of patients who do not use their inhalers correctly may even be under-estimated as GPs tend to over-estimate correct inhalation technique. Dry powder inhalers (DPIs) have many advantages over pMDIs. Unlike pMDIs, they are environmentally-friendly, contain no propellant gases and, more importantly, they are breath-activated, so that the patient does not need to coordinate actuation of the inhaler with inspiration. Three key parameters for correct inhaler use should be considered when evaluating existing or future DPI devices and especially when choosing the appropriate device for the patient: (1) usability, (2) particle size distribution of the emitted drug and (3) intrinsic airflow resistance of the device. The Novolizer is a breath-activated, multidose, refillable DPI. It is easy to use correctly, has multiple feedback and control mechanisms which guide the patient through the correct inhalation manoeuvre. In addition, the Novolizer has an intelligent dose counter, which resets only after a correct inhalation and may help to monitor patient compliance. The Novolizer has a comparable or better lung deposition than the Turbuhaler at similar or higher peak inspiratory flow (PIF) rates. A flow trigger valve system ensures a clinically effective fine particle fraction (FPF) and sufficient drug delivery, which is important for a good lung deposition. The FPF produced through the Novolizer is also relatively independent of flow rate and the device shows better reproducibility of metering and delivery performance compared to the Turbuhaler. The low-to-medium airflow resistance means that the Novolizer is easy for patients to use correctly. Even children, patients with severe asthma and patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) have no problems to generate the trigger inspiratory flow rate required to activate the Novolizer. The Novolizer uses an advanced DPI technology and may improve patient compliance.

Administration, Inhalation↗

PubMed1998

Memory impairment in abstinent MDMA ("Ecstasy") users.

BACKGROUND: Methylenedioxymethamphetamine (MDMA, or "Ecstasy") is a popular recreational drug of abuse that is known to damage brain serotonergic neurons in animals and possibly humans. Few functional consequences of MDMA-induced serotonin (5-HT) neurotoxicity have been identified, either in animals or humans. This study sought to determine whether individuals with a history of extensive MDMA use showed evidence of memory impairment, because brain serotonin has been implicated in mnemonic function. METHOD: The authors compared 24 abstinent MDMA users and 24 control subjects on several standardized tests of memory, after matching subjects for age, gender, educational level, and vocabulary score (a surrogate of verbal intelligence). The authors also explored correlations between changes in memory function and decrements in CSF 5-hydroxyindoleacetic acid (5-HIAA), which serves as a marker of central 5-HT neural function. RESULTS: Greater use of MDMA (total milligrams per month) was associated with greater impairment in immediate verbal memory (p < 0.02) and delayed visual memory (p < 0.06). Furthermore, lower vocabulary scores were associated with stronger dose-related effects, with men having greater dose-related deficits than women. Lastly, lower concentrations of CSF 5-HIAA were associated with poorer memory performance. CONCLUSION: Abstinent MDMA users have impairment in verbal and visual memory. The extent of memory impairment correlates with the degree of MDMA exposure and the reduction in brain 5-HT, as indexed by CSF 5-HIAA.

Adult↗

PubMed2005

Intelligent hydrogels for the oral delivery of chemotherapeutics.

A novel approach toward improvements of oral chemotherapeutic formulations has evolved, which combines solubilisation (molecular dispersion) of the hydrophobic anticancer drugs in micelles attached to large macromolecules or microparticles. The large size of the macromolecules or microgels prevents the gel components from being transported into the systemic circulation. The discussed gels comprise copolymers of poly(acrylic acid) (PAA) and Pluronic surfactants, linked via C-C bonds. The Pluronic-PAA copolymers are non-irritating when administered orally. The micelles formed in the Pluronic-PAA solutions and in crosslinked microgels can be loaded with chemotherapeutic drugs and then released in contact with the intestine. The microgels are collapsed at the acidic pH of the stomach and expand, thus releasing the loaded drugs at the pH of the lower gastrointestinal tract. Yet the microgels are mucoadhesive and enable longer retention time and prolonged release in the colon. Ease of preparation and formulation of the drugs with the Pluronic-PAA polymers and gels may enable the wider use of oral chemotherapy, resulting in a better patient compliance and improved quality of life of the patients.

Acrylic Resins↗

PubMed1998

Effects of magnesium sulfate tocolysis on maternal mental status.

Objective: Magnesium sulfate is the most commonly used agent for tocolysis in the management of preterm labor. Anecdotally both clinicians and patients have noted alterations in mental status of women receiving high doses of magnesium infusion, and central nervous system depression including lethargy and depression of deep tendon reflexes has been documented. Our hypothesis is that intravenous magnesium sulfate at tocolytic doses significantly affects maternal mental status.Materials and Methods: Eligibility criteria included admission or transport to University Hospital between 25 and 34 weeks gestation with an initial episode of spontaneous premature labor. Patients were consented and given an initial mental status examination prior to magnesium sulfate infusion. Those patients transported to University Hospital diagnosed with premature labor and already on magnesium were consented and given an initial mental status examination at the time of arrival. Once a therapeutic level of magnesium was documented a repeat mental status examination was performed, with a third examination performed 24 hours after the magnesium infusion has been discontinued. As a control group pregnant women hospitalized for premature rupture of the membranes not in labor had the examinations performed initially, after 24 hours of hospitalization, and again after 72 hours of hospitalization. Exclusion criteria included underlying mental illness, administration of other medications that might affect mental status, cervical dilation greater than 4 cm, clinical evidence of chorioamnionitis, or the presence of any significant abnormalities in the fetal heart rate tracing. The mental status examination consisted of the mini mental state exam, the comprehension portion of the Wechsler Adult Intelligence Scale, and the Bender-Gestalt Indicator. The results of these examinations were scored in a blinded fashion by a psychiatrist.Results: There were 22 patients in the study group and 9 patients in the control group. There were no differences in the age, gravidity, parity, or gestational age of the two groups. Out of a possible 102 points, the mean mental status scores were as follows:The mean serum magnesium level at the time of therapy was 5.1 mg/dL. The time required for response to the Wechsler test was significantly different although the scoring of the comprehension was unchanged (15.2 +/- 3.6 min vs 22.3 +/- 4.7 min, P <.05).Conclusions: This prospective blinded study reveals no differences in maternal mental status during magnesium sulfate infusion at the levels recorded in our study. There was an increase in the length of time required to answer the comprehension and judgment portion of the examination. These findings have significant clinical implications suggesting that patients on magnesium sulfate can make appropriate judgments and can, therefore, participate in clinical discussions and trials.

Journal Article↗

PubMedDate not supplied

Molecular diversity in chemical databases: comparison of medicinal chemistry knowledge bases and databases of commercially available compounds.

A molecular descriptor space has been developed which describes structural diversity. Large databases of molecules have been mapped into it and compared. This analysis used five chemical databases, CMC and MDDR, which represent knowledge bases containing active medicinal agents, ACD and SPECS, two databases of commercially available compounds, and finally the Wellcome Registry. Together these databases contained more than 300,000 structures. Topological indices and the free energy of solvation were computed for each compound in the databases. Factor analysis was used to reduce the dimensionality of the descriptor space. Low density observations were deleted as a way of removing outliers, which allowed a further reduction in the descriptor space of interest. The five databases could then be compared on an efficient basis using a metric developed for this purpose. A Riemann gridding scheme was used to subdivide the factor space into subhypercubes to obtain accurate comparisons. Most of the 300,000 structures were highly clustered, but unique structures were found. An analysis of overlap between the biological and commercial databases was carried out. The metric provides a useful algorithm for choosing screening sets of diverse compounds from large databases.

Artificial Intelligence↗

PubMed1998

Low bone mineral density in a case of mosaicism Klinefelter syndrome: rapid response to testosterone therapy.

Male hypogonadism has been recognized as one of the major causes of secondary osteoporosis, but most cases seem to be left undiagnosed. We report a 54-year-old case of mosaicism Klinefelter syndrome lacking typical clinical features such as tall stature or low intelligence, who was found to have marked decrease in lumbar bone mineral density (BMD: 0.686 g/cm2) during treatment of diabetes mellitus. In investigation for etiologies of secondary osteoporosis, he was diagnosed as having mosaicism Klinefelter syndrome (XXY/XY/XX). Although he was infertile, he lacked typical clinical features of Klinefelter syndrome. Testosterone replacement was started, which resulted in an increase in BMD up to 0.712 g/cm2 two months after the initiation of therapy. The fact that BMD increased shortly after the initiation of testosterone replacement therapy in the present case supported a beneficial effect of testosterone on BMD, as recently suggested in idiopathic hypogonadotropic hypogonadism. Although the present case was diagnosed as having mosaicism Klinefelter syndrome by investigating etiologies for osteoporosis, it may be stressed that male hypogonadism, in general, should be adequately suspected in the presence of infertility and from the findings of physical examination.

Bone Density↗

PubMed2001

History of the development and use of biological weapons.

The United States began its BW program based on intelligence information and a very thorough evaluation of that information by a panel of scientists, engineers, medical personnel from a variety of areas including the military, other government agencies, industry, and the academic community. Initial efforts were directed toward defense against BW, but it soon became clear defense required a knowledge of offensive capabilities. The initial offensive studies started with a definition of what infectious organisms were available, how they could grow in quantities to support a munitions program, what kind of facilities were required, and where they could be positioned. Further studies were then initiated to design and evaluate testing sites and methodologies to evaluate the weapons. During all of these phases, concurrent medical and safety programs were studied, emphasized, and implemented. These studies resulted in the development of a number of vaccines, toxoids, treatments, therapies, and facility personnel management. The US program had one of the lowest, if not the lowest, personnel lost time because of personnel infections. The overall conclusion was that BW, offensive and defensive, was possible, and efficiencies could be obtained. The work accomplished by this group of very dedicated military and civilian personnel at military installations, universities, research institutes, and industrial organizations presented truly a combined operation with numerous achievements. Many of the detailed achievements were published in the open scientific, peer-reviewed journals, and many patents were obtained. The current defensive program is breaking new scientific ground and there is evidence indicating that very rapid detection and identification of BW agents is possible and will be instrumented.

Biological Warfare↗

PubMed2026

Investigating the relationship between Toll-like receptor activity, low-grade inflammation, cognitive deficits, and antipsychotic drug dose in schizophrenia patients: a moderation analysis.

BACKGROUND: Schizophrenia (SZ) is a debilitating psychiatric disorder where patients experience cognitive decline. Antipsychotic drugs alleviate positive symptoms but do not improve cognitive performance. We previously demonstrated that Toll-like receptors (TLRs), involved in cytokine production, can predict cognitive deficits in SZ patients. In this study, we aim to investigate the potential moderating effects of antipsychotic drugs on the associations between cytokines, TLRs, and cognition. METHODS: In total, 280 participants (201 controls and 79 cases of SZ) were recruited in Ireland. Venous blood from the participants was stimulated with TLR ligands. Levels of cytokines were measured from plasma and post-blood stimulation. The participants were administered a battery of cognitive tasks using the Cambridge Neuropsychological Test Automated Battery and Wechsler Adult Intelligence Scale-IIIR. Olanzapine equivalents were calculated using the defined daily dose method. RESULTS: The results indicate that antipsychotic drug dose does not predict TLR activity or cognition, indicating that antipsychotic drug dose does not have a direct effect on cognition or TLR activity. However, the relationship between TLR4 activity and visual learning and memory is moderated by the antipsychotic drug dose (B = -0.065; p < 0.001), where increasing doses have a decreasing impact on their relationship. CONCLUSIONS: Our data indicate that the dose of antipsychotic drugs alone cannot predict changes in cognitive performance and TLR4-activity. It also suggests that antipsychotic drug doses significantly affect TLR activity and its relationship with cognition. These effects are more pronounced on some domains than others. These findings open up new avenues for understanding the complex interplay between antipsychotic drugs, TLRs, and cognitive deficits in SZ.

Humans↗

PubMed1985

Learning by statistical cooperation of self-interested neuron-like computing elements.

Since the usual approaches to cooperative computation in networks of neuron-like computating elements do not assume that network components have any "preferences", they do not make substantive contact with game theoretic concepts, despite their use of some of the same terminology. In the approach presented here, however, each network component, or adaptive element, is a self-interested agent that prefers some inputs over others and "works" toward obtaining the most highly preferred inputs. Here we describe an adaptive element that is robust enough to learn to cooperate with other elements like itself in order to further its self-interests. It is argued that some of the longstanding problems concerning adaptation and learning by networks might be solvable by this form of cooperativity, and computer simulation experiments are described that show how networks of self-interested components that are sufficiently robust can solve rather difficult learning problems. We then place the approach in its proper historical and theoretical perspective through comparison with a number of related algorithms. A secondary aim of this article is to suggest that beyond what is explicitly illustrated here, there is a wealth of ideas from game theory and allied disciplines such as mathematical economics that can be of use in thinking about cooperative computation in both nervous systems and man-made systems.

Adaptation, Physiological↗

PubMed2004

Using distributed partial memories to improve self-organizing collective movements.

Past self-organizing models of collectively moving "particles" (simulated bird flocks, fish schools, etc.) have typically been based on purely reflexive agents that have no significant memory of past movements. We hypothesized that giving such individual particles a limited distributed memory of past obstacles they encountered could lead to significantly faster travel between goal destinations. Systematic computational experiments using six terrains that had different arrangements of obstacles demonstrated that, at least in some domains, this conjecture is true. Furthermore, these experiments demonstrated that improved performance over time came not only from the avoidance of previously seen obstacles, but also (surprisingly) immediately after first encountering obstacles due to decreased delays in circumventing those obstacles. Simulations also showed that, of the four strategies we tested for removal of remembered obstacles when memory was full and a new obstacle was to be saved, none was better than random selection. These results may be useful in interpreting future experimental research on group movements in biological populations, and in improving existing methodologies for control of collective movements in computer graphics, robotic teams, particle swarm optimization, and computer games.

Algorithms↗

PubMed2006

Neuropsychological functions predict 1- and 3-year outcome in first-episode psychosis.

OBJECTIVE: To examine neuropsychological performance as a possible predictor of course and outcome in first-episode psychotic (FEP) patients. METHOD: A group of consecutive FEP patients (n = 120) tested with Wechsler Adult Intelligence Scales-Revised (WAIS-R) at baseline was compared with a healthy group (n = 30) matched for age, education and gender. Relationship between WAIS-R and both Brief Psychiatric Rating Scale and Global Assessment of Function (GAF) ratings were studied at baseline and at 1- and 3-year follow-ups. RESULTS: The performance of FEP patients was significantly lower (P < 0.001) than that of healthy comparison subjects on all WAIS-R subtests except for Information and Comprehension. The WAIS-R scores of patients with schizophrenia syndromes (DSM-IV) were lower than those of patients with non-schizophrenia syndromes on Block Design. Low WAIS-R Full-Scale IQ scores in FEP patients predicted the presence of negative symptoms at 1-year follow-up and of low GAF ratings at 3-year follow-up. CONCLUSION: Neurocognitive performance at admission appears to predict various aspects of functional outcome in FEP.

Adolescent↗

PubMed1977

A syndrome of functional hypogonadotropic hypogonadism and sterility in a male with elevated serum estradiol.

A 36-year-old male complaining of impotence was examined. He was a genotypic male. Phenotypically, he exhibited signs of long-standing estrogen excess, such as feminine body build, gynecomastia, and varicose veins. His testes were soft and borderline small, and his prostate was small and soft. However, he had a normal-sized penis, normal male hair distribution, normal sense of smell, and normal intelligence. The laboratory data were compatible with mild hypogonadotropic hypogonadism. Serum estradiol (E2) levels were consistently elevated. The patient had azoospermia and a decreased semen volume. Inappropriately low levels of luteinizing hormone and follicle-stimulating hormone responded normally to gonadotropin-releasing hormone and clomiphene citrate. Levels of both testosterone (T) and E2 increased dramatically after prolonged clomiphene medication and in response to human chorionic gonadotropin. There was no change in either T or E2 levels in response to manipulations of the pituitary-adrenal axis. It is concluded that the elevated E2 level was responsible for suppression of gonadotropins which, in turn, caused mild hypogonadism and sterility in this patient. According to the stimulation tests, the source of the elevated E2 levels was testicular.

Adolescent↗

PubMed1993

Quantification of postural sway patterns in tardive dyskinesia.

An assessment was made of the orientation and variability in postural center of pressure patterns in individuals with tardive dyskinesia (TD) and/or developmental disability during quiet standing. Postural patterns were compared and contrasted between four groups of individuals: those with (a) TD and developmentally disabled (severely and profoundly retarded); (b) developmental disability only; (c) TD but of normal intelligence; and (d) a healthy control group. The center of pressure displacements were derived from the lateral, vertical, and anterior-posterior force and moment components of force platform measurements. Analyses demonstrated that individuals with TD in combination with developmental disability had a different center of pressure orientation and variability compared to healthy individuals and individuals suffering only from developmental disability or TD. The center of pressure pattern in the developmentally disabled TD group was characterized by a more prominent lateral orientation, whereas in the other three groups, it had a more predominant anterior-posterior orientation. In addition, the variability in these orientation components was much smaller in the developmentally disabled TD group, indicating a more regular pattern of sway in the center of pressure during quiet standing in these individuals. These findings show that assessments of postural center of pressure profile orientation and variability may be useful indicators for investigating TD, especially in distinguishing between developmental disability and TD.

Adult↗

PubMed1994

Schizophrenic deficits: neuroleptics and the prefrontal cortex.

Modern techniques have been applied to brain modeling, based on recent approaches in the artificial intelligence field that use brain-like "connectionistic" computational architectures. The model proposed by Cohen and Servan-Schreiber uses a gain parameter which they identify with dopamine function. They apply their model to neuroleptically treated schizophrenia patients who show improved task performance which they link to increased dopamine function and increased gain in the prefrontal cortex. However, evidence indicates that antipsychotic medications block dopamine (especially D2) receptors, decreasing mesolimbic and mesocortical dopamine function. If therapeutic dosages of neuroleptics diminish dopamine function, this would decrease gain in context modules needed for adequate task performance. Schizophrenia patients would perform more poorly by further reducing gain in their already compromised context modules. The current investigators suggest three possible ways to resolve this difficulty, to explain why normals perform more poorly when taking neuroleptics, although acute schizophrenia patients' performance may be enhanced in several areas. Evidence would suggest that multiple processes occur simultaneously in neuroleptically treated patients with some processes counterbalancing others.

Antipsychotic Agents↗

PubMed2006

Neurocognitive function in unmedicated manic and medicated euthymic pediatric bipolar patients.

OBJECTIVE: A systematic evaluation of neuropsychological functioning in individuals with pediatric bipolar disorder is necessary to clarify the types of cognitive deficits that are associated with acutely ill and euthymic phases of the disorder and the effects of medication on these deficits. METHOD: Unmedicated (N=28) and medicated (N=28) pediatric bipolar patients and healthy individuals (N=28) (mean age=11.74 years, SD=2.99) completed cognitive testing. Groups were matched on age, sex, race, parental socioeconomic status, general intelligence, and single-word reading ability. A computerized neurocognitive battery and standardized neuropsychological tests were administered to assess attention, executive function, working memory, verbal memory, visual memory, visuospatial perception, and motor skills. RESULTS: Subjects with pediatric bipolar disorder, regardless of medication and illness status, showed impairments in the domains of attention, executive functioning, working memory, and verbal learning compared to healthy individuals. Also, bipolar subjects with comorbid attention deficit hyperactivity disorder (ADHD) performed worse on tasks assessing attention and executive function than patients with bipolar disorder alone. CONCLUSIONS: The absence of differences in the deficits of neurocognitive profiles between acutely ill unmedicated patients and euthymic medicated patients suggests that these impairments are trait-like characteristics of pediatric bipolar disorder. The cognitive deficits found in individuals with pediatric bipolar disorder suggest significant involvement of frontal lobe systems supporting working memory and mesial temporal lobe systems supporting verbal memory, regardless of ADHD comorbidity.

Adolescent↗

PubMed1997

DT-Planner: an environment for managing dynamic decision problems.

The problem of formulating plans under uncertainty and coping with dynamic decision problems is a major task of both artificial intelligence and control theory applications in medicine. In this paper we will describe a software package, called DT-Planner, designed to represent and solve dynamic decision problems that can be modelled as Markov decision processes, by exploiting a novel graphical formalism, called influence view. An influence view is a directed acyclic graph that depicts the probabilistic relationships between the problem state variables in a generic time transition; additional variables, called event variables, may be added, in order to describe the conditional independencies between state variables. By using the specified conditional independence structure, an influence view may allow a parsimonious specification of a Markov decision process. DT-Planner lets the user specify and manage models through a user-friendly graphical interface, and implements efficient for policy determination algorithms. DT-Planner is written in C with Open Interface libraries and can be obtained, for non commercial use, via anonymous ftp without charge.

Algorithms↗

PubMed2005

Neural network-longitudinal assessment of the Electronic Anti-Retroviral THerapy (EARTH) cohort to follow response to HIV-treatment.

HIV infection is for the most part a chronic and asymptomatic disease. To properly monitor the health status of infected individuals it is important to use host and viral surrogate markers as well as pharmacokinetic parameters. Disease progression, assessment of the antiviral potency of the drugs and response to therapy can only be monitored by repetitive measures of viral and host parameters. To prevent the emergence of antiviral drug-resistance, long term side effects and to decide on the appropriate treatment choices, a comprehensive assessment of all contributing factors, medical and non-medical, is necessary. However, the relationship between treatment outcomes with disease markers and other contributing factors is not simple. To date, a model that accurately predicts the likelihood of disease progression or treatment failure in HIV infected patients does not exist. Extending our previous work in this area, we developed temporal Artificial Intelligence models based on Jordan-Elman networks to longitudinally follow viral surrogate markers together with demographics, biochemical and laboratory data to describe the drug-virus-host interactions in over 4000 HIV adult patients. In an international (multi-continent) study of HIV clinical and laboratory data, the profiles of drug-naïve as well as treated patients were evaluated during a 20 year follow-up. Validation of models on a subset of this cohort (n=595) estimated the sensitivity and specificity of treatment success/failure, under different management modalities for individual patients. ROC-curves predicted: virologic success from baseline (ROC=0.871) in drug-naïve previously non-treated patients, switch from virologic success/ failure to failure/success if ever and when (ROC=0.625), switch to virologic success/failure from failure/success within 6 months (ROC=0.722) following a previous switch. This tool may be helpful in the design of longitudinal clinical trials.

Adult↗