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PubMed1995

[Contemporary strategies and methods of modeling antiparasitic drugs].

Contemporary methods of directed chemotherapy are based on multi-step procedures, which require co-ordinated activities of interdisciplinary teams of biochemists, pharmacologists, geneticists, crystallographers as well as computer scientists. Biochemists select the proper target, such as an enzyme, throughout screening of the biochemical influence of compounds-potential drugs on this target. For further research they use targets with very low inhibition constants (> 10(-6) M). Determination of the relation between therapeutic activity of the compound and modelling of its chemical structure constitutes an important part of the procedure. The most important part of the procedure is the recognition of the primary structure of the target. The two following pathways allow to do that: 1. isolation of DNA and gDNA or cDNA-started cloning of a gene responsible for production of the target protein and then its sequencing. 2. purification and crystallization of the target protein and further computer-aided processing of crystallographic data in order to determine the primary structure. Computational chemistry (C/C) methods are the basic part of the procedure of molecular modelling (M/M) of a target molecule and its interactions with a molecule of the future drug. Data obtained using a technology which engages the C/C and M/M methods not only allow to determine the aminoacid sequence of the target protein in question (e.g. a unique parasite enzyme); they also enable to further speculate on its secondary and tertiary structures. Such structure includes specified number of repeated motifs of alpha-helixes, beta-sheets and loops or turns. Particularly, the "barrel" structure is very common in numerous enzymes. Two following examples of research on target-antiparasitic drug interactions is presented. They are the interaction between phosphoglicerate kinase in Leishmania and drug suramin and malic enzyme of Trichinella and drug closantel. New promising targets for new anti-protozoan drugs (protozoa of Trypanosoma species) include e.g. microbody translocation signal in kinetosom proteins (SKL) or protein blocking the transport of proteins to glycosomes-metabolic centres in Trypanosoma (repetitive groups of QRLQ). Recently, scientists from Arris Pharmaceutical (San Francisco) have considered, employing new data, up to 100 to fully characterize the surface structure of a molecule, using the systems of artificial intelligence.

Anthelmintics↗
PubMed1984

Adverse pregnancy outcome: sensitive periods, types of adverse outcomes, and relationships with critical exposure periods.

A wide variety of agents has been demonstrated to be capable of affecting the fetus in utero. Certain generalizations can be made concerning these teratogens. Two of the most important of these principles are the specificity of the agent and the time during gestation of the exposure. Although noticeable adverse effects are structural malformations, there are numerous functional malformations, such as lower intelligence and poor reproductive outcome, that may follow exposure to these agents. There is some evidence that future behavior may be affected by in utero teratogen exposure; however, this field has been infrequently investigated and no firm conclusions can be drawn.

Abnormalities, Drug-Induced↗
PubMed1997

Retention of asthmatic patients in a longitudinal clinical trial.

BACKGROUND: Prevention of study patient attrition and assessment of its impact on outcome data are problems that receive little attention despite their obvious importance in asthma research. OBJECTIVE: The medical, demographic, and psychologic characteristics of asthmatic children and adults who dropped out of a yearlong medication trial were assessed to determine whether this group differed from those who completed the study, potentially introducing bias into the data set and interfering with completion of the study's objectives. METHODS: Profiles of 362 adult and pediatric asthmatic patient dropouts from the multicenter trial were contrasted with profiles of those who completed the study. Despite a 1-month prerandomization screening, 24% of patients failed to complete the trial for varied reasons, which largely included noncompliance and treatment dissatisfaction. RESULTS: Although attrition rates were equal among adults and children, dropout-completer differentiation was not. Adult completers did not differ from dropouts in any variables. However, pediatric dropouts were more likely than completers to be female (67% and 36%, p = 0.008) and to have more reactive airways (PD20, 2.29 +/- 1.32 and 5.2 +/- 1.23, p = 0.05), to have reduced scores on tests of intelligence (Full Scale IQ, 102.2 +/- 2.6 and 112.5 +/- 1.6, p = 0.002) and problem solving (Wisconsin Card Sorting Test Error Scores, 39.8 +/- 4.1 and 29.1 +/- 2.0, p = 0.01), and to have increased behavioral problems (Child Behavior Checklist Total Problem Score, 60.7 +/- 2.5 and 53.6 +/- 1.1, p = 0.003). CONCLUSION: These findings demonstrate the potential of patient attrition to bias outcome in clinical trials and underscore the necessity of: (1) preventing its occurrence, (2) correctly assessing its causes, and (3) determining its ultimate impact on study results. Strategies for each of these three tasks should be implemented at the study's initial planning stages.

Adolescent↗
PubMed1998

Discrimination between chronic pancreatitis and pancreatic adenocarcinoma using artificial intelligence-related algorithms based on image cytometry-generated variables.

The incidence of pancreatic adenocarcinomas (PA) is increased in the setting of chronic pancreatitis. Distinguishing chronic pancreatitis from pancreatic adenocarcinomas is often difficult, and is based on routine brush cytological specimens provided during endoscopic retrograde cholangiopancreatography (ERCP). Reactive epithelial changes in chronic pancreatitis may appear similar to those of a well-differentiated cancer. Brush cytology specimens were obtained during ERCP from 49 patients with diseases for which the differential diagnosis included chronic pancreatitis and/or pancreatic adenocarcinoma Image cytometry was performed involving the assessment of between 200-400 Feulgen-stained nuclei per case; for each case, 40 quantitative cytometric variables were generated. Data analysis was performed using artificial intelligence methods of data classification that produced decision trees and production rule systems. Different classification models were produced for a subset of 34 patients. The best models were identified by the use of a sampling technique (leave-one-out), and were tested on the remaining 15 patients. These models were based on 5 of the 40 variables associated with a significant discriminatory function. Pancreatic adenocarcinoma was diagnosed in the training data set of 34 patients during a leave-one-out process with an estimated sensitivity of 91% and specificity of 87%. Both sensitivity and specificity were 80% in the independent test set of 15 patients. We conclude that inflammatory and malignant pancreatic epithelia exhibit distinct morphological features that can be distinguished by decision tree-based classifiers employing image-cytometric numerical data.

Adenocarcinoma↗
PubMed1978

Interference in word associations in schizophrenia.

Assessed the effect of response interference on the word associations of male and female process and reactive schizophrenics in two studies that used the difference in associative disturbances between high and low interference (low and high commonality stimulus words) as the measure. The reactives showed a significantly greater increase in disturbances in the high interference condition than did process schizophrenics in both studies. These results occurred in process and reactive groups that did not differ in age, IQ, institutionalization, and current level of physiological arousal and symptom severity in Study I. Findings supported predictions from a qualitative differences theory of cognitive deficit in schizophrenia.

Antipsychotic Agents↗
PubMed1995

Neuropsychological characteristics of parkinsonian patients with lateralized motor impairment.

Parkinsonians with predominantly unilateral signs provide an interesting experimental means to evaluate if asymmetric nigro-striatal degeneration may affect neuropsychological functions. The aim of our study was to establish if the side of onset of idiopathic Parkinson's disease, right (PDR) or left (PDL), determines a selective pattern of cognitive performances. Furthermore, we verified if PDR and PDL groups show a different frequency of dementia. PDR and PDL patients with at least seven years of disease duration, matched for age, schooling, severity of extrapyramidal symptomatology and index of lateralization, were evaluated by using an extensive neuropsychological battery aimed at assessing hemispheric cognitive asymmetries. Current side of greater motor impairment was the same as the one affected at the onset of the disease. Only subtle differences in the profile of neuropsychological dysfunction emerged from the comparison of PDR and PDL subjects. Moreover, the number of parkinsonians showing dementia syndrome was the same in both groups. Our results suggest that the side of onset of motor impairment does not significantly influence the cognitive performances in PD. Subcortical anatomic and/or functional asymmetries seem to play a less important role in the intellectual functions than in motor activities.

Aged↗
PubMed1994

Will the Nineties Be the Decade We Lost the Battle Against Drug-Resistant Microbes?

Antimicrobial resistance is reaching epidemic proportions. Bacteria have developed an impressive array of defenses to protect themselves against potent compounds. The widespread emergence of resistance has complicated the treatment of infections due to Staphylococcus, Streptococcus, Enterococcus, Neisseria, Haemophilus, gram-negative enteric bacilli, and Pseudomonas. Multidrug-resistant tuberculosis poses a grave public health problem, particularly among the homeless and those infected with HIV. HIV resistance to nucleoside analogs such as zidovudine is increasingly common and seriously threatens their clinical usefulness. It is apparent that simply producing new drugs is not a viable solution to the resistance crisis. Rational use of existing antimicrobial agents is vital, and combination regimens must be intelligently deployed. State-of-the-art molecular epidemiology will aid in the detection, analysis, and termination of resistance epidemics. Control of drug-resistant Mycobacterium tuberculosis will require appropriate initial treatment regimens, proper therapeutic modification using the latest susceptibility testing methods, and strong emphasis on measures ensuring compliance. HIV resistance is a challenging problem, and novel strategies will be necessary to combat it. Recognition that drug resistance among bacteria and viruses is a rapidly growing threat worldwide is an important first step toward finding effective long-term solutions.

Journal Article↗
PubMed1985

Photosensitive epilepsy.

Although epilepsy remains an unsolved medical problem, there is a type of epilepsy known as 'photosensitive epilepsy' described in the medical literature that could serve as the window to understanding the pathophysiology of all epilepsies. Photosensitive epilepsy is a seizure phenomenon caused by exposure to bright and/or flickering light. This type of epilepsy has been estimated to occur in one of every 10,000 people. The nurse's role in this pathological state includes meticulous notations of seizure activity, adverse medication reactions, and psychological assessment of the photosensitive epileptic client.

Adolescent↗
PubMed1992

Amyloid beta protein precursors with kunitz-type inhibitor domains and acetylcholinesterase in cerebrospinal fluid from patients with dementia of the Alzheimer type.

We used the ELISA to measure the concentration of amyloid protein precursor with Kunitz type trypsin inhibitor domains (APPI) in CSF of dementia of the Alzheimer type (DAT) and examined the correlation of APPI with acetylcholinesterase (AChE) and somatostatin (SRIF). We found the APPI concentration in CSF of DAT to be significantly elevated compared with that of multi-infarct dementia and controls. We could significantly correlate APPI with AChE, but not correlate APPI with SRIF. The present results suggest that measurement of CSF APPI levels may be useful for diagnosis of DAT and the change of APPI may closely be associated with abnormality of acetylcholine system in DAT that has been reported.

Acetylcholinesterase↗
PubMed1997

Longitudinal study of behavioral and affective patterns in girls with central precocious puberty during long-acting triptorelin therapy.

The aim of the present study was to evaluate the behavioral and affective characteristics and the changes in psychosocial functioning resulting from precocious puberty in 15 girls with central precocious puberty treated for 2 y using the GnRH agonist long-acting triptorelin, and in 5 untreated girls. After diagnosis of precocious puberty at 6.6-10.4 y of age, height, weight and pubertal development were evaluated at 3-month intervals over 2 y. Semi-structured interviews were carried out with the patient, the parents and the pediatric endocrinologists at 1, 8, 16 and 24 months after diagnosis. Standardized questionnaires (Child Behavior Checklist, Self-esteem Inventory) were administered at 1 and 24 months or 16 and 24 months, respectively. There was a mean 1.5-y delay between the observation of signs of puberty as reported by the parents and the diagnosis of precocious puberty at the first consultation of a pediatric endocrinologist. Before follow-up, all 20 girls were very concerned about physical differences from peers, particularly breast development. During therapy, breast regression to minimal or absent development occurred in 5/15 treated patients, who then no longer felt embarrassed about pubertal development in contrast to the other patients. Fear of sexuality remained obvious throughout the study in most patients. Feelings of loneliness and exemplary behavior were observed and tended to decrease in the treated patients and to increase in the untreated patients. Elevated scores of withdrawal, anxiety/depression and somatic complaints at Child Behavior Checklist were still observed after 2 y. These changes in behavioral and affective characteristics appeared to be related neither to height and weight, nor to development of pubic hair, which progressed in most patients. After 2 y, the physical differences remained a concern for 13 girls and the risk of short adult stature for 6. In summary, some behavioral and affective characteristics and particularities in psychosocial functioning are observed in girls with precocious puberty. During treatment with long acting triptorelin, problematic behavior and functioning decrease slightly, particularly in the few girls showing breast regression to minimal or absent development.

Affect↗
PubMed1988

Intellectual impairment in Parkinson's disease: clinical, pathologic, and biochemical correlates.

The prevalence of overt dementia in 27 studies representing 4,336 Parkinson's disease (PD) patients was 39.9%. The studies reporting the highest incidence of intellectual impairment (69.9%) used psychologic assessment techniques, whereas studies identifying the lowest prevalence of dementia (30.2%) depended on nonstandardized clinical examinations. Neuropsychologic investigations reveal that PD patients manifest impairment in memory, visuospatial skills, and set aptitude. Language function is largely spared. Intellectual deterioration in PD correlates with age, akinesia, duration, and treatment status. Neuropathologic and neurochemical observations demonstrate that PD is a heterogeneous disorder: the classic subcortical pathology with dopamine deficiency may be complicated by atrophy of nucleus basalis and superimposed cortical cholinergic deficits, and a few patients have the histopathologic hallmarks of Alzheimer's disease. Mild intellectual loss occurs with the classic pathology, and the more severe dementia syndromes have cholinergic alterations or Alzheimer's disease. Thus, PD includes several syndromes of intellectual impairment with variable pathologic and neurochemical correlates.

Aged↗
PubMed2000

Potential savings in the cost of caring for Alzheimer's disease. Treatment with rivastigmine.

OBJECTIVE: To estimate savings in the cost of caring for patients with Alzheimer's disease (AD) during 6 months, 1 year and 2 years of treatment with rivastigmine. An intermediate objective was to estimate the relationship between disease progression and institutionalisation. DESIGN AND SETTING: We assessed the relationship between Mini-Mental State Examination (MMSE) score and institutionalisation using a piecewise Cox proportional hazard model. To estimate cost savings from treatments lasting 6 months, 1 year and 2 years, estimates of the probability of institutionalisation were integrated with data from two 6-month phase III clinical trials of rivastigmine and a hazard model of disease progression. MAIN OUTCOME MEASURES AND RESULTS: Our data suggest that savings in the overall cost of caring for patients with mild and moderate AD can be as high as $US4839 per patient after 2 years of treatment. Furthermore, the probability of institutionalisation increases steadily as MMSE score falls. Among our study individuals, age, race, level of education and marital status were significant predictors of institutionalisation, whereas gender had little effect. CONCLUSIONS: Using rivastigmine to treat AD results in a delay in disease progression for patients who begin treatment during the mild or moderate stages of the disease. By delaying the probability that a patient will be institutionalised, the cost of caring for AD patients can be significantly reduced.

Aged↗
PubMed2000

A neural network based virtual high throughput screening test for the prediction of CNS activity.

A virtual high throughput screening test to identify potentially CNS-active drugs has been developed. Discrimination was based on the knowledge available in databases containing CNS-active (Cipsline from Prous Science) and inactive compounds (Chemical Directory from Sigma-Aldrich). Molecular structures were represented using 2D Unit y fingerprints and a feedforward neural network was trained to classify molecules regarding their CNS activity. The parameterized network was validated by reclassification of the training set elements, by the classification of a test set preselected from the Prous database, and also by the prediction of activity for known CNS drugs not used in the training set but available in the Medchem database (Daylight). These tests revealed that our neural net recognized at least 89% of CNS-active compounds and would be suitable for use in our virtual screening protocol.

Artificial Intelligence↗
PubMed1998

Reversibility of functionally injured neurotransmitter systems with shunt placement in hydrocephalic rats: implications for intellectual impairment in hydrocephalus.

UNLABELLED: Intellectual impairment has been related to alteration of neuronal innervation in the following regions: cholinergic basal forebrain nuclei (Ch1-Ch6, learning and memory), dopaminergic ventral tegmental area (emotional control), and noradrenergic locus ceruleus (cognition). Recent studies have implicated neuronal injury in the pathogenesis of hydrocephalus. OBJECT: The authors used immunohistochemical techniques to investigate functional injury in these regions in animals with progressive hydrocephalus, following shunt placement for cerebrospinal fluid (CSF) drainage. METHODS: Hydrocephalus was induced in 20 Wistar rats by intracisternal injection of 0.05 ml of 25% kaolin solution. Four control animals (Group 1) received the same volume of saline. Ventriculoperitoneal shunts were inserted in eight rats at 2 and 4 weeks after kaolin injection and the animals were killed at 8 weeks (Group 2). The other 12 hydrocephalic animals were killed at 2, 4, and 8 weeks without undergoing shunt placement (Group 3). Immunoreactive (IR) neurons to choline acetyltransferase (ChAT) in Ch1-Ch6, tyrosine hydroxylase (TH) in the ventral tegmental area, and dopamine B-hydroxylase (DBH) in the locus ceruleus, as well as IR projection fibers in the terminal areas, were compared between groups. The number of ChAT- and TH-IR neurons in rats with and without shunt placement was counted for quantitative analysis. The number of ChAT-IR neurons was progressively reduced during the development of hydrocephalus in Ch1, Ch2, Ch3, and Ch4 (p < 0.05). Tyrosine-hydroxylase-immunoreactive neurons were also reduced in number, and demonstrated decreased projection fibers and terminals. Early shunting (at 2 weeks) restored ChAT and TH immunoreactivity to control levels, but late shunting (at 4 weeks) did not (p < 0.05). The DBH-IR neurons in the locus ceruleus were remarkably compressed by the dilated fourth ventricle, and diminished immunoreactivity was observed in the terminal areas. Shunt placement for CSF also restored the immunoreactivity in this system. CONCLUSIONS: These findings indicate that a progressive functional injury occurs in the cholinergic, dopaminergic, and noradrenergic systems as a result of hydrocephalus. This may contribute to intellectual impairment and might be prevented by early treatment with shunt placement.

Animals↗