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PubMed1994

Cytotoxic evaluation of some 3,5-diarylidene-4-piperidones and various related quaternary ammonium compounds and analogs.

A number of 3,5-diarylidene-4-piperidones (1) and some related quaternary ammonium salts (5) as well as closely related analogs were prepared principally as candidate cytotoxic agents in two screens. The first test system used an average of 54 human tumor cell lines from eight neoplastic diseases, namely leukemia, melanoma, colon, non-small-cell lung, small-cell lung, central nervous system, ovarian, and renal cancers. Selective toxicity was demonstrated by some of the compounds, especially toward leukemia. The second screen used L1210 lymphoid leukemia cells. In general, the compounds were less cytotoxic than the reference drug melphalan in both screens. Linear plots were made between the Hammett (sigma), fragment (f), and molar refractivity (MR) constants of the nuclear substituents in series 1 and 5 with the IC50 figures of both the human tumor cell lines and L1210 cells. Evaluation against the human tumor cell lines revealed that increases in the f values were correlated with elevation of cytotoxicity in both series 1 and 5; MR constants were also important in series 5. In the L1210 screen, sigma and MR constants were positively correlated with cytotoxicity. X-ray crystallography was undertaken on 3,5-bis-[[4'-(methylthio)phenyl]methylene]-1-methyl-4-piperidone methiodide (5d), which had significant cytotoxicity, and 3,5-bis(4-pyridylmethylene)-1-methyl-4-piperidone methiodide (6), which was virtually inactive in both screens.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1998

Designer drugs: the evolving science of drug discovery.

Drug discovery and design are fundamental to drug development. Until recently, most drugs were discovered through random screening or developed through molecular modification. New technologies are revolutionizing this phase of drug development. Rational drug design, using powerful computers and computational chemistry and employing X-ray crystallography, nuclear magnetic resonance spectroscopy, and three-dimensional quantitative structure activity relationship analysis, is creating highly specific, biologically active molecules by virtual reality modeling. Sophisticated screening technologies are eliminating all but the most active lead compounds. These new technologies promise more efficacious, safe, and cost-effective medications, while minimizing drug development time and maximizing profits.

Biotechnology↗
PubMed1998

[Virtual colonoscopy using CT and MRI].

PURPOSE: To evaluate experimentally and in patients the sensitivity and effective dose of virtual electron-beam tomography (EBT) colonoscopy for detecting small colon tumors and to compare the methods and results with virtual colonoscopy using spiral CT and MR imaging in a review of the literature. MATERIALS AND METHODS: Six polyps with diameters between 3 and 12 mm were created and randomly placed in resected pig colon. After distension with air, the pig colon was scanned with continuous volume scanning (CVS, 3 mm collimation) and a pitch of 0.4, 0.8 and 1.5. Twenty patients positive for the fecal blood test were examined after rectal CO2 insufflation and i.v. administration of 1 mg glucagon. A 13 s CVS scan was used to cover the entire colon within one breath-hold. 3D volume-rendered fly-throughs were evaluated by two independent radiologists. Effective dose equivalent was estimated using an Alderson phantom equipped with thermoluminescence dosimeters. RESULTS: In the tumor model, all polyps were detectable at a pitch of 1.5. A further reduction of the pitch ratio did not improve the conspicuity of the polyps. In patient studies, all tumors (n = 4) and polyps (n = 3) were correctly identified on 3D fly-throughs. Two false positive results were obtained. Effective dose equivalent was calculated at 3.2 mSv per scan. CONCLUSIONS: Our preliminary results indicate that virtual EBT colonoscopy holds promise for fast screening for colon polyps. The best technique for virtual colonoscopy (Spiral CT, EBT, MRI) has not yet been determined and the future role of virtual colonoscopy must still be defined.

Colonic Polyps↗
PubMed1996

Impact of a mailed intervention on annual mammography and physician breast examinations among women at high risk of breast cancer.

Only a few studies have examined repeat annual mammography rates, and most studies find that such regularity is low, ranging from < 5% in the general population to between 14 and 20% of first-degree relatives. The present study tested the effectiveness of a mailed intervention designed to improve compliance with breast cancer screening guidelines among women at elevated familial risk. The study used a pretest-posttest control group design; 369 twin sisters of breast cancer cases were assigned alternately to an intervention or a control group on the basis of sequential registration numbers. The intervention consisted of written materials, an audiotape, and mailed reminders. The posttest was mailed 2.5 years after the intervention in order to provide adequate time to assess the regularity of screening. The intervention and control groups were virtually identical with respect to demographic and baseline screening characteristics. Of those who returned the follow-up questionnaire, annual physician breast examinations were 12.8% higher and annual mammograms were 10.3% higher in the intervention group than in the control group. The probability of annual screening with physician breast examination and mammography was higher in the intervention group, and the probability of annual mammography continued to be higher for women over age 52 years after controlling for baseline screening, year of diagnosis, education, and status of the twin. This result is consistent with improvements found in other studies. Women who did not return follow-up questionnaires were more likely to have had fewer physician breast examinations and mammograms and more likely to be in the intervention group than those who stayed in the study. Additionally, those who dropped out of the intervention arm perceived themselves to be less susceptible and perceived screening to be less effective than did those who dropped out of the control arm. Although the intervention caused many women to be screened more regularly, those who had not been screened in the past and those who held opinions that were not conducive to screening were more likely to drop out. This mailed intervention for high-risk women increased their rate of screening. Characteristics of women resistant to such programs have been identified; alternative strategies need to be developed to reach this small percentage of high-risk women who ignore their elevated susceptibility.

Adult↗
PubMed1998

Variants in the alpha2A AR adrenergic receptor gene in psychiatric patients.

In various studies of psychiatric patients, alterations in adrenergic receptor (AR) expression or function have been suggested. Herein, the alpha2A AR gene was screened in 206 patients with schizophrenia, attention deficit hyperactivity disorder (ADHD), autism, alcohol dependence, or cocaine dependence. The entire coding region was examined for single base pair changes, using restriction endonuclease fingerprinting (REF), a screening method that can detect virtually 100% of mutations in 2-kb DNA segments. In the approximately 600 kb of screened sequence, six novel nucleotide changes were identified. The changes resulted in four missense changes (A25G, N251K, R368L, and K370N), and a sequence in the 3' untranslated region. In addition, a silent change (G363G) was found at high frequency in Asians and Native Americans. Of the four missense changes, two found in patients with alcohol/drug dependence occur in highly conserved amino acids, suggesting that these are of likely functional significance. As the alpha2A ARs are widely distributed both pre- and postsynaptically, and as many pharmacological agents with multiple effects target these receptors, the novel missense changes described herein may be candidates for involvement in alcohol/drug dependence, in other clinical disorders or traits, or in differential response to pharmacotherapy.

Animals↗
PubMed1993

HTLV-I among Northern Territory blood donors.

OBJECTIVE: Human T-lymphotropic virus type I (HTLV-I) is known to be endemic among Northern Territory (NT) Aborigines, therefore evidence was sought of HTLV-I infection in NT blood donors. DESIGN: Samples were screened for HTLV-I antibodies using the Serodia HTLV-I particle-agglutination assay. Repeatedly reactive sera were tested by western blot. Viro- logical and molecular investigations were also performed. SERA: Aliquots from all 11,121 blood donations collected between June 1991 and August 1992. RESULTS: Four (0.036% of total) blood donations, each from different donors, were repeatedly reactive by particle-agglutination assay. One (0.009%) sample, from a 52-year-old non-Aboriginal man with no verified risk factors, was confirmed as HTLV-I seropositive by western blot. A viral isolate and a 431 base pair polymerase chain reaction product from the env gene were obtained from a culture of his peripheral blood mononuclear cells. Sequencing of the polymerase chain reaction product demonstrates that this isolate is a prototype strain and not the variant identified among Aborigines. The remaining three repeatedly reactive donors, including the positive donor's wife, were western blot indeterminate. CONCLUSIONS: There is a low prevalence of HTLV-I carriage among blood donors in the NT, and presumably in other States. However, most repeatedly reactive donations prove to be western blot indeterminate, therefore additional tests are required to detect or exclude HTLV-I infection. Although universal screening of donations would virtually eliminate HTLV-I transmission by transfusion, it has disadvantages, including financial cost.

Adult↗
PubMed2006

Walking from thought.

Online analysis and classification of single electroencephalogram (EEG) trials during motor imagery were used for navigation in the virtual environment (VE). The EEG was recorded bipolarly with electrode placement over the hand and foot representation areas. The aim of the study was to demonstrate for the first time that it is possible to move through a virtual street without muscular activity when the participant only imagines feet movements. This is achieved by exploiting a brain-computer interface (BCI) which transforms thought-modulated EEG signals into an output signal that controls events within the VE. The experiments were carried out in an immersive projection environment, commonly referred to as a "Cave" (Cruz-Neira, C., Sandin, D.J., DeFanti, T.A., Surround-screen projection-based virtual reality: the design and implementation of the CAVE. Proceedings of the 20th annual conference on Computer graphics and interactive techniques, ACM Press, 1993, pp. 135-142) where participants were able to move through a virtual street by foot imagery only. Prior to the final experiments in the Cave, the participants underwent an extensive BCI training.

Adult↗
PubMed1997

Virtual reality for the treatment of autism.

Autism is a mental disorder which has received attention in several unrelated studies using virtual reality. One of the first attempts was to diagnose children with special needs at Tokyo University using a sandbox playing technique. Although operating the computer controls proved to be too difficult for the individuals with autism in the Tokyo study, research at the University of Nottingham, UK, is successful in using VR as a learning aid for children with a variety of disorders including autism. Both centers used flat screen computer systems with virtual scenes. Another study which concentrated on using VR as a learning aid with an immersive headset system is described in detail in this chapter. Perhaps because of the seriousness of the disorder and the lack of effective treatments, autism has received more study than attention deficit disorders, although both would appear to benefit from many of the same technology features.

Autistic Disorder↗
PubMed2002

[Virtual colonoscopy].

Colorectal cancer is a leading cause of cancer death in the western world. Virtual colonoscopy is a new method for 2-D and 3-D imaging of the colon, using a multislice helical CT technology. This method has already demonstrated excellent results in polyp and cancer detection, having similar accuracy to endoscopic colonoscopy in the detection of polyps above 6 mm in size. The major application of this novel technique is in diagnosing cases where conventional colonoscopy fails to demonstrate the entire colon due to technical problems. The second important application is to investigate the colon proximal to an obstructing tumor, where both barium enema and colonoscopy cannot overcome the obstruction. The possibility of widespread application remains in evaluating the use of virtual colonoscopy in a purely screening population. Further developments, including stool tagging, computer aided detection of polyps and faster scanners will contribute to accuracy and patient compliance with widespread use of virtual colonoscopy. This examination may dramatically improve population participation in screening programs and play a major role in minimizing the impact of colorectal cancer.

Colonic Polyps↗
PubMed2003

Modulating the experience of agency: a positron emission tomography study.

This study investigated agency, the feeling of being causally involved in an action. This is the feeling that leads us to attribute an action to ourselves rather than to another person. We were interested in the effects of experimentally modulating this experience on brain areas known to be involved in action recognition and self-recognition. We used a device that allowed us to modify the subject's degree of control of the movements of a virtual hand presented on a screen. Four main conditions were used: (1) a condition where the subject had a full control of the movements of the virtual hand, (2) a condition where the movements of the virtual hand appeared rotated by 25 degrees with respect to the movements made by the subject, (3) a condition where the movements of the virtual hand appeared rotated by 50 degrees, and (4) a condition where the movements of the virtual hand were produced by another person and did not correspond to the subject's movements. The activity of two main brain areas appeared to be modulated by the degree of discrepancy between the movement executed and the movement seen on the screen. In the inferior part of the parietal lobe, specifically on the right side, the less the subject felt in control of the movements of the virtual hand, the higher the level of activation. A reverse covariation was observed in the insula. These results demonstrate that the level of activity of specific brain areas maps onto the experience of causing or controlling an action. The implication of these results for understanding pathological conditions is discussed.

Adult↗
PubMed2004

Ligand.Info small-molecule Meta-Database.

Ligand.Info is a compilation of various publicly available databases of small molecules. The total size of the Meta-Database is over 1 million entries. The compound records contain calculated three-dimensional coordinates and sometimes information about biological activity. Some molecules have information about FDA drug approving status or about anti-HIV activity. Meta-Database can be downloaded from the http://Ligand.Info web page. The database can also be screened using a Java-based tool. The tool can interactively cluster sets of molecules on the user side and automatically download similar molecules from the server. The application requires the Java Runtime Environment 1.4 or higher, which can be automatically downloaded from Sun Microsystems or Apple Computer and installed during the first use of Ligand.Info on desktop systems, which support Java (Ms Windows, Mac OS, Solaris, and Linux). The Ligand.Info Meta-Database can be used for virtual high-throughput screening of new potential drugs. Presented examples showed that using a known antiviral drug as query the system was able to find others antiviral drugs and inhibitors.

Databases, Genetic↗
PubMedDate not supplied

Data shaving: a focused screening approach.

The number of compounds available for evaluation as part of the drug discovery process continues to increase. These compounds may exist physically or be stored electronically allowing screening by either actual or virtual means. This growing number of compounds has generated an increasing need for effective strategies to direct screening efforts. Initial efforts toward this goal led to the development of methods to select diverse sets of compounds for screening, methods to cluster actives into related groups of compounds, and tools to select compounds similar to actives of interest for further screening. In this work we extend these earlier efforts to exploit information about inactive compounds to help make rational decisions about which sets of compounds to include as part of a continuing screening campaign, or as part of a focused follow-up effort. This method uses the information from inactive compounds to "shave" off or deprioritize compounds similar to inactives from further consideration. This methodology can be used in two ways: first, to provide a rational means of deciding when sufficient compounds containing certain structural features have been tested and second as a tool to enhance similarity searching around known actives. Similarity searching is improved by deprioritizing compounds predicted to be inactive, due to the presence of structural features associated with inactivity.

Journal Article↗
PubMed1994

The Canadian National Breast Screening Study: a perspective on criticisms.

Recently published 7-year results from the Canadian National Breast Screening Study (NBSS) generated much controversy and criticism. In women aged 40 to 49 years at entry, no reduction in breast cancer mortality was observed when screened women were compared with virtually unscreened women. In women aged 50 to 59 years, breast cancer mortality was similar when annual screening with mammography and physical examination was compared with annual screening with physical examination alone. Although NBSS results in 40- to 49-year-old women are similar to those from previously published screening studies, critics have attacked the study's design, randomization, execution, mammography, follow-up procedures, contamination of controls, and analysis. The absence of benefit observed in mammographically screened women who were 50 to 59 years old has been used to support criticism of mammography. Important facts have been ignored. The NBSS controls, aged 50 to 59 years, unlike in other studies, received thorough annual physical examinations. Cancer detection rates in both age groups were higher in the mammography than the comparison groups. Screen and interval cancer detection rates, sensitivity and specificity estimates, and prevalence to incidence ratios at first screen met or exceeded standards established by other screening studies. Claims that randomization was flawed, in particular, that more symptomatic women were assigned to mammography, are not supported by the distribution of descriptive variables collected before randomization was done. As for the "contamination" of 26% of controls aged 40 to 49 years, who reported receiving mammography, it is improbable that single or occasional diagnostic mammograms in one quarter of the control group could obliterate the benefit of four or five annual mammograms in almost 100% of the mammography group. Much remains unknown about the efficacy of breast screening.

Adult↗
PubMedDate not supplied

The virtual mole clinic: preliminary results from the Plymouth skin cancer screening study using telemedicine.

This study evaluated a skin cancer screening service between primary and secondary care in Plymouth using a store and forward telemedicine system. The primary objective was to minimize the time from a patient presenting to a GP with a suspicious lesion to the lesion being assessed and diagnosed by a plastic surgeon. This study retrospectively assessed the practical, technical and operational aspects of incorporating telemedicine into everyday practice and patient satisfaction. Both the GP practice and plastic surgeons were equipped with the appropriate technology for creating, transmitting and accessing an electronic telemedicine record (ETR) via an ISDN 2 line. Patients with suspicious lesions accessed the GP via Mole Check Clinics. The GP captured and transmitted an ETR consisting of digital images and relevant clinical data. In a virtual mole clinic, the plastic surgeon accessed and reviewed the ETR. The expert opinion was entered directly into the ETR and transmitted to the GP within 48 hours. All patients were offered a face-to-face consultation at a real mole clinic within 7 days. Outcomes demonstrated patient and clinician satisfaction and the ability to deliver high quality diagnostic images and resulting expert opinion. This study informed a larger study for future applications of telemedicine.

Humans↗
PubMed2000

[Prevention of colorectal carcinoma. Annual hemoccult test and sigmoidoscopy every 5 years].

The slow development of colorectal carcinoma from adenoma over dysplastic state to malignancy within 10-15 years results in a long preclinical phase during which the tumor is readily detectable and curable. Therefore and because of the lack of early alerting signs colorectal cancer is highly suited to screening. The faecal occult blood test has been added to the yearly program of cancer prevention for each individual age 45 and higher. This test has been evaluated in controlled prospective trials. For several reasons the combination of faecal occult blood test with flexible sigmoidoscopy at five year intervals is recommended. Concerning colonoscopy as a screening test to date no data from controlled trails are available. Virtual colonoscopy and gene-based screening which are currently being developed may be future options.

Aged↗
PubMed2002

Reliability of MR imaging-based virtual cystoscopy in the diagnosis of cancer of the urinary bladder.

OBJECTIVE: Our purpose was to evaluate MR imaging-based virtual endoscopy in patients with urinary bladder cancer compared with conventional cystoscopy as the gold standard. SUBJECTS AND METHODS: Twenty-five patients with urinary bladder cancer diagnosed on conventional cystoscopy underwent MR imaging of the pelvis. Patients were examined without external bladder filling or administration of IV contrast medium. No medications were administered. The data obtained by MR imaging were reconstructed for virtual endoscopy on a workstation. The locations and sizes of tumors were individually determined and compared with results of conventional cystoscopy. RESULTS: Twenty-four patients were evaluated; one patient's examination was excluded from analysis because of metallic artifacts. Seventeen patients were diagnosed with a single bladder tumor. Five patients had two tumors each, and two patients had three tumors. Tumor diameter ranged from 0.4 to 6.4 cm. Thirty (90.9%) of 33 tumors detected on cystoscopy were visualized with virtual endoscopy. The detection rate for 23 tumors of 1 cm or greater was 100%. Difficult conditions for conventional cystoscopy, including hematuria, anterior wall involvement, and urethral strictures, had no deleterious impact on virtual cystoscopy. Difficulties in detection on virtual endoscopy were associated with flat bladder tumors with minimal surface elevation. CONCLUSION: The results of this study suggest a high reliability in the diagnosis of urinary bladder cancer by MR imaging-based virtual cystoscopy-a noninvasive method, independent of medication or contrast enhancement, that may be of value for screening, primary diagnosis, and surveillance. Virtual MR cystoscopy may be indicated when conventional cystoscopy cannot be performed or is ineffective.

Aged↗
PubMed2003

Applicability of traditional and revised models of psychopathy to the Psychopathy Checklist: screening version.

Recently, psychopathy has become virtually synonymous with the Psychopathy Checklist (PCL) measures. However, the "gold standard" 2-factor model that underlines these measures has been questioned for its uncertain empirical support and emphasis on antisocial behavior that is not specific to psychopathic personality deviation. This study (N = 870 civil psychiatric patients) compares the fit of the traditional 2-factor model with that of a revised 3-factor model of psychopathy. The revised model better describes the structure of the Screening Version of the PCL (PCL:SV) than the traditional model. Although the revised model's exclusion of some items that assess antisocial behavior reduces the PCL:SV's power in predicting patient violence, this model arguably assesses psychopathy in a more specific, theoretically coherent fashion that may reduce misapplications of the construct. Implications for future research are discussed.

Adult↗
PubMed2005

Diffusion NMR spectroscopy in supramolecular and combinatorial chemistry: an old parameter--new insights.

Intermolecular interactions in solution play an important role in molecular recognition, which lies at the heart of supramolecular and combinatorial chemistry. Diffusion NMR spectroscopy gives information over such interactions and has become the method of choice for simultaneously measuring diffusion coefficients of multicomponent systems. The diffusion coefficient reflects the effective size and shape of a molecular species. Applications of this technique include the estimation of association constants and mapping the intermolecular interactions in multicomponent systems as well as investigating aggregation, ion pairing, encapsulation, and the size and structure of labile systems. Diffusion NMR spectroscopy can also be used to virtually separate mixtures and screen for specific ligands of different receptors, and may assist in finding lead compounds.

Combinatorial Chemistry Techniques↗