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PubMed1984

In vitro cytotoxicity assays. Potential alternatives to the Draize ocular allergy test.

A short-term cytotoxicity assay carried out in multiwell test plates and a supplementary colony forming assay are both useful for screening and range finding of toxic concentrations of test agents. The highest tolerated dose (HTD), a concentration at which only minimal morphological changes were observed, was designated as endpoint in the assay. Epithelial rabbit cornea cells, murine fibroblasts, Chinese hamster lung cells, human hepatoma cells and mouse macrophage cultures were used as targets. Several of the alcohols tested at HTD in the colony forming assay were found to inhibit colony formation. An ID50 of colony formation was used as a quantitative corroborating test. The ranking of 34 toxicants was found to be virtually the same with all cell types examined. This easily reproducible, rapid in vitro test is cost-effective and can be used for preliminary large scale screening of potential toxicants.

Animal Testing Alternatives↗
PubMed2005

An fMRI study of the Trail Making Test.

This study investigated the cerebral correlates of the Trail Making Test (TMT), used commonly as a measure of frontal lobe function. Such work sheds additional light on the known shortcomings of the TMT as a localizing instrument, as indicated, for example, by studies of patients with focal brain lesions. Functional magnetic resonance imaging (fMRI) was used to record brain activity while participants performed the TMT using a custom-built, fiber-optic fMRI-compatible writing device, the "virtual stylus". Unlike in a previous fMRI study that used a verbal adaptation of the TMT, the virtual stylus enabled a closer depiction of the brain regions engaged by the actual paper-and-pencil task. Twelve, right-handed healthy young adults participated. In Part A of the task, participants were required to link in ascending order numbers (1-2-3 ...) that were randomly distributed on a computer screen. In Part B, participants were required to link alternately between numbers and letters (1-A-2-B ...). Although behavioral performance was somewhat less than typically obtained with the TMT due to use of the virtual stylus, distinct left-sided dorsolateral and medial frontal activity was revealed when comparing Part B versus Part A. These findings agree with existing literature showing sensitivity of the TMT to frontal regions in the left hemisphere. However, other activity was also observed (left middle and superior temporal gyrus) reinforcing that the brain-behavior correlations for the TMT are multifaceted and not restricted to the frontal lobe.

Adult↗
PubMed2003

A prospective randomized trial comparing a virtual reality simulator to bedside teaching for training in sigmoidoscopy.

BACKGROUND AND STUDY AIMS: Clinical investigation using endoscopy simulators is now possible due to recent advances in virtual reality technology. A prospective randomized trial was conducted to compare the exclusive use of a virtual reality endoscopy simulator with bedside teaching for training in sigmoidoscopy. MATERIALS AND METHODS: Internal medicine residents were randomly assigned to training exclusively using a virtual reality simulator (group 1) or via bedside teaching (group 2). Residents were then observed performing five sigmoidoscopic procedures in asymptomatic patients referred for colorectal cancer screening. Endoscopic examinations were evaluated for procedure duration, completion, ability to perform retroflexion, and level of patient comfort/discomfort. Each examination was scored from 1 (inability to insert the endoscope beyond the rectum) to 5 (able to complete the entire examination independently in less than 20 min). RESULTS: Sixty-six sigmoidoscopic examinations were completed by nine residents in group 1 (simulator-trained group) and seven residents in group 2 (traditional teaching group). Participants in group 1 had more difficulty with initial endoscope insertion and negotiation of the rectosigmoid junction (mean score +/- SEM 2.9 +/- 0.2) than those in group 2 (3.8 +/- 0.2) ( P < 0.001). The splenic flexure was reached independently in 10 of 34 examinations (29 %) in group 1, compared with 23 of 32 examinations (72 %) in group 2 ( P = 0.001). Retroflexion was successfully performed by 19 of 34 (56 %) in group 1 compared to 27 of 32 (84 %) in group 2 ( P = 0.02). The average procedure time, patient satisfaction, and discomfort associated with the procedure did not differ statistically between the two groups. CONCLUSIONS: The use of a state-of-the-art virtual reality-based endoscopy simulator is inferior to traditional bedside teaching techniques when used exclusively for training medical residents to perform sigmoidoscopy.

Adult↗
PubMed2004

Rapid detection of common CARD15 variants in patients with inflammatory bowel disease.

BACKGROUND: Three mutations (R702W, G908R, and 1007fs) within the CARD15 gene have been identified as independent risk factors for the development of Crohn's disease (CD). Virtually all studies investigating the occurrence of these mutations in patients with CD have used separate PCR-based methods to screen patient DNA, here we describe a novel multiplex amplification refractory mutation system (ARMS) assay that allows the simultaneous detection of R702W, G908R, and 1007fs, and a fourth CARD15 variant, P268S, at a fraction of the cost of the pre-existing genotyping assays. METHODS: Allele-specific primer sets were designed for each CARD15 variant, optimized separately for annealing temperature and MgCl2 and then multiplexed. The mutant- and wild-type-specific primers were split across two tubes so that each multiplex reaction was internally controlled for amplification failure. An additional primer pair specific to beta2-microglobulin was included as an independent control for DNA quality. The specificity of each primer set was tested using positive controls that had been validated by sequencing, and the robustness of the final ARMS assay was assessed by genotyping 111 Caucasian patients with inflammatory bowel disease (IBD). RESULTS: The specificity of each primer set was confirmed using a sequence validated positive control for each of the four CARD15 variants. Of the 111 DNA samples screened with our ARMS assay, a clear CARD15 genotype was obtained for 109 patients. DISCUSSION AND CONCLUSIONS: Given the potential predictive value of R702W, G980R, and 1007fs, a robust genotyping method for these variants would be of considerable value both in diagnostic and research settings. Our ARMS assay only takes 3-4 hours to perform once DNA has been extracted and requires only 1U of Taq DNA polymerase, making it a rapid, reliable, and cost-effective alternative to current CARD15 genotyping methods.

DNA Mutational Analysis↗
PubMed1995

Incidence of photosensitive epilepsy: a prospective national study.

We undertook a prospective nationwide study to determine the incidence of photosensitive epilepsy (PE). Virtually all EEG departments in Great Britain (providing approximately 90% coverage of all EEGs performed on people with newly diagnosed seizures) screened cases referred to them over a 3 month period and identified all new cases of epilepsy (defined as one or more recognised seizures) whose first EEG showed a photoparoxysmal response (PPR) on intermittent photic stimulation (IPS). 191 cases were identified, 143 of whom had type 4 PPRs (generalised spike and wave on IPS) on their first EEG. The annual incidence of cases of epilepsy with type 4 PPRs on their first EEG was conservatively estimated to be 1.1 per 100,000, representing approximately 2% of all new cases of epilepsy. When restricted to the age range 7-19 years, the annual incidence rose to 5.7 per 100,000-approximately 10% of all new cases of epilepsy presenting in this age range. To ascertain if there was a significant seasonal variation in PE, 5 EEG departments (which together contributed 15% of cases in the first study period) were visited during a second 3 month study period to identify all new cases of epilepsy with type 4 PPRs on their first EEG. No significant seasonal variation in incidence between summer and winter was found.

Adolescent↗
PubMed1989

tctex-1: a candidate gene family for a mouse t complex sterility locus.

The t complex of the mouse has an important role in male germ cell development and function. Multiple mutations in the t complex interact to alter profoundly the transmission ratio of t complex-bearing sperm or to cause complete sterility or semisterility. We have isolated a multigene family, tctex-1, by screening a testicular cell cDNA library with two reciprocally subtracted testicular cDNA probes. The tctex-1 gene family produces an abundant, virtually germ cell-specific transcript that is 8-fold overexpressed in t homozygotes. The aberrant expression of tctex-1 is solely dependent on the t haplotype genes and occurs only in germ cells. The chromosomal location and pattern of expression of tctex-1 make it a candidate for involvement in male sterility.

Amino Acid Sequence↗
PubMed2006

Virtual colonoscopy in the detection of colonic polyps and neoplasms.

First introduced in 1994, CT colonography (Virtual colonoscopy) has emerged as an accurate, non-invasive test that will likely play a future role in colorectal cancer screening. Over the past 3 years, there have been dramatic improvements in both hardware and software technology relating to CT colonography resulting in shorter scan times, enhanced user-friendliness and improved performance statistics. Published results show the accuracy of CT colonography to be comparable to conventional colonoscopy for detection of polyps >6mm in size with few false-positives. While many of the technical aspects of CT colonography have now been standardised current interest focuses on the development of faecal tagging agents to avoid full bowel catharsis and the use of low dose multislice CT acquisition to reduce patient radiation exposure. This chapter will summarise the development of CT colonography to date, document its published performance in detection of colorectal polyps and cancers, and review its current and potential future uses.

Colonic Neoplasms↗
PubMed2006

Headaches in the pediatric population.

Headaches are an extremely common complaint encountered in the pediatric population. The headache history establishes the diagnosis in the vast majority and most importantly identifies features suggesting a secondary cause. The headache history outlined will aid in headache classification and screen for ominous causes. A comprehensive headache examination is aimed at excluding secondary causes. Headaches resulting from serious organic causes are virtually always associated with neurologic signs at the time of presentation. Investigations are not routinely required for pediatric headache, but neuroimaging should be strongly considered in children with an abnormal neurologic examination or history worrisome for intracranial pathology. The management approach for children with primary headaches should focus on reassurance and education. Developing an individualized therapeutic strategy requires knowledge of the child's headache-related disability and impact on quality of life. Treatment should begin with a nonpharmacologic approach, which influences lifelong prevention and management of headaches. Pharmacologic interventions target both acute symptomatic treatment and prophylactic medications. Preventative treatment may be beneficial when headaches result in significant disability and impaired quality of life. The limited available evidence for prophylactic treatment options is reviewed. Research into pediatric headache prevention and management remains a priority given the potential lifelong morbidity associated with headache.

Headache↗
PubMed1994

Transfusion-related transmissible diseases: detection by polymerase chain reaction-amplified genes of the microbial agents.

The detection of blood-borne microbes by PCR has broadly and rapidly progressed in the past 5 years as briefly described in this article. This progress has been largely because of the scientific developments made at Roche Molecular Systems by Sninsky et al through collaborations with academic and Government institutions. This unprecedented cooperation propels the continuing work at Roche Molecular Systems to bring the PCR technology into routine laboratory diagnosis. Whether the success of EIA in virtual elimination of hepatitis and retroviral infections can be matched by the cost-effectiveness of putative application of PCR in screening blood supply remains to be determined.

Bacterial Infections↗
PubMed2003

Isolation of mutations in the catalytic domain of the snf1 kinase that render its activity independent of the snf4 subunit.

Activation of the Snf1 kinase requires at least two events, phosphorylation of the activation loop on threonine 210 and an Snf4-dependent process that is not completely defined. Snf4 directly interacts with a region of the regulatory domain of Snf1 that may otherwise act as an autoinhibitory domain. In order to gain insight into the regulation of Snf1 kinase by Snf4, deletions in the regulatory domain of the catalytic subunit were engineered and tested for their effect on Snf1 function in the absence of Snf4. Deletion of residues 381 to 488 from the Snf1 protein resulted in a kinase that was activated by glucose limitation even in the absence of the Snf4 protein. A larger deletion (amino acids 381 to 608) encompassing virtually the entire regulatory domain resulted in complete inactivation of the Snf1 kinase even in the presence of Snf4. A genetic screen for amino acid substitutions that conferred an Snf4-independent phenotype identified four point mutations in the Snf1 catalytic domain. One very conservative mutation, leucine 183 to isoleucine, conferred nearly wild-type levels of Snf1 kinase function in the absence of the Snf4 protein. Purified Snf1 kinase was inactive when isolated from snf4Delta cells, whereas the Snf1-L183I kinase exhibited significant activity in the absence of Snf4. Our data support the idea that Snf1 kinase activity is constrained in cis by an autoinhibitory domain and that the Snf4-mediated activation of Snf1 can be bypassed by subtle conformational changes in the catalytic domain of the Snf1 kinase.

AMP-Activated Protein Kinases↗
PubMed2003

Effects of altering initial position on movement direction and extent.

The purpose of this study was to examine the relative influence of initial hand location on the direction and extent of planar reaching movements. Subjects performed a horizontal-plane reaching task with the dominant arm supported above a table top by a frictionless air-jet system. A start circle and a target were reflected from a horizontal projection screen onto a horizontally positioned mirror, which blocked the subject's view of the arm. A cursor, representing either actual or virtual finger location, was only displayed between each trial to allow subjects to position the cursor in the start circle. Prior to occasional "probe trials," we changed the start location of the finger relative to the cursor. Subjects reported being unaware of the discrepancy between cursor and finger. Our results indicate that regardless of initial hand location, subjects did not alter the direction of movement. However, movement distance was systematically adjusted in accord with the baseline target position. Thus when the hand start position was perpendicularly displaced relative to the target direction, neither the direction nor the extent of movement varied relative to that of baseline. However, when the hand was displaced along the target direction, either anterior or posterior, movements were made in the same direction as baseline trials but were shortened or lengthened, respectively. This effect was asymmetrical such that movements from anterior displaced positions showed greater distance adjustment than those from posterior displaced positions. Inverse dynamic analysis revealed substantial changes in elbow and shoulder muscle torque strategies for both right/left and anterior/posterior pairs of displacements. In the case of right/left displacements, such changes in muscle torque compensated changes in limb configuration such that movements were made in the same direction and to the same extent as baseline trials. Our results support the hypothesis that movement direction is specified relative to an origin at the current location of the hand. Movement extent, on the other hand, appears to be affected by the workspace learned during baseline movement experience.

Acceleration↗
PubMed2001

Computed tomography colonography.

Computed tomography colonography (virtual colonoscopy) is an exciting technique that continues to evolve but promises to be a valuable tool for diagnosis of and screening for colorectal neoplasia.

Colonography, Computed Tomographic↗
PubMed2002

A probabilistic approach to high throughput drug discovery.

A methodology is presented in which high throughput screening experimental data are used to construct a probabilistic QSAR model which is subsequently used to select building blocks for a virtual combinatorial library. The methodology is based upon statistical probability estimation and not regression. The methodology is applied to the construction of two focused virtual combinatorial libraries: one for cyclic GMP phosphodiesterase type V inhibitors and one for acyl-CoA:cholesterol O-acyltransferase inhibitors. The results suggest that the methodology is capable of selecting combinatorial substituents that lead to active compounds starting with binary (pass/fail) activity measurements.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1998

Virtual reality: a new clinical setting lab.

Virtual Reality (VR) is a new technology halfway between television and computer. It constitutes another step in the evolution of our use of a tool that allows us to see, to hear and to feel in a world created graphically in three dimensions, and to interact with it. VR is, mainly, a mental experience which makes the user believe that "he is there", that he is present in the virtual world. With this new tool, the user is no longer a mere observer of that which is happening on a screen, but he "feels" that he is immersed in that world and participates in it, in spite of the fact that they are spaces and objects that only exist in the memory of the computer and in the user's mind. This chapter seeks to carry out different reflections at different levels. First, we will analyze the relationships between VR and Psychology, one of the disciplines that has made more efforts in order to understand how we obtain knowledge from the world and from ourselves. We will also analyze the impact VR can have in one of the applied disciplines of Psychology, which is Clinical Psychology. With regard to this application environment, VR becomes a tool which can generate useful models for Psychology (both normal and abnormal), and it is offered as a research context for Clinical Psychology; as a "realistic" laboratory where we can study behaviours, emotions, thoughts, etc.; and a new means to develop psychological treatments.

Computer Simulation↗
PubMedDate not supplied

Preventing substance abuse as an integral part of worksite health promotion.

Problems of substance abuse damage the well-being of many workers and drain substantial resources from the organization. While companies have adopted drug testing to screen out drug users and employee assistance programs to provide services to troubled workers, serious substance abuse prevention strategies have been virtually ignored. The authors describe some of the obstacles to implementing substance abuse programs. Attempts to integrate these programs into worksite health promotion are described and a model for a health-oriented substance abuse program is presented.

Alcoholism↗
PubMed1996

Brucellosis surveillance and control in Zimbabwe: bacteriological and serological investigation in dairy herds.

Brucellosis in dairy cattle is endemic in Zimbabwe. The prevalence continues to be monitored intensively. Only milk and serum samples are routinely screened. Attempts to culture Brucella spp. from clinical specimens are seldom made. Consequently, incidence of various Brucella spp. within Zimbabwe is virtually unknown, despite the high serepositivity reported. This information is paramount in understanding the transmission cycle and is also significant to public health; particularly as B melitensis infects humans more often than do the other brucellae. This paper describes the results of bacteriological and serological investigations of brucellosis in a dairy from near Bulawayo. The said farm was selected for the present pilot study because of the high incidence of reported abortion. The milk ring test was employed to test the bulk pooled milk samples once a month for 14 months. The test was recorded highly positive on all 14 occasions. To locate reactors, milk samples from 36 individual cows were similarly tested. Of these, 21 (almost 59%) were found to be reacting positively. One hundred and seventy-seven animals were marked for serotesting. Of these 40 (approximately 25%) showed quite high serum titres (> 1:360) in both the STT and the Rosebengal test. The farmer was advised to havet all abortions full investigated. However, all the clinical material from cases of abortion, except one, were received in an advanced state of putrefaction. From this, Brucella was isolated on culture from stomach contents and cotyledons. The isolates from both the sites were characterized in detail, employing dye inhibition, phagetyping; the oxidative metabolic test and agglutination with monospecific sera. Both the isolates belonged to B. abortus biovar I, which was confirmed by the Central Veterinary Research Laboratory, Weybridge. The significance of isolation and the need to intensify similar studies have been discussed.

Animals↗
PubMed1997

Determination of HLA-A,B residue mismatch acceptability for kidneys transplanted into highly sensitized patients: a report of a collaborative study conducted during the 12th International Histocompatibility Workshop.

BACKGROUND: During the 12th International Histocompatibility Workshop, a collaborative study between 35 laboratories was conducted on a group of highly allosensitized patients who had received a kidney transplant from 1981 to 1995. The major goal of the study was to assess how serum screening against a large cell panel could determine donor HLA mismatch acceptability in relation to graft outcome. METHODS: Twenty laboratories participated in an extensive screening of 92 high panel-reactive antibody (PRA) sera from patients at 29 transplant centers worldwide; each patient had received a kidney allograft from an HLA-A,B mismatched unrelated donor. Screening was done by complement-dependent lymphocytotoxicity and antihuman globulin augmentation techniques using a common protocol and shared standardized reagents. After an extensive quality-control assessment, we selected data from 14 participants who had screened the sera against a combined panel of 535 HLA-typed cells. RESULTS: With the 2x2 table-based Multiscreen computer program, we could readily determine for virtually every patient the significant correlations between serum reactivity and the presence of panel cell markers, including private and public HLA-A,B epitopes and amino acid residues assigned from published sequencing data. Donor mismatch acceptability was assessed at the amino acid residue level. In the complement-dependent lymphocytotoxicity (n=49; PRA=84.1+/-12.1%) and antihuman globulin (n=60; PRA=92.5+/-5.8%) groups, the 3-month graft survivals were 28% and 30% lower for unacceptable residue mismatches. CONCLUSIONS: These studies underscore the importance of a comprehensive serum screening analysis in the selection of appropriately mismatched donors for highly sensitized transplant patients.

Antibody Specificity↗
PubMed1994

Mutation detection by fluorescent chemical cleavage: application to hemophilia B.

Chemical mismatch detection when combined with PCR or RT-PCR amplification represents one of the most efficient mutation screening methods. This procedure has been used for the analysis of both large populations of mutants and large and complex genes because it detects and locates virtually all sequence variations in segments of DNA of up to 1.7 kb cleaving at, and/or adjacent to, mismatches in heteroduplexes formed by target and probe DNA. By using fluorescent tags and an automatic gel scanning system, the efficiency of the method has been increased fourfold with gains also in the safety and quality control of probes and in the flexibility of the procedure. Using 12 hemophilia B patients, 8 with known mutations and 4 chosen at random, we show how the chemical mismatch cleavage of up to four DNA segments can be multiplexed and examined in a single gel lane and how the increase in efficiency thus obtained can be used either totally to maximize the DNA screened per lane or partly to locate the mutation unequivocally so that only one sequencing reaction is needed to characterize it fully.

DNA Mutational Analysis↗