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PubMed2003

[Virtual colonography].

Recent technical developments in computed tomography (CT) and magnetic resonance imaging (MRI) have made a virtual presentation of the colon possible. The results of clinical investigations comparing virtual colonography and conventional colonoscopy up to now are promising. Virtual colonography is a potential tool for colorectal carcinoma screening in the future, but it still has an unsatisfactory sensitivity for the detection of small and flat lesions and exposes the patient to substantial doses of ionizing radiation. Recent investigations using ultra-low-dose (< 2 mSv) multislice CT colonography show promising results. Magnetic resonance (MR) colonography as a radiation-free modality is the technique of the future. Although encouraging results using virtual MR colonography for the detection of colorectal polyps have been reported, the sensitivity of detecting small polyps (</= 10 mm) and flat lesions is poor. Main reason is the limited spatial resolution in MRI of the colon. The potential role of virtual colonography in the prevention of colorectal cancer is not yet clear. Larger studies with asymptomatic persons at average risk are needed, and further improvements in the detection of flat and very small (< 5 mm) lesions need to be achieved before advocating the use of virtual colonography for routine colorectal cancer screening.

Adenoma↗
PubMedDate not supplied

Assessment of screening as a preventive technology: the example of HTLV-III/LAV antibody testing.

Screening for disease control can be defined as a preventive technology that is used to examine asymptomatic people in order to classify them as likely or unlikely to have the disease that is the object of screening. Screening may consist of routine physical examinations, radiologic procedures, semi-invasive procedures such as endoscopy, or serologic tests. In this paper, a new serologic test is considered. Acquired immunodeficiency syndrome (AIDS) is a devastating disease with high mortality, recently shown to be caused by a retrovirus named human T-lymphotropic virus Type III (HTLV-III) or lymphadenopathy-associated virus HTLV-III antibody in serum specimens. Performance characteristics are excellent with high sensitivity and specificity when reactive serum specimens are checked for consistency of response by enzyme immunoassay (EIA). This test is now part of the screening protocol for all blood donation centers to decrease the risk of HTLV-III transmission via blood or blood products. About 0.2% (1 in 400) of blood donors have repeatedly reactive EIA tests to HTLV-III antibody. Approximately one-third of these donors have other laboratory evidence of infection. Screening for HTLV-III is a new technology that illustrates virtually all of the factors that need consideration in an assessment of disease screening. This paper explores these technical, epidemiologic, economic, legal, social, and ethical factors.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Free energy calculations on dimer stability of the HIV protease using molecular dynamics and a continuum solvent model.

Dimerization of HIV-I protease (HIV PR) monomers is an essential prerequisite for viral proteolytic activity and the subsequent generation of infectious virus particles. Disrupting dimerization of the enzyme can inhibit its activity. We have calculated the relative binding free energies between different dimers of the HIV protease using molecular dynamics and a continuum model, which we call MM/PBSA. We examined the dominant negative inhibition of the HIV PR by a mutated form of the protease and found relative dimerization free energies of homo- and hetero-dimerization consistent with experimental data. We also developed a rapid screening method, which was called the virtual mutagenesis method to consider other mutations which might stabilize non-wild-type heterodimers. Using this approach, we considered the mutations near the dimer interface which might cause dominant negative inhibition of the HIV PR. The rapid method we developed can be used in studying any ligand-protein and protein-protein interaction, in order to identify mutations that can enhance the binding affinities of the complex.

Anions↗
PubMed1998

The molecular biology and pathophysiology of hypertrophic cardiomyopathy due to mutations in the beta myosin heavy chains and the essential and regulatory light chains.

Hypertrophic cardiomyopathy (HCM) is perhaps the most common cause of inherited sudden death in otherwise healthy young individuals. There are presently seven known genes in which mutations have been shown to cause the disease. The first identified disease gene was beta myosin heavy chain (BMHC). Our laboratory has identified 32 distinct BMHC gene mutations in 62 kindreds after screening representatives of over 400 kindreds. Virtually all but one of approximately 50 known mutations are restricted to the head or head-rod junction region of the molecule. We have used the mutant alleles of the BMHC gene to demonstrate that both mutant message and protein is present in the skeletal muscle of patients with HCM. Muscle biopsies from patients with identified BMHC mutations show abnormal histology. Isolated myosin and skinned fibers from these patients have abnormal mechanical properties. The BMHC gene mutations are clustered in 4 regions of the myosin head. Because one of these regions is adjacent to the ELC, we scanned HCM patient DNA for mutations in either the ELC or RLC. Linkage analysis showed that a unique mutation in the ELC caused a rare phenotype of HCM in one family. Other mutations in either light chain were also associated with the same rare phenotype in other families. Through several lines of reasoning we hypothesized that the light chain mutations interfere with the stretch-activation response of papillary muscle and adjacent ventricular tissue. This property is critical to oscillatory power output of insect flight muscle. We conjectured that this property is also exploited by portions of the heart to increase power output. In order to test this hypothesis we constructed transgenic mouse lines expressing either the human normal or mutant ELC. The cardiac morphology and mechanical properties of the transgenic mouse papillary muscle is now being studied.

Animals↗
PubMed2006

Limitations of cellular models in Parkinson's disease research.

Cell cultures for Parkinson's disease research have the advantage of virtually unlimited access, they allow rapid screening for disease pathogenesis and drug candidates, and they restrict the necessary number of animal experiments. Limitations of cell cultures, include that the survival of neurons is dependent upon the culture conditions; that the cells do not develop their natural neuronal networks. In most cases, neurons are deprived from the physiological afferent and efferent connections. In Parkinson's disease research, mesencephalic slice cultures, primary immature dopaminergic neurons and immortalized cell lines--either in a proliferating state or in a differentiated state--are used. Neuronal cultures may be plated in the presence or absence of glial cells and serum. These different culture conditions as well as the selection of outcome parameters (morphological evaluation, viability assays, biochemical assays, metabolic assays) have a strong influence on the results of the experiments and the conclusions drawn from them. A primary example is the question of whether L-Dopa is toxic to dopaminergic neurons or whether it provides neurotrophic effects: In pure, neuronal-like cultures, L-Dopa provides toxicity, whereas in the presence of glial cells, it provides trophic effects when applied. The multitude of factors that influence the data generated from cell culture experiments indicates that in order to obtain clear-cut and unambiguous results, investigators need to choose their model carefully and are encouraged to verify their main results with different models.

Cell Line↗
PubMed2006

Difference in sensorimotor adaptation to horizontal and vertical mirror distortions during ballistic arm movements.

When learning a novel motor task, the sensorimotor system must develop new strategies to efficiently control the limb(s) involved, and this adaptation appears to be developed through the construction of a behavioral map known as an 'internal model'. A common method to uncover the mechanisms of adaptation and reorganization processes is to expose the system to new environmental conditions, typically by introducing visual or mechanical distortions. The present study investigated the adaptation mechanisms of the human sensorimotor system to horizontal and vertical mirror distortions (HMD and VMD) during the execution of fast goal-directed arm movements. Mirror distortions (MDs) were created by means of virtual visual feedback on a computer screen while the movement was executed on a graphics tablet. Twenty healthy adult participants were recruited and assigned to one of two groups of 10 people each. Tests were divided in two subsequent blocks of five trials. The first block consisted of trials with no mirror distortion (NMD), while the second block was recorded when exposing one group to HMD and the other to VMD. Both MDs resulted in kinematic changes: during the tests with the MDs the participants did not reach the performance level found at the NMD test. Motor performance during HMD appeared to be globally better than during VMD and the adaptation process to VMD appeared to be slower than to HMD, but data interpretation was hampered by large within-participant and between-participant variability. In-depth analyses of the data revealed that most of the motor performance information was contained in the direction of movement. The data supported the idea that the internal model for HMD was already partially built.

Adult↗
PubMed2001

Differential gene expression in fully-grown oocytes between gynogenetic and gonochoristic crucian carps.

Silver crucian carp (Carassius auratus gibelio) is a unique triploid bisexual species that can reproduce by gynogenesis. As all other gynogenetic animals, it keeps its chromosome integrity by inhibiting the first meiosis division (no extrusion of the first pole body). To understand the molecular events governing this reproduction mode, suppression subtractive hybridization was used to identify the genes differentially expressed in fully-grown oocytes of the gynogenetic and gonochoristic crucian carp (gyno-carp and gono-carp). From two specific subtractive cDNA libraries, the clones screened out by dot blots and virtual Northern blots were chosen to clone full-length cDNA by RACE. Four differentially expressed genes were obtained. Two are novel genes and are expressed specifically in the oocytes. The gyno-carp stores much more mRNA of cyclin A2, a new member of the fish A-type cyclin gene, in its fully-grown oocyte than in the gono-carp. The last gene is histone H2A. The histone H2As of these two closely related crucian carps are quite different in the C-terminus. Preliminary characterization of the four genes has been analyzed by nucleotide and deduced amino acid sequence and Northern analysis.

Amino Acid Sequence↗
PubMedDate not supplied

Rapid evaluation of synthetic and molecular complexity for in silico chemistry.

Methods that rapidly evaluate molecular complexity and synthetic feasibility are becoming increasingly important for in silico chemistry. We propose a new metric based on relative atomic electronegativities and bond parameters that evaluate both synthetic and molecular complexity (SMCM) starting from chemical structures. Against molecular weight, SMCM has the lowest fraction of adjusted variance (R2=0.535) on a series of 261,048 diverse compounds, when compared to the complexity metric of Baron and Chanon (R2=0.777; J. Chem. Inf. Comput. Sci. 2001, 41, 269-272) and Rücker (R2=0.895 for log complexity values; J. Chem. Inf. Comput. Sci. 2004, 44, 378-386), respectively. These metrics are in general agreement when the metabolic synthesis of cholesterol from S-3-hydroxy-3-methyl-glutaryl coenzyme A is monitored, indicating that SMCM can be useful in discerning increases in complexity. Because the presence of substructure patterns can be directly incorporated into this scheme, SMCM is relatively straightforward and can be easily tailored to rapidly evaluate virtual (combinatorial) libraries and high throughput screening hits.

Acyl Coenzyme A↗
PubMed1993

Anticonvulsant activities of some arylsemicarbazones displaying potent oral activity in the maximal electroshock screen in rats accompanied by high protection indices.

Various semicarbazones derived from aryl aldehydes, phenylalkyl aldehydes, and phenylalkyl ketones as well as some related compounds were evaluated for anticonvulsant activity. Most of the compounds displayed anticonvulsant activity in the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) screens accompanied by neurotoxicity when given to mice by the intraperitoneal route. However quantitative data revealed protection indices (TD50/ED50) of less than 4 in general. Oral administration of the compounds to rats led to excellent potency in the MES screen accompanied by high protection indices while virtually no activity in the scPTZ test was displayed. These observations support the theory that one large hydrophobic group (in this case the aryl ring) and two electron donor atoms (present in the semicarbazono group) are requirements for protection in the MES screen. In general, the semicarbazones had rapid onsets of action, and one of the ways in which these compounds displayed their anticonvulsant activity is likely to be interaction with chloride channels. Empirical and semiempirical conformational calculations indicated that certain molecular fragments and hydrophobicity of these molecules affect bioactivity.

Administration, Oral↗
PubMed2002

Identification of potent and novel alpha4beta1 antagonists using in silico screening.

The antigen alpha4beta1 (very late antigen-4, VLA-4) plays an important role in the migration of white blood cells to sites of inflammation. It has been implicated in the pathology of a variety of diseases including asthma, multiple sclerosis, and rheumatoid arthritis. We describe a series of potent inhibitors of alpha4beta1 that were discovered using computational screening for replacements of the peptide region of an existing tetrapeptide-based alpha4beta1 inhibitor (1; 4-[N'-(2-methylphenyl)ureido]phenylacetyl-Leu-Asp-Val) derived from fibronectin. The search query was constructed using a model of 1 that was based upon the X-ray conformation of the related integrin-binding region of vascular cell adhesion molecule-1 (VCAM-1). The 3D search query consisted of the N-terminal cap and the carboxyl side chain of 1 because, upon the basis of existing structure-activity data on this series, these were known to be critical for high-affinity binding to alpha4beta1. The computational screen identified 12 reagents from a virtual library of 8624 molecules as satisfying the model and our synthetic filters. All of the synthesized compounds tested inhibit alpha4beta1 association with VCAM-1, with the most potent compound having an IC(50) of 1 nM, comparable to the starting compound. Using CATALYST, a 3D QSAR was generated that rationalizes the variation in activities of these alpha4beta1 antagonists. The most potent compound was evaluated in a sheep model of asthma, and a 30 mg nebulized dose was able to inhibit early and late airway responses in allergic sheep following antigen challenge and prevented the development of nonspecific airway hyperresponsiveness to carbachol. Our results demonstrate that it is possible to rapidly identify nonpeptidic replacements of integrin peptide antagonists. This approach should be useful in identification of nonpeptidic alpha4beta1 inhibitors with improved pharmacokinetic properties relative to their peptidic counterparts.

Administration, Inhalation↗
PubMed2004

Computer-aided diagnosis for CT colonography.

CT colonography, or virtual colonoscopy, is a promising alternative screening tool for colon cancer. Computer-aided diagnosis (CAD) for CT colonography has the potential to increase radiologists' diagnostic performance in the detection of polyps and to reduce variability of the diagnostic accuracy among readers. Technical developments have advanced CAD for CT colonography substantially during the last several years. This paper describes the key techniques used for CAD for detection of polyps and masses in CT colonography, the current detection performance, and challenges and the future of CAD.

Colonic Polyps↗
PubMed2001

[Hydrocolonic sonography--potentials and limitations of ultrasonographic diagnosis of colon diseases].

Hydrocolonic sonography - potentials and limitations of ultrasonographic diagnosis of colon diseases. Ultrasonic examination has become increasingly important in the diagnosis of diseases of the gastrointestinal tract. In neoplastic diseases of the large intestine, however, the diagnostic value of conventional transabdominal sonography is limited. The sonographic evaluation of the colon could be improved by the retrograde instillation of water into the colon in a procedure called hydrocolonic sonography. This technique allows the visualization of the colon sonographically from the rectosigmoid transition to the cecum. Hydrocolonic sonography enables a detailed sonographic examination of the hypoechoic colonic lumen, the five individual layers of the colon wall and the surrounding connective tissue, thus providing additional information and allowing a more precise diagnosis of many diseases of the colon. Colonic polyps and carcinomas appear sonographically as echogenic structures projecting from the intestinal wall into the lumen. Colonic polyps larger than 7 mm in diameter and carcinomas of the colon can be detected with great sensitivity. In addition, detailed evaluation of the structure of the bowel wall permits more precise staging of tumors of the colon. Aside from such localized changes, hydrocolonic sonography can also demonstrate changes in the wall structure in chronic inflammatory large bowel diseases such as Crohn's disease and ulcerative colitis. In addition hydrocolonic sonography has been proven to be of great value for the ultrasonographically-guided hydrostatic reduction of intussusception in children. On the other hand virtual colonoscopy is another promising new imaging method for the diagnosis of colon diseases. The differences between hydrcolonic sonography and virtual colonoscopy and their potential for screening purposes of colon cancer will be discussed.

Colon↗
PubMed1977

Cloning specific segments of the mammalian genome: bacteriophage lambda containing mouse globin and surrounding gene sequences.

We have developed a general approach to the cloning of specific segments of the mammalian genome that involves a two-step purification of EcoRI fragments of mammalian DNA and their in vitro insertion into a suitably constructed EK2 derivative of bacteriophage lambda. The combination of fragment purification, exclusion of parental-type recombinants, and simple phage screening techniques permits the isolation of virtually any gene segment for which there is an identifying hybridization probe. We illustrate the approach by describing the cloning of an approximately 7000-base-long segment of mouse DNA containing globin and surrounding gene sequences.

Animals↗
PubMed1980

The emergence of infection surveillance and control programs in US hospitals: an assessment, 1976.

To assess the current state of hospitals' infection surveillance and control programs (ISCPs) nationwide and to provide a sampling frame for selecting hospitals for later phases of the SENIC Project, the authors mailed a screening questionnaire in March, 1976, to virtually all US hospitals; 86% of those in the SENIC target universe responded. Of these, 64% (2299) reported that their ISCPs were being supervised by a physician or a microbiologist with special interest in infection control, and 42% had an infection control nurse (ICN), or equivalent, working at least half time. In contrast to the supervisors, most of the ICN's had recieved special training in hospital infection epidemiology and spent the majority of their time doing surveillance. Almost all hospitals (87%) had practiced some form of infection surveillance. Almost all hospitals (87%) had practiced some form of infection surveillance, with half reporting very active programs. Larger hospitals with ISCP staff tended to use active clinical casefinding methods, while smaller hospitals tended to use passive techniques. Most hospitals (76%) were collecting relatively large numbers of environmental cultures routinely, although a growing number (about 25%) had reduced or discontinued this practice. Routine culturing was more often performed in hospitals employing passive surveillance methods. Although the adoption of selected infection control policies and practices has varied widely, chronological data indicate that a major infection control movement has emerged since 1970.

Cross Infection↗
PubMed2004

Different cortical activations for subjects using allocentric or egocentric strategies in a virtual navigation task.

Subjects were required to navigate through a virtual 3D labyrinth presented on a screen while fMRI images were obtained. Contrasting the fMRI images obtained during the navigation trials with appropriate control conditions revealed a bilateral network comprising the parietal lobe (including the intraparietal sulcus) and various lateral and medial premotor areas. The subjects using an allocentric strategy showed stronger activation in the medial temporal areas including the parahippocampal region, the hippocampus, and the thalamus. In addition, the cerebellum was also active in those subjects. We believe that this activation pattern is related to visually guided memory retrieval based on generalized spatial maps. The stronger activation in the thalamic-basal ganglia-cerebellar-loop points to a more automatic support of memory and attentional processes possibly supporting memorization of spatial maps.

Adult↗
PubMedDate not supplied

Computer-aided design and modeling of workstations and radiology reading rooms for the new millennium.

Three-dimensional (3D) computer modeling, simulation, and rendering techniques were used to redesign the diagnostic workstations and radiology reading rooms for a proposed hospital with particular attention given to lighting conditions, noise reduction, and optimal use of limited workspace. The results were presented to a panel of multidisciplinary experts and iteratively improved and redesigned with the development or addition of new design criteria or requirements. These 3D techniques allowed faster, more efficient design and presentation of multiple options than is possible with traditional two-dimensional drawings, thereby expediting decision making and resulting in significant savings. The current workstation designs can easily be developed and implemented with available technology at a reasonable cost. They can also accommodate anticipated advances in computer and display technology as well as new imaging paradigms (eg, changes in keyboard and control ergonomics such as adjustable virtual keys on touch-sensitive screens, digital drawing tablets for annotations and controls, direct film digitizing, personal identification devices, offline media readers such as compact disks and digital videodisks, and speech recognition and voice activation). Use of 3D techniques in designing other parts of the radiology department (eg, examination rooms, technologists' areas, physicians' offices) could greatly improve and facilitate the design and implementation of complex settings in these work areas.

Computer Simulation↗
PubMed2002

Functional cloning using pFB retroviral cDNA expression libraries.

Retroviral cDNA expression libraries allow the efficient introduction of complex cDNA libraries into virtually any mitotic cell type for screening based on gene function. The cDNA copy number per cell can be easily controlled by adjusting the multiplicity of infection, thus cell populations may be generated in which >90% of infected cells contain one to three cDNAs. We describe the isolation of two known oncogenes and one cell-surface receptor from a human Burkitt's lymphoma (Daudi) cDNA library inserted into the high-titer retroviral vector pFB.

3T3 Cells↗
PubMed1999

Beyond the "hot-and-cold" game: a demonstration of computer-controlled shaping.

Shaping, or the method of successive approximations, is widely taught in introductory psychology and the psychology of learning as a procedure for establishing new behavior. This article illustrates a computer-controlled shaping demonstration that allows the user to specify several critical parameters of the shaping process and that then shapes the user's mouse movements toward an arbitrary virtual (invisible) target on the computer screen. The relative effectiveness of different shaping parameters can be assessed by examining several dependent measures, such as the distance of the cursor from the target across time and the rate at which reinforcers were earned. This demonstration allows students to move beyond the notion that shaping is simply the application of the "hot-and-cold" game and to understand that there is a science underlying the art of shaping.

Computer-Assisted Instruction↗