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PubMed2005

Reengineering the pharmaceutical industry by crash-testing molecules.

The recent decline in drug approvals and the increase in late-stage failures indicate that the ability to generate and screen large numbers of molecules has not improved the drug pipeline. Perhaps the pharmaceutical industry should follow the example of the automotive industry and agree upon a shared modeling language with vendors and academics to enable integration of predictive computational tools across the industry. This will then enable the virtual 'crash-testing' of drugs before synthesis, biological testing and, most importantly, clinical trials. This represents an ambitiously progressive approach using the models for simulating every stage of the drug discovery and development process. Combining the relevant computational algorithms into a grand unified model would enable prioritization of the best ideas before pursuing a discovery program, selecting a target or synthesizing a molecule. The successful application of these virtual crash-testing principles by any of its current proponents could revitalize the pharmaceutical industry so that failure is avoided.

Chemistry, Pharmaceutical↗
PubMed1991

Similarity of tactual and visual picture recognition with limited field of view.

Subjects attempted to recognize simple line drawings of common objects using either touch or vision. In the touch condition, subjects explored raised line drawings using the distal pad of the index finger or the distal pads both of the index and of the middle fingers. In the visual condition, a computer-driven display was used to simulate tactual exploration. By moving an electronic pen over a digitizing tablet, the subject could explore a line drawing stored in memory; on the display screen a portion of the drawing appeared to move behind a stationary aperture, in concert with the movement of the pen. This aperture was varied in width, thus simulating the use of one or two fingers. In terms of average recognition accuracy and average response latency, recognition performance was virtually the same in the one-finger touch condition and the simulated one-finger vision condition. Visual recognition performance improved considerably when the visual field size was doubled (simulating two fingers), but tactual performance showed little improvement, suggesting that the effective tactual field of view for this task is approximately equal to one finger pad. This latter result agrees with other reports in the literature indicating that integration of two-dimensional pattern information extending over multiple fingers on the same hand is quite poor. The near equivalence of tactual picture perception and narrow-field vision suggests that the difficulties of tactual picture recognition must be largely due to the narrowness of the effective field of view.

Adult↗
PubMedDate not supplied

A real-time anesthesia record keeping system using video.

A real-time, Automated Anesthesia Record Keeping (AARK) system was constructed using commercially available video hardware. This system can acquire all of the information that is presented visually to an anesthesiologist directly from monitor screens. The information is recorded on VHS format tape. Use of such a system avoids the need for digital processing while capturing all waveforms, trends, data messages and numerics. Since the data are stored directly to tape, subsequent data analysis can be accomplished. This system can be used with virtually any medical monitor.

Anesthesia Department, Hospital↗
PubMed2007

Identification of genes displaying differential expression in the nuc-2 mutant strain of the mold Neurospora crassa grown under phosphate starvation.

Subtractive hybridization was used to isolate transcripts up-regulated in the nuc-2 mutant strain of Neurospora crassa grown under phosphate starvation. Following differential screening, 66 cDNA clones of the total enriched were screened in a second round by reverse Northern hybridization. The 17 cDNA candidates displaying visual positive differential expression were sequenced, and functional grouping identified putative proteins possibly involved in diverse cellular processes as, for example, protein synthesis, signal transduction mechanisms, and transport facilitation. Four of them, confirmed by both virtual and Northern blot analyses, revealed genes involved in the initiation of mRNA translation that are significantly up-regulated in the nuc-2 mutant strain, which may be relevant to a further understanding of the molecular events involved in the phosphorus sensing in N. crassa.

Ankyrin Repeat↗
PubMed2002

Fast drops: a high-throughput approach for setting up protein crystal screens.

There is significant demand to rapidly obtain protein structure information for both structural genomics and drug discovery applications. To meet this demand, all steps in the process of determining protein structure by X-ray crystallography need to be optimized and streamlined with high-throughput methodologies. This communication describes a method that brings high-throughput technology to protein crystallization in both manual and automated modes, suitable for virtually every crystallography laboratory.

Crystallization↗
PubMed2005

A surgical simulator for planning and performing repair of cleft lips.

UNLABELLED: The objective of this project was to develop a computer-based surgical simulation system for planning and performing cleft lip repair. This system allows the user to interact with a virtual patient to perform the traditional steps of cleft-lip repair (rotation-advancement technique). MATERIALS AND METHODS: The system interfaces to force-feedback (haptic) devices to track the user's motion and provide feedback during the procedure, while performing real-time soft-tissue simulation. An 11-day-old unilateral cleft lip, alveolus and palate patient was previously CT scanned for ancillary diagnostic purposes using standard imaging protocols and 1mm slices. High-resolution 3D meshes were automatically generated from this data using the ROVE software developed in-house. The resulting 3D meshes of bone and soft tissue were instilled with physical properties of soft tissues for purposes of simulation. Once these preprocessing steps were completed, the patient's bone and soft tissue data are presented on the computer screen in stereo and the user can freely view, rotate, and otherwise interact with the patient's data in real time. The user is prompted to select anatomical landmarks on the patient's data for preoperative planning purposes, then their locations are compared against that of a 'gold standard' and a score, derived from their deviation from that standard and time required, is generated. The user can then move a haptic stylus and guide the motion of the virtual cutting tool. The soft tissues can thus be incised using this virtual cutting tool, moved using virtual forceps, and fused in order to perform any of the major procedures for cleft lip repair. Real-time soft tissue deformation of the mesh realistically simulates normal tissues and haptic-rate (>1 kHz) force-feedback is provided. The surgical result of the procedure can then be immediately visualized and the entire training process can be repeated at will. A short evaluation study was also performed. Two groups (non-medical and plastic surgery residents) of six persons each performed the anatomical marking task of the simulator four times. RESULTS: Results showed that the plastic surgery residents scored consistently better than the persons without medical background. Every person's score increased with practice, and the length of time needed to complete the 11 markings decreased. The data was compiled and showed which specific markers consistently took users the longest to identify as well as which locations were hardest to accurately mark. CONCLUSION: These findings suggest that the simulator is a valuable training tool, giving residents a way to practice anatomical identification for cleft lip surgery without the risks associated with training on a live patient. Educators can also use the simulator to examine which markers are consistently problematic, and modify their training to address these needs.

Cleft Lip↗
PubMed1999

Can duplex ultrasound replace arteriography in screening for mesenteric ischemia?

Duplex examination of the mesenteric vasculature is not a widely performed examination, but the published literature documents the ability of this test to accurately identify chronic atherosclerotic occlusive disease. The test is a recent addition to the armamentarium of noninvasive duplex technology, with studies of adequate size for statistical analysis appearing only since 1991. Two primary sets of diagnostic threshold values for significant stenoses of the superior mesenteric artery (SMA) and the celiac artery have been published and subsequently tested for accuracy. One of these recommends use of peak systolic velocity (PSV), whereas end diastolic velocity (EDV) was found to be most accurate in the other. Both sets of criteria identify overall accuracy of greater than 90% for identification of SMA stenosis, and greater than 80% for diagnosis of celiac stenosis. Identification of celiac disease may be aided by analysis of blood flow direction in the common hepatic artery. The finding of retrograde hepatic flow is virtually diagnostic of severe celiac stenosis or complete occlusion. Duplex also has been shown capable of identifying anatomic anomalies of the mesenteric vessel origins, a situation that occurs in approximately 20% of the population. Finally, mesenteric duplex has utility in a variety of less common abdominal visceral disorders, but statistical analysis of accuracy and adequate identification of quantitative velocity thresholds have not been performed. Skilled technologists who have access to appropriate training and equipment can master this test. There is little doubt that it can replace angiography as a screening tool in the setting of suspected chronic mesenteric ischemia.

Acute Disease↗
PubMed2006

Leishmania donovani: an in vitro study of antimony-resistant amphotericin B-sensitive isolates.

Drug sensitivity of clinically antimony-unresponsive Leishmania donovani isolates from Eastern Sudan was evaluated in an in vitro culture system against sodium stibogluconate (Pentostam) and Amphotericin B. Eight isolates, six from antimony-resistant and two from clinically responsive patients were included in the study. Parasites were tested as promastigotes and four of them were selected to be tested as amastigotes using a murine macrophage-like cell line. The results indicated that the conventional promastigotes and amastigotes-screening assays did not correlate with the clinical picture of patients. In vivo unresponsiveness does not necessarily mean primary parasite resistance. Amphotericin B could be a suitable second line drug in patients unresponsive to pentostam and without concomitant diseases, if close hospital monitoring is available. Promastigotes sensitivity testing concentrations are virtually incomparable with the in vivo clinically curable doses and the amastigotes/macrophage test concentrations.

Amphotericin B↗
PubMed1997

Preliminary assessment of three-dimensional magnetic resonance imaging for various colonic disorders.

BACKGROUND: Improvements in magnetic resonance imaging (MRI) technology have enabled the acquisition of three-dimensional MRI datasets in a single breath hold. We adopted this technique to make a three dimensional intraluminal and extraluminal assessment of the colon in three patients with various colonic disorders. METHODS: One patient was studied after having a double-contrast barium enema. Two patients had MRI scans after colonoscopy, which showed three colonic tumours in one and multiple polyps in the ascending colon of the other. The process of rectal filling with 1.5-2.0 L water mixed with 15-20 mL 0.5 mol/L gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) was monitored with MR fluoroscopic sequence. Three-dimensional datasets of the contrast-filled colon were taken with patients in prone (before and after intravenous administration of 0.1 mmol/kg bodyweight Gd-DTPA) and supine positions. 64 sections with a voxel-resolution of 2.0 x 2.0 x 1.25 mm3-were taken during a 28 s breath hold. Three-dimensional maximum intensity projection, multiplanar reconstruction, and virtual colonoscopic images of the colon were created from these. FINDINGS: Analysis of the coronal source images in conjunction with multiplanar reconstructions revealed all relevant abnormalities, including diverticula, carcinomas, and polyps. Three dimensional maximum-intensity projections gave a morphological overview of the whole colon. Targeted projections, made up of a limited number of coronal source images, showed diverticula and smaller polyps more clearly. After patients were given intravenous contrast all colonic mass lesions were enhanced. Datasets obtained in prone patients gave the best intraluminal views of the colon. Virtual magnetic resonance colonoscopy showed colonic haustra as well as the ileocaecal valve, but did not show clearly the diverticula. All intraluminal mass lesions, on the other hand, were easy to see. INTERPRETATION: The potential of three-dimensional colonic MRI to provide accurate, minimally invasive, cost-effective polyp screening, as well as comprehensive colonic tumour staging, warrants further investigation.

Aged↗
PubMed2006

Tuning silence: conditional systems for RNA interference.

RNA interference (RNAi) has emerged as a powerful tool to downregulate the expression of specific genes. Drug-inducible systems allowing for conditional RNAi that offer the unique potential to modulate expression of virtually any endogenous gene in the cell have been recently developed. Their applications are very broad, ranging from basic studies of gene function to translational research including modeling of human diseases, analysis of potential side effects of candidate drugs, testing of gene-based therapies and loss-of-function screens. Here we summarize the state of the art of systems allowing for drug-controllable knockdown, and provide a description of their current and future applications.

Genetic Vectors↗
PubMed2003

Virtual reality simulator for vitreoretinal surgery.

AIM: To develop computer simulation of steps in vitreoretinal surgery using virtual reality technology. MATERIAL AND METHODS: A workstation with three-dimensional position tracking stylus was attached to a Pentium II desktop PC with a graphic accelerator. Computer algorithms were developed using Open GL and Microsoft Visual C++ languages to control the interaction and update the visual feedback tracking the instruments. Soft tissue computer modelling was carried out to mimic the removal of a vitreous opacity. Lens touch with the instruments was also detected. Mathematical modelling to allow for lens distortion was taken into account. RESULTS: A virtual reality computer model has been developed that can simulate initial steps of vitreoretinal surgery. Soft tissue modelling of the vitreous opacity and its removal by the vitrector was successfully simulated. The movements of the active and passive instruments in the dummy eye corresponded to the movements on the computer screen. On evaluation of the system, there was a minimal but discernable time lag between the stylus movement and the visual feedback. There was no tactile feedback when the lens touch was simulated. No further complex vitreoretinal surgery simulation was possible at this stage.

Algorithms↗
PubMed2005

Identification of a novel adult-onset primary open-angle glaucoma (POAG) gene on 5q22.1.

Glaucoma is a leading cause of blindness in virtually every country. Development of an accurate diagnostic test for presymptomatic detection of individuals at risk is an urgent requisition for this condition. Herein, we report mapping of a new adult-onset primary open-angle glaucoma (POAG) locus on 5q22.1 (GLC1G) and identification of its defective gene. Mutation screening of seven candidate genes from the GLC1G critical region (approximately 2 Mb between D5S1466 and D5S2051) identified only one significant alteration in the WDR36 (WD40-repeat 36) gene. This mutation (i.e. D658G) was segregated in all affected members of our first GLC1G-linked family but it was absent in 476 normal control chromosomes. Further screening of WDR36 in a total of 130 POAG families revealed 24 DNA variations. Overall, four mutations (N355S, A449T, R529Q and D658G) were identified in 17 (5.02-6.92%) unrelated POAG subjects, 11 with high-pressure and six with low-pressure glaucoma. These mutations were absent in a minimum of 200 normal control chromosomes and, further they were conserved between WDR36 orthologues in mouse, rat, dog, chimp and human. WDR36 is a novel gene with 23 exons, which encodes for 951 amino acids and a protein with multiple G-beta WD40 repeats. By northern blotting, two distinct mRNA transcripts of 5.9 and 2.5 kb were observed in human heart, placenta, liver, skeletal muscle, kidney and pancreas. WDR36 gene expression in lens, iris, sclera, ciliary muscles, ciliary body, trabecular meshwork, retina and optic nerve were established by RT-PCR. In mouse, two transcripts of 3.5 and 2.9 kb showed analogous expression patterns to human. mRNA expressions were detected in 7-, 11-, 15- and 17-day-old developing mouse embryos. In summary, WDR36 is a novel causative gene for adult-onset POAG at the GLC1G locus. Specific ocular expressions and observed mutations are consistent with WDR36 role in etiology of both high- and low-pressure glaucoma.

Amino Acid Substitution↗
PubMed2006

A population-based binational register for monitoring long-term outcome and possible disease concordance among blood donors and recipients.

BACKGROUND AND OBJECTIVES: Even with appropriate donor deferrals and advanced screening tests, the risk of disease transmission through blood transfusion cannot be completely disregarded. Efficient monitoring of possible disease transmission between blood donors and recipients should be an important component of a comprehensive haemovigilance system. MATERIALS AND METHODS: We assembled the Scandinavian Donations and Transfusions (SCANDAT) database, with data on virtually all blood donors and recipients who have been registered at least once in any of the computerized local blood bank databases in Sweden and Denmark since the start of computerized registration in 1966. The records of these individuals, with their entire computerized donation and/or transfusion histories and all donor-component-recipient connections, were linked to nationwide population and health registers to attain essentially complete follow-up for up to 36 years regarding reproduction, hospital morbidity, cancer, and death. RESULTS: After data cleaning, the database contained 1,134,290 blood donors who contributed 15,091,280 records of donations and 1,311,079 recipients who received 11,693,844 transfusions. The data quality in the existing data sources was satisfactory. From the data obtained from local blood banks, 4.6%, 1.6%, and 6.4% of the person, donation, and transfusion records, respectively, had to be discarded after review of the legitimacy of recorded values, and comparisons with independent, external databases. CONCLUSION: It is possible to use existing computerized data, collected in routine health care, in haemovigilance systems for monitoring long-term outcome and disease concordance in blood donors and transfusion recipients.

Blood Donors↗
PubMed2005

Quantifying in vivo somatic mutations using transgenic mouse model systems.

This chapter describes the use of the bacteriophage cII positive selection assay with the MutaMouse transgenic model system. The assay is similar to others involving a transgenic target, including the cII and lacI assays in the Big Blue(R) Mouse, lacZ in the MutaMouse, and the gpt delta assay. Briefly, high-molecular-weight DNA is purified from the tissue of interest and used as substrate during in vitro packaging reactions, in which the lambda transgenes are excised from the genome and assembled into viable phage. Phage containing the mutational targets are then adsorbed into an appropriate bacterial host, and mutations sustained in vivo are evidenced by either standard recombinant screening or selection assays. Mutant frequencies are reported as the ratio of mutant phage to total phage units analyzed. The lambda-based transgenic mouse assays are used to study and characterize in vivo mutagenesis, as well as for mutagenicity assessment. The models permit the enumeration of mutations sustained in virtually any tissue of the mouse and are sensitive and robust. Application of the assays is simple, not requiring resources beyond those commonly found in most academic laboratories.

Animals↗
PubMed2000

Viral safety of haemophilia treatment products.

The epidemics of HIV and hepatitis C in treated haemophiliacs spurred rapid technological advances in the viral safety of clotting factor concentrates produced from large donor pools. Sequential steps are now employed to minimize infectious risks. The initial viral burden is reduced by screening donors and by testing individual donations and plasma pools for antivirus antibodies, viral antigens, and nucleic acid. These techniques are supplemented by nonspecific viral reduction steps based on physical partitioning and inactivation of pathogens by physical (eg, heat) or chemical (eg, solvent-detergent) means. Although these processes have virtually eliminated the transmission of HIV and hepatitis B and C, there is still evidence that concentrates can transmit small nonenveloped viruses, such as parvovirus B19 and hepatitis A virus. Furthermore, new agents which may not be susceptible to current viral inactivation procedures continue to be identified. Concerns such as these have also given impetus to the development of recombinant clotting factor proteins. Recombinant factor IX concentrate is now produced without the use of human plasma proteins at any step in the manufacturing or formulation process. In practice, the risk of viral transmission by clotting factor concentrates is now so remote that any manipulations to further reduce this risk may be counter-productive, by enhancing cost (hence compromising availability) and potentially promoting other adverse effects such as immunogenicity.

Blood Substitutes↗
PubMed1999

[Which strategies for eradication of tuberculosis?].

Eradication of tuberculosis is biologically feasible because infectious tuberculosis is relatively easy to identify, is treatable and curable, with cure rates approaching 100% when modern short-course therapy is used. Early diagnosis and effective treatment reduce transmission. Infected persons at increased risk of developing infectious tuberculosis can be identified through tuberculin screening of high-risk populations and tuberculosis is, at least partly, preventable by the administration of preventive therapy (chemoprophylaxis) and BCG vaccination. Humans are the primary reservoir of the tubercle bacillus. In industrialized countries, tuberculin testing of dairy cattle and slaughter of infected animals and pasteurization of milk have virtually eliminated the problem. In industrialized countries, tuberculosis has retreated into focal pockets that can be targeted for intensified control efforts. Elimination of tuberculosis in these countries depends in part on global elimination because of imported cases. In developing countries, the immediate task is to control tuberculosis, and DOTS is the key detection and treatment strategy. Joint efforts should address the issue of the global implementation of DOTS strategy and of the research needs for effective vaccine, new drugs and new delivery services.

Animals↗
PubMed1975

Value of the Gravlee Jet Washer in the diagnosis of endometrial cancer.

in 220 women with gynecologic symptoms, endometrial washings were obtained with the Gravlee Jet Washer-in 135 outpatients before office curettage without anesthesia or analgesia; in 85 hospitalized patients before fractional dilatation and curettage under anesthesia. The method was simple, inexpensive, virtually painless, and free of complications. Endometrial adenocarcinoma was present in 12 patients; the jet washing samples were diagnostic in 6 of these. Reported variations in diagnostic accuracy for endometrial carcinoma and precancerous phases raise doubts as to the value of this technic in asymptomatic patients. It is valid for screening symptomatic patients provided results other than normal or positive are further evaluated. Laboratory handling and interpretation must be improved if jet washing is to succeed in mass screening programs.

Adenocarcinoma↗
PubMed1986

Genetic studies on the Tharu population of Nepal: restriction endonuclease polymorphisms of mitochondrial DNA.

The mitochondrial DNAs (mtDNAs) of 91 Tharus from Nepal were screened for restriction fragment length polymorphisms (RFLPs) using six highly informative restriction endonucleases. One pattern (morph) was found for BamHI, two for HpaI and HincII, three for HaeII, four for AvaII, and six for MspI. Two of the AvaII and four of the MspI morphs were "new" (not previously described). Virtually all of the "old" morphs found in the Tharus were previously observed in Orientals. The Oriental HaeII morph (HaeII-5) previously observed at a frequency of 5% was present in 25% of the Tharus. Of the 13 Tharu mtDNA types (defined by the six restriction endonuclease morphs) observed, five had previously been described ("old" types), all in Orientals. Three of these were unique for Orientals. All of the remaining eight "new" Tharu mtDNAs were all closely related to Oriental mtDNAs. Two of the "old" Tharu mtDNA types included the HpaI/HincII morph 1, a morph possibly indicative of the earliest human mtDNA types. From these data we have concluded that the Tharu mtDNAs are closely related to those of other Oriental populations. Further, our data support the hypothesis that human mtDNAs radiated from Asia.

Asian People↗