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PubMed1998

Validation of transgenic mice harboring the human prototype c-Ha-ras gene as a bioassay model for rapid carcinogenicity testing.

Studies were conducted to validate the transgenic (Tg) mice harboring human prototype c-Ha-ras gene, namely the rasH2 mice (CB6F1), as a model for rapid carcinogenicity testing. Short-term (26 weeks) carcinogenicity testing of 18 mutagenic (Salmonella) trans-species carcinogens, two mutagenic single-species (mouse-only) carcinogens, six non-mutagenic trans-species carcinogens, one non-mutagenic single-species (mouse-only) carcinogen, four mutagenic non-carcinogens and four non-mutagenic non-carcinogens were completed. The studies revealed that the Tg mice are able to detect various types of mutagenic carcinogens and may also detect various non-mutagenic carcinogens within 26 weeks. Dose-dependent tumor responses were observed with various carcinogens except for a few equivocal cases. The validation studies also revealed that the Tg mice are generally much more susceptible to both mutagenic and non-mutagenic carcinogens than control non-Tg mice. Most of the malignant tumors were observed in the carcinogen-treated Tg mice and only very few or none in the corresponding non-Tg mice. Most of the carcinogens tested induced some of the target organ tumors observed in B6C3F1 mice in a 2-year bioassay as well as certain types of tumors specific to the Tg mice, i.e. lung alveolar epithelial tumors, spleen hemangiosarcomas, forestomach squamous cell tumors. No significant tumor induction has been observed in the Tg mice either with mutagenic or non-mutagenic non-carcinogens. Although further validation studies are still required, the rasH2 mouse seems to be a promising candidate as an animal model for the development of a rapid carcinogenicity testing system.

Animals↗
PubMed2003

Messenger RNA profiling: a prototype method to supplant conventional methods for body fluid identification.

Conventional methods of body fluid identification use a variety of labor-intensive, technologically diverse techniques that are performed in a series, not parallel, manner and are costly in terms of time and sample. Theoretically, the identification of a body fluid may be made by determining a sufficient number of mRNAs that are expressed exclusively in cells that collectively comprise that body fluid. Advantages of an mRNA-based approach, compared to conventional biochemical methods of analysis, include greater specificity, simultaneous and semi-automatic analysis through a common assay format, improved timeliness, decreased sample consumption and compatibility with DNA extraction methodologies. In this report, we demonstrate that RNA is stable in biological stains and can be recovered in sufficient quantity and quality for analysis. Messenger RNA from the housekeeping genes S15, beta-actin and GAPDH was detected in blood, semen and saliva stains using a sensitive reverse transcriptase-polymerase chain reaction assay (RT-PCR). Additionally, we have identified a number of candidate tissue-specific genes, statherin, histatin 3, PRB1, PRB2 and PRB3 that may be useful for the positive identification of saliva. Messenger RNAs from these genes were detectable in saliva stains but not in blood or semen stains. Collectively these findings constitute the basis of a prototype RNA based assay system that may eventually supplant conventional methods for body fluid identification.

Actins↗
PubMed1993

A prototype stable RNA identification cassette for monitoring plasmids of genetically engineered microorganisms.

A prototype stable RNA identification cassette for monitoring genetically engineered plasmids carried by strains of Escherichia coli has been developed. The cassette consists of a Vibrio proteolyticus 5S ribosomal RNA (rRNA) gene surrounded by promoters and terminators from the rrnB operon of Escherischia coli. The identifier RNA is expressed and successfully processed so that approximately 30% of the 5S rRNA isolated from either whole cells or 70S ribosomes is of the V. proteolyticus type. Cells carrying the identifier are readily detectable by hybridization. Accurate measurements show that the identification cassette has little effect on fitness compared to a strain containing an analogous plasmid carrying wild type E. coli 5S rRNA, and the V. proteolyticus 5S rRNA gene is not inactivated after prolonged growth. These results demonstrate the feasibility of developing small standardized identification cassettes that can utilize already existing highly sensitive rRNA detection methods. Cassettes of this type could in principle be incorporated into either the engineered regions of recombinant plasmids or their hosts.

Base Sequence↗
PubMed2003

Biplane stress echocardiography using a prototype matrix-array transducer.

BACKGROUND: Rapid image acquisition after cessation of exercise is essential for accurate stress echocardiography. Recently, a prototype matrix-array transducer has been developed that allows simultaneous acquisition of 2 imaging planes (biplane [BP] imaging). METHODS: In all, 19 healthy volunteers underwent 2 separate stress echocardiographic studies. Images were acquired in traditional 2-dimensional or BP format pre-exercise and postexercise. RESULTS: Total image acquisition time for 2-dimensional stress echocardiography was 38 +/- 8 seconds versus 29 +/- 8 seconds for BP imaging (P <.05). Heart rates were acquired closer to age-predicted maximum with BP imaging in the apical 3- and 2-chamber and parasternal long- and short-axis views (82%, 75%, 70%, 70% for BP vs 76%, 72%, 68%, 66% for 2-dimensional, respectively). CONCLUSION: BP imaging using a recently developed matrix-array probe allows more rapid imaging postexercise, resulting in acquisition of poststress images at higher heart rates without compromising image quality.

Acoustics↗
PubMed1998

Acute heat stress model of seizures in weanling rats: influence of prototypic anti-seizure compounds.

The present study tested the therapeutic potential for prototype anti-epilepsy drugs using an animal model of infantile febrile seizures. The model consisted of immersion of weanling rats (21 days old) in a 45 degrees C water bath for a maximum of 4 min (four exposures over a 2 week period) and observing for the progression to stage-5 seizures. All compounds were administered orally at the respective ED50 for prevention of seizures in the maximal electroshock (MES) test. Clonazepam effectively lowered the score for seizure grade, shortened the duration of seizures, as well as reduced the number of animals experiencing seizures during three of the four testing periods. MK801 reduced both the maximum seizure grade, and the number of animals experiencing seizures during sessions two and three. However, the dose of MK801 caused behavioral side effects. Valproate actively decreased seizure grade, while it modestly acted to attenuate seizure duration, extended the time to seizure onset, and reduced the number of animals experiencing seizures on testing day 1. Remacemide hydrochloride and phenobarbital were not effective. The method appears useful for evaluating the potential of agents to prevent acute febrile seizures.

Acute Disease↗
PubMed1991

Restriction site mapping of subgenus D adenoviruses, prototypes 42-47, intermediate and atypical strains.

Restriction site maps with the endonucleases BamHI, BgIII, and HindIII were elaborated for 19 adenovirus strains of subgenus D, namely candidates AV42 to 47, 6 intermediate and 7 atypical strains. On the basis of several types mapped by biochemical methods, the physical maps for the 19 strains were constructed by adapting restriction fragments of defined molecular weight to the known maps, as the homology among strains within this subgenus is considerable. Other prototypes mapped by adaptation were also used for reference. The localization of the restriction sites on the genome was analyzed for all mapped types or strains of subgenus D (except AV8). The sites appeared to be randomly distributed; only one site was common to all strains.

Adenoviruses, Human↗
PubMed2003

Collagenous transmembrane proteins: collagen XVII as a prototype.

Collagenous transmembrane proteins are an emerging group of biologically versatile molecules which function as both cell surface receptors and matrix molecules. The seven group members have interesting structural similarities: they are integral membrane proteins in type II orientation and have one or more collagenous domains in the extracellular C-terminus; interspersed by non-collagenous stretches which confer structural flexibility to the ectodomain. A conserved coiled-coil sequence (linker domain) immediately adjacent to the extracellular face of the cell membrane presumably serves as a nucleus for trimerization and triple-helix folding of each collagen. Intriguingly, the ectodomains of at least some of these molecules are proteolytically shed from the cell surface, releasing a shorter form of the collagen into the extracellular matrix. Collagenous transmembrane proteins are expressed in many different tissues and cells, and are involved in a broad spectrum of biological functions, reaching from epithelial and neural cell adhesion, and epithelial-mesenchymal interactions during morphogenesis to host defense against microbial agents. Several group members are involved in the molecular pathology of genetic and acquired human diseases including epidermolysis bullosa, ectodermal dysplasia, bullous pemphigoid or Alzheimer disease. An extensively investigated member is collagen XVII, a keratinocyte surface protein, which attaches the epidermis to the basement membrane in the skin. In this review, the structure and functions of the currently known collagenous transmembrane proteins are summarized and, as a 'prototype' of the group, collagen XVII and its biology and pathophysiology are delineated.

Amino Acid Sequence↗
PubMed1998

Molecular lipophilicity potential by CLIP, a reliable tool for the description of the 3D distribution of lipophilicity: application to 3-phenyloxazolidin-2-one, a prototype series of reversible MAOA inhibitors.

The capacity factor of eleven derivatives belonging to a prototype series of 3-phenyloxazolidin-2-one, reversible MAO inhibitors, was measured and compared to the calculated log Pcalc using the CLIP package. We demonstrate that this Molecular Lipophilicity Potential (MLP) approach is a valuable tool to estimate log Pcalc of such compounds.

Chromatography, High Pressure Liquid↗
PubMed2000

Calmodulin: a prototypical calcium sensor.

Calmodulin is the best studied and prototypical example of the E-F-hand family of Ca2+-sensing proteins. Changes in intracellular Ca2+ concentration regulate calmodulin in three distinct ways. First, at the cellular level, by directing its subcellular distribution. Second, at the molecular level, by promoting different modes of association with many target proteins. Third, by directing a variety of conformational states in calmodulin that result in target-specific activation. The calmodulin-dependent regulation of protein kinases illustrates the potential mechanisms by which Ca2+-sensing proteins can recognize and generate affinity and specificity for effectors in a Ca2+-dependent manner.

Amino Acid Sequence↗
PubMed2001

Escherichia coli GlpE is a prototype sulfurtransferase for the single-domain rhodanese homology superfamily.

BACKGROUND: Rhodanese domains are structural modules occurring in the three major evolutionary phyla. They are found as single-domain proteins, as tandemly repeated modules in which the C-terminal domain only bears the properly structured active site, or as members of multidomain proteins. Although in vitro assays show sulfurtransferase or phosphatase activity associated with rhodanese or rhodanese-like domains, specific biological roles for most members of this homology superfamily have not been established. RESULTS: Eight ORFs coding for proteins consisting of (or containing) a rhodanese domain bearing the potentially catalytic Cys have been identified in the Escherichia coli K-12 genome. One of these codes for the 12-kDa protein GlpE, a member of the sn-glycerol 3-phosphate (glp) regulon. The crystal structure of GlpE, reported here at 1.06 A resolution, displays alpha/beta topology based on five beta strands and five alpha helices. The GlpE catalytic Cys residue is persulfurated and enclosed in a structurally conserved 5-residue loop in a region of positive electrostatic field. CONCLUSIONS: Relative to the two-domain rhodanese enzymes of known three-dimensional structure, GlpE displays substantial shortening of loops connecting alpha helices and beta sheets, resulting in radical conformational changes surrounding the active site. As a consequence, GlpE is structurally more similar to Cdc25 phosphatases than to bovine or Azotobacter vinelandii rhodaneses. Sequence searches through completed genomes indicate that GlpE can be considered to be the prototype structure for the ubiquitous single-domain rhodanese module.

Amino Acid Sequence↗
PubMed2002

Structure of acetylglutamate kinase, a key enzyme for arginine biosynthesis and a prototype for the amino acid kinase enzyme family, during catalysis.

N-Acetyl-L-glutamate kinase (NAGK), a member of the amino acid kinase family, catalyzes the second and frequently controlling step of arginine synthesis. The Escherichia coli NAGK crystal structure to 1.5 A resolution reveals a 258-residue subunit homodimer nucleated by a central 16-stranded molecular open beta sheet sandwiched between alpha helices. In each subunit, AMPPNP, as an alphabetagamma-phosphate-Mg2+ complex, binds along the sheet C edge, and N-acetyl-L-glutamate binds near the dyadic axis with its gamma-COO- aligned at short distance from the gamma-phosphoryl, indicating associative phosphoryl transfer assisted by: (1) Mg2+ complexation; (2) the positive charges on Lys8, Lys217, and on two helix dipoles; and (3) by hydrogen bonding with the y-phosphate. The structural resemblance with carbamate kinase and the alignment of the sequences suggest that NAGK is a structural and functional prototype for the amino acid kinase family, which differs from other acylphosphate-making devices represented by phosphoglycerate kinase, acetate kinase, and biotin carboxylase.

Amino Acid Sequence↗
PubMed1999

Crystal structure of the ATPase domain of translation initiation factor 4A from Saccharomyces cerevisiae--the prototype of the DEAD box protein family.

BACKGROUND: Translation initiation factor 4A (elF4A) is the prototype of the DEAD-box family of proteins. DEAD-box proteins are involved in a variety of cellular processes including splicing, ribosome biogenesis and RNA degradation. Energy from ATP hydrolysis is used to perform RNA unwinding during initiation of mRNA translation. The presence of elF4A is required for the 43S preinitiation complex to bind to and scan the mRNA. RESULTS: We present here the crystal structure of the nucleotide-binding domain of elF4A at 2.0 A and the structures with bound adenosinediphosphate and adenosinetriphosphate at 2.2 A and 2.4 A resolution, respectively. The structure of the apo form of the enzyme has been determined by multiple isomorphous replacement. The ATPase domain contains a central seven-stranded beta sheet flanked by nine alpha helices. Despite low sequence homology to the NTPase domains of RNA and DNA helicases, the three-dimensional fold of elF4A is nearly identical to the DNA helicase PcrA of Bacillus stearothermophilus and to the RNA helicase NS3 of hepatitis C virus. CONCLUSIONS: We have determined the crystal structure of the N-terminal domain of the elF4A from yeast as the first structure of a member of the DEAD-box protein family. The complex of the protein with bound ADP and ATP offers insight into the mechanism of ATP hydrolysis and the transfer of energy to unwind RNA. The identical fold of the ATPase domain of the DNA helicase PcrA of B. stearothermophilus and the RNA helicase of hepatitis C virus suggests a common fold for all ATPase domains of DExx- and DEAD-box proteins.

Adenosine Diphosphate↗
PubMedDate not supplied

Calibration of a prototype in vivo total body composition analyser using 14 MeV neutron activation and the associated particle technique.

A prototype in vivo total body composition analyser has been constructed for determining the total body contents of nitrogen (TBN), carbon (TBC) and oxygen (TBO) in young experimental animals such as sheep or pigs by 14 MeV neutron activation using a commercially available associated particle sealed tube neutron generator (APSTNG). The instrument was calibrated by scanning phantoms of different sizes in the mass range 10-36 kg, filled with a mixture of elements as found in a normal human body. Good agreement was found between the measured and expected values of N, O and C when two phantoms of similar dimensions but of different composition were scanned. With four 15 cm x 15 cm cross section and 45 cm long NaI(T1) gamma detectors and a radiation dose of approximately 20 microSv due to neutrons, the expected precisions for a 28 kg animal, CV% (based on counting statistics) are N: 9.3, C: 2.3 and O: 1.4.

Animals↗
PubMed1999

Self-adapting washer system for lag screw fixation of mandibular fractures. Part II: In vitro mechanical characterization of 2.3 and 2.7 mm lag screw prototypes and in vivo removal torque after healing.

The aim of this study was to mechanically characterize self-tapping 2.3 and 2.7 mm titanium lag screw prototypes which are part of the newly developed 'self-adapting washer' maxillofacial lag screw osteosynthesis system. In vitro in a screw testing machine the insertion torque, maximum locking torque and axial force and the ultimate torsional strength were assessed. In vivo in six miniature pigs using a mandibular symphyseal fracture model, the removal torques after 3 and 6 months of healing were measured. Additionally the bone-metal contact (BMC) of the screws was assessed histometrically. The maximum insertion torque (0.185 Nm) was far below the mechanical limits of the screws (2.3 mm = 0.96 Nm, 2.7 mm = 1.6 Nm). A tightening of the 2.7 mm screw with an axial force of 1000 N and of the 2.3 mm screw with 500-550 N leaves a safety margin of approximately one-third on the ultimate torsional strength. Clinically these values permit the use of two 2.3 mm lag screws or one 2.7 mm lag screw in mandibular symphysis fractures since 1000 N tensile axial force are required in this indication. During screw removal after 6 months healing, torque levels close to the mechanical limits of the screws were recorded and screw failures were observed. This failure rate may have been due to the BMC of 49.8% which was in the range of titanium dental implants. Accordingly the screw heads were reinforced to prevent fractures.

Animals↗
PubMed1997

A prototype simulator for endovascular repair of abdominal aortic aneurysms.

A prototype simulator for training in endovascular repair of abdominal aortic aneurysms (AAA) has been developed. Employing transparent models of human AAA complete with renal, iliac and femoral arteries, this system allows accurate simulation of aortography, road-mapping, catheter guidewire manipulation and stent-graft deployment while obviating the need for ionising radiation.

Aortic Aneurysm, Abdominal↗
PubMed1997

Preliminary experience with medical applications of rapid prototyping by selective laser sintering.

Rapid prototyping techniques, originally developed for building components from computer aided designs in the motor industry, are now being applied in medicine to build models of human anatomy from high resolution multiplanar imaging data such a computed tomography (CT). The established technique of stereolithography and the more recent selective laser sintering (SLS), both build up an object layer by layer. Models have applications in surgical planning, for the design of customised implants and for training. Preliminary experience of using the SLS technique for medical applications is described, addressing questions regarding image processing, data transfer and manufacture. Pilot models, built from nylon, included two skills (a child with craniosynoslosis and an adult with hypertetorism) and a normal femur which was modelled for use in a bioengineering test of an artificial hip. The dimensions of the models were found to be in good agreement with the CT data from which they were built-for the child's skull the difference between the model and the CT data was less than 1.0 +/- 0.5 mm in each direction. Our experience showed that, with care, a combination of existing software packages may be used for data conversion. Ideally, image data of high spatial resolution should be used. The pilot models generated sufficient clinical interest for the technique to be pursued in the orthopaedic field.

Adult↗
PubMed1998

In-house development of test equipment for quality control and training. Case study: a prototype ECG simulator-tester.

The support services for biomedical technology address a variety of technical and administrative issues, concerning the safe and efficient operation of medical equipment over the period of its intended use and the training of hospital personnel in issues concerning safety and quality. Clinical Engineering Departments undertake the responsibility of developing and operating training programs in medical equipment utilisation apart from the traditional role of training and supervising technicians involved in testing, calibration and preventive/corrective maintenance of electromedical equipment. In view of the above, the Institute of Biomedical Technology and the Centre of Biomedical Engineering collaborated for the design and development of a prototype digital ECG and arrhythmia simulator. In the absence of internationally accepted inspection protocols for ECG simulators, the verification phase of the project involved mainly the inspection of the device's conformity to its initial technical specifications. The results demonstrated that this tester. due to simplicity in construction and easiness of use could be a practical, reliable and economical solution for electrocardiograph and ECG monitor testing and waveform recognition training.

Arrhythmias, Cardiac↗