Biomedical subjects

T Wilson

Publications and source records attributed to T Wilson.

At least 91 records · Page 5Linked to original sources

PubMed1999

Dissociation of mismatch recognition and ATPase activity by hMSH2-hMSH3.

MSH2-MSH3 directs the repair of insertion/deletion loops of up to 13 nucleotides in vivo and in vitro. To examine the biochemical basis of this repair specificity, we characterized the mispair binding and ATPase activity of hMSH2-hMSH3. The ATPase was found to be regulated by a mismatch-stimulated ADP --> ATP exchange, which induces a conformational transition by the protein complex. We demonstrated strong binding of hMSH2-hMSH3 to an insertion/deletion loop containing 24 nucleotides that is incapable of provoking ADP --> ATP exchange, suggesting that mismatch recognition appears to be necessary but not sufficient to induce the intrinsic ATPase. These studies support the idea that hMSH2-hMSH3 functions as an adenosine nucleotide-regulated molecular switch that must be activated by mismatched nucleotides for classical mismatch repair to occur.

Adenosine Diphosphate↗

PubMed1999

Apoptosis induced by overexpression of hMSH2 or hMLH1.

Mutations of the mismatch repair genes hMSH2 and hMLH1 have been found in a high proportion of individuals with hereditary nonpolyposis colon cancer (HNPCC), establishing the link between mismatch repair and cancer. Tumor cell lines that are deficient in mismatch repair develop a mutator phenotype that appears to drive the accumulation of mutations required for tumor development. However, mutations of other mismatch repair genes such as hPMS2 can lead to a mutator phenotype, although inherited mutations of these genes are rare in HNPCC families. Here, we show that overexpression of hMSH2 or hMLH1 but not of hMSH3, hMSH6, or hPMS2 induces apoptosis in either repair-proficient or -deficient cells. Furthermore, primary mouse embryo fibroblasts derived from Msh2-deficient mice lose their ability to undergo apoptosis after treatment with N-methyl-N'-nitro-N-nitrosoguanidine. These results suggest that the mismatch repair proteins hMSH2 and hMLH1 may be components of a pathway that influences apoptosis. We consider the possibility that loss of apoptosis as a result of hMSH2 or hMLH1 deficiency may be an additional factor in cancer predisposition in HNPCC.

Adaptor Proteins, Signal Transducing↗

PubMed1999

hMSH2-hMSH6 forms a hydrolysis-independent sliding clamp on mismatched DNA.

Mismatch recognition by the human MutS homologs hMSH2-hMSH6 is regulated by adenosine nucleotide binding, supporting the hypothesis that it functions as a molecular switch. Here we show that ATP-induced release of hMSH2-hMSH6 from mismatched DNA is prevented if the ends are blocked or if the DNA is circular. We demonstrate that mismmatched DNA provokes ADP-->ATP exchange, resulting in a discernible conformational transition that converts hMSH2-hMSH6 into a sliding clamp capable of hydrolysis-independent diffusion along the DNA backbone. Our results support a model for bidirectional mismatch repair in which stochastic loading of multiple ATP-bound hMSH2-hMSH6 sliding clamps onto mismatch-containing DNA leads to activation of the repair machinery and/or other signaling effectors similar to G protein switches.

Adenosine Triphosphatases↗

PubMed1999

A method for characterizing longitudinal chromatic aberration of microscope objectives using a confocal optical system

We describe a novel method of characterizing the longitudinal chromatic aberration of microscope objectives by recording a series of axial responses as a function of wavelength as a plane reflector is scanned through the focal region of a confocal microscope. Measurements are presented for a variety of objectives with differing degrees of correction. The use of the chromatic focal shift to measure surface profiles is also discussed.

Journal Article↗

PubMed1999

A regional registration technique for automated interval change analysis of breast lesions on mammograms.

Analysis of interval change is a useful technique for detection of abnormalities in mammographic interpretation. Interval change analysis is routinely used by radiologists and its importance is well-established in clinical practice. As a first step to develop a computerized method for interval change analysis on mammograms, we are developing an automated regional registration technique to identify corresponding lesions on temporal pairs of mammograms. In this technique, the breast is first segmented from the background on the current and previous mammograms. The breast edges are then aligned using a global alignment procedure based on the mutual information between the breast regions in the two images. Using the nipple location and the breast centroid estimated independently on both mammograms, a polar coordinate system is defined for each image. The polar coordinate of the centroid of a lesion detected on the most recent mammogram is used to obtain an initial estimate of its location on the previous mammogram and to define a fan-shaped search region. A search for a matching structure to the lesion is then performed in the fan-shaped region on the previous mammogram to obtain a final estimate of its location. In this study, a quantitative evaluation of registration accuracy has been performed with a data set of 74 temporal pairs of mammograms and ground-truth correspondence information provided by an experienced radiologist. The most recent mammogram of each temporal pair exhibited a biopsy-proven mass. We have investigated the usefulness of correlation and mutual information as search criteria for determining corresponding regions on mammograms for the biopsy-proven masses. In 85% of the cases (63/74 temporal pairs) the region on the previous mammogram that corresponded to the mass on the current mammogram was correctly identified. The region centroid identified by the registration technique had an average distance of 2.8+/-1.9 mm from the centroid of the radiologist-identified region. These results indicate that our new registration technique may be useful for establishing correspondence between structures on current and previous mammograms. Once such a correspondence is established an interval change analysis could be performed to aid in both detection as well as classification of abnormal breast densities.

Breast Neoplasms↗

PubMed1999

Metabolic studies on BMS-200475, a new antiviral compound active against hepatitis B virus.

BMS-200475 was recently shown to have potent antiviral activity against hepatitis B virus (50% effective concentration = 3.7 nM; 50% cytotoxic concentration = 30 microM). In metabolic studies in both HepG2 and hepatitis B virus-transfected 2.2.15 human hepatoma cell lines, the metabolism was similar, the primary products being the di- and triphosphates. The accumulation of triphosphate was rapid and detectable down to a 5 nM concentration of added drug. When cells were labeled at 25 microM, the intracellular triphosphate concentration attained 30 pmol/10(6) cells ( approximately 30 microM). The intracellular half-life of the triphosphate was about 15 h. Compared with five other nucleoside analogs of medical interest (lamivudine, penciclovir, ganciclovir, acyclovir, and lobucavir), BMS-200475 was most efficiently phosphorylated to the triphosphate in HepG2 cells.

Antiviral Agents↗

PubMed1999

Immune responses induced in cattle by virulent and attenuated Mycobacterium bovis strains: correlation of delayed-type hypersensitivity with ability of strains to grow in macrophages.

Comparison of immune responses induced in cattle by virulent and attenuated strains of Mycobacterium bovis will assist in identifying responses associated with resistance or susceptibility to disease. Four strains of M. bovis, one which is virulent in guinea pigs (WAg201) and three which are attenuated in guinea pigs (an isoniazid-resistant strain [WAg405], ATCC 35721, and BCG) were compared for their abilities to induce immune responses in cattle and to grow in bovine lung alveolar macrophage cultures. Extensive macroscopic lesions were found only in cattle inoculated with the virulent M. bovis strain. Strong antibody responses to M. bovis culture filtrate, as well as persistently high levels of gamma interferon and interleukin-2 released from purified protein derivative (PPD)-stimulated peripheral blood lymphocyte cultures, were observed in the cattle inoculated with the virulent strain compared to those inoculated with the attenuated strains. All cattle inoculated with the virulent strain or two of the attenuated strains (WAg405 and ATCC 35721) elicited strong delayed-type hypersensitivity responses to PPD in skin tests, while animals inoculated with BCG induced only a weak response. The three strains which produced strong skin test responses proliferated well in bovine alveolar macrophages and induced high levels of proinflammatory cytokine mRNAs compared to BCG. Our study showed that skin test responsiveness to PPD correlated with the ability of the strains to grow in alveolar macrophages rather than to their pathogenicity in cattle.

Animals↗

PubMed1999

Vaccination of guinea pigs with nutritionally impaired avirulent mutants of Mycobacterium bovis protects against tuberculosis.

Four nutritionally impaired strains of Mycobacterium bovis produced by illegitimate recombination were tested for their ability to protect guinea pigs against intratracheal challenge with virulent M. bovis. All four strains and M. bovis BCG induced significant levels of protection as measured by the reduced spread of infection to the spleen and liver. In animals vaccinated with BCG or two of the other strains, the bacterial counts from the lungs were significantly lower than those of the nonvaccinated animals.

Animals↗

PubMed1999

Physical and functional interactions between the herpes simplex virus UL15 and UL28 DNA cleavage and packaging proteins.

Herpes simplex virus (HSV) DNA is cleaved from concatemers and packaged into capsids in infected cell nuclei. This process requires seven viral proteins, including UL15 and UL28. UL15 expressed alone displays a nuclear localization, while UL28 remains cytoplasmic. Coexpression with UL15 enables UL28 to enter nuclei, suggesting an interaction between the two proteins. Additionally, UL28 copurified with UL15 from HSV-infected cells after ion-exchange and DNA affinity chromatography, and the complex sedimented as a 1:1 heterodimer upon sucrose gradient centrifugation. These findings are evidence of a physical interaction of UL15 and UL28 and a functional role for UL15 in directing UL28 to the nucleus.

Animals↗

PubMed1999

A student selection method and predictors of success in a graduate nursing program.

This article describes the development and implementation of a graduate student selection method and preliminary results validating the effectiveness of the process. A detailed description of the process is presented to allow replication. Preliminary investigations indicate that the new process is more efficient of faculty time and that students admitted using the new process function at least as well as those admitted under a previous method.

Education, Nursing, Graduate↗

PubMed1999

Interlaboratory comparison of ultrasonic backscatter, attenuation, and speed measurements.

In a study involving 10 different sites, independent results of measurements of ultrasonic properties on equivalent tissue-mimicking samples are reported and compared. The properties measured were propagation speed, attenuation coefficients, and backscatter coefficients. Reasonably good agreement exists for attenuation coefficients, but less satisfactory results were found for propagation speeds. As anticipated, agreement was not impressive in the case of backscatter coefficients. Results for four sites agreed rather well in both absolute values and frequency dependence, and results from other sites were lower by as much as an order of magnitude. The study is valuable for laboratories doing quantitative studies.

1-Propanol↗

PubMed1999

Linking 1991 population statistics to the 1998 local government geography of Great Britain.

This article describes how 1991 population statistics and other data based on the 1991 Census areas can be produced for the 1998 local authority geography of Great Britain. Since 1991 a large number of boundary changes have taken place rendering comparisons of population data before and after the changes problematic. Re-basing 1991 statistics on the current set of boundaries allows real demographic change over the period since 1991 to be measured. The article focuses on two sets of population statistics: 1991 Census data and mid-1991 estimates.

Adolescent↗

PubMed1998

Primary care groups. View to a skill.

Training is of critical importance to the successful development of PCGs. There are particular needs for developing strategic planning capacities. PCGs will need to understand and adopt many public health skills.

Group Practice↗

PubMed1998

Cranberry extract inhibits low density lipoprotein oxidation.

Cranberry juice consumption is often used for the treatment of urinary tract infections, but the effect of cranberry juice on heart disease has not been investigated. We evaluated how a cranberry extract containing 1,548 mg gallic acid equivalents/liter (initial pH=2.50) affected low density lipoprotein (LDL) oxidation induced by 10 micromolar cupric sulfate. When LDL oxidation took place in the presence of diluted cranberry extracts, the formation of thiobarbituric acid reactive substances (TBARS) and LDL electrophoretic mobility were reduced. LDL electrophoretic migration was also reduced when the cranberry extract had a pH of 7.00 prior to dilution. This study suggests that cranberry extracts have the ability to inhibit the oxidative modification of LDL particles.

Adult↗

PubMed1998

Liposome encapsulated prostaglandin E1 in erectile dysfunction: correlation between in vitro delivery through foreskin and efficacy in patients.

OBJECTIVES: To test the delivery of prostaglandin E1 (PGE1) in novel transdermal liposomal formulations through foreskin and to determine whether there is a correlation between in vitro transdermal absorption and in vivo efficacy in patients with erectile dysfunction. METHODS: The in vitro transdermal absorption of PGE1 through excised foreskin from liposomal formulations was tested in diffusion cells using radiolabeled drug. The in vivo studies were carried out on 5 patients (aged 54 to 70 years) in a double-blind, placebo-controlled fashion. The patients were treated topically on the penis with three different active formulations containing 0.05% PGE1 and a placebo at least 1 week apart. The change in systolic peak flow velocities in the cavernosal arteries after treatment was monitored by duplex color Doppler ultrasonography with spectral analysis every 15 minutes for 1 hour. RESULTS: The permeability coefficient (Kp) of PGE1 from the three liposomal formulations tested was found to be 0. 10, 1.66, and 3.82 x 10(-4) cm/hr, respectively. Peak systolic flow velocities in the deep cavernosal arteries of patients increased significantly compared with preapplication values (0.05 < P < or = 0.1) after application of two of the transdermal liposomal PGE1 formulations tested (the two with the highest Kp). The highest mean peak systolic flow velocity was achieved at 45 minutes after application of the formulations. The most effective formulation in this study resulted in a sevenfold increase in mean flow velocity compared with baseline values. CONCLUSIONS: Topical application of PGE1 in a novel transdermal liposomal delivery system can enhance penetration of the drug into the deep cavernosal bodies and increase peak systolic flow velocities in patients with erectile dysfunction. The transdermal flux and permeability of PGE1 measured in vitro correlate well with the color Doppler ultrasound results in patients. The efficacy of a formulation in the development process may be predicted from in vitro absorption studies.

Aged↗

PubMed1998

Identification of potential CD8+ T-cell epitopes of the 19 kDa and AhpC proteins from Mycobacterium tuberculosis. No evidence for CD8+ T-cell priming against the identified peptides after DNA-vaccination of mice.

Mycobacterium tuberculosis is one of the major killers among infectious agents. It is of great importance to develop an efficient vaccine against M. tuberculosis since the only available vaccine, M. bovis-BCG, has a low efficacy. Furthermore, the emergence of multi-drug-resistant M. tuberculosis strains makes it difficult to cure the disease. CD8+ T cells have been implied to play an important role in protective immunity against M. tuberculosis. A good vaccination strategy for the induction of cytotoxic CD8+ T-cell responses is naked DNA-injection of eukaryotic expression vectors. The use of DNA-injection in an attempt to induce cytotoxic CD8+ T-cell responses against epitopes of the 19 kDa or AhpC proteins from M. tuberculosis in mice was studied. MHC class I binding assays, of peptides derived from these proteins, demonstrated the presence of potential CD8+ T-cell epitopes. However, CD8+ T-cell responses against the peptides after DNA-injection were not detected. Furthermore, no difference in the kinetics of bacterial clearance was observed in vaccinated versus unvaccinated animals, even though 19 kDa and AhpC specific antibodies were readily detected in the serum of vaccinated animals. Taken together these results suggest that the 19 kDa and AhpC genes are not good candidates for DNA vaccines against M. tuberculosis.

Amino Acid Sequence↗

PubMed1998

Case report: management of significant incisor root resorption associated with maxillary canine impaction.

Orthodontic and periodontic management of a patient with bilaterally impacted maxillary canines and advanced resorption of the adjacent lateral incisors is presented. In treating the patient, the affected laterals were retained and the canines were surgically exposed, then moved away from the roots of the laterals and into position in the arch. Alternative treatment strategies are discussed. Long-term follow-up evaluation revealed successful maintenance of the dentition and of periodontal health.

Adolescent↗

PubMed1998

Real-time three-dimensional imaging of macroscopic structures.

We describe an extremely simple method of obtaining optically sectioned images with conventional low-power imaging systems in real time. A single spatial frequency grid pattern is projected onto an object. Images taken at three spatial positions of the grid projection are processed to provide 3D images of macroscopic structures.

Journal Article↗