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Biomedical subjects

M Collins

Publications and source records attributed to M Collins.

At least 73 records · Page 4Linked to original sources
PubMed2000

Prevention and treatment of factor VIII inhibitors in murine hemophilia A.

Inhibitory antibody formation is a major complication of factor VIII replacement therapy in patients with hemophilia A. To better understand the pathogenesis of this immunologic reaction, we evaluated the role of T-cell costimulatory signals for antifactor VIII antibody formation in a murine model of hemophilia A. Repeated intravenous injections of factor VIII in these factor VIII-deficient mice induced an antifactor VIII inhibitor antibody response. This response was shown to be T-cell dependent by its absence in hemophilic mice also deficient for the T-cell costimulatory ligand B7-2. In separate experiments, injection of murine CTLA4-Ig completely blocked the primary response to factor VIII in hemophilic mice with intact B7 function. This reagent also prevented or diminished further increases in antifactor VIII when given to hemophilic mice with low antifactor VIII antibody titers. These studies suggest that strategies targeting the B7-CD28 pathway are potential therapies to prevent and treat inhibitory antifactor VIII antibodies. Moreover, because the development of antibodies to replaced proteins may limit the success of many human gene therapy approaches, our results may be broadly applicable. (Blood. 2000;95:1324-1329)

Abatacept↗
PubMed2000

Procedural costs of digital vs. analog archiving of diagnostic cardiac catheterizations.

The use of digital technology in the cardiac catheterization laboratory is expanding at a rapid pace. The cost-effectiveness of this new technology is yet to be proven. The aims of this study were to determine the direct cost differences of digital versus analog media (CDs) for the storage of diagnostic cardiac catheterizations and to explore the factors influencing these differences. Procedural costs of all diagnostic angiograms (n = 109), from three physicians, performed in an analog catheterization laboratory (room A) and a digital catheterization laboratory (room C) were compared during a 9-month period. The mean procedural cost was higher in room A than in room C ($1,102 vs. $1,087, P < 0.001). This cost difference was eliminated when recording media costs were excluded from analysis ($1,079 vs. $1,080, P = 0.931). Therefore, we conclude there is a procedural cost savings in a cardiac catheterization room that uses digital CDs versus cineangiogram film as the archival media. Cathet. Cardiovasc. Intervent. 49:246-250, 2000.

Cardiac Catheterization↗
PubMed2000

Paradoxical inhibition of T-cell function in response to CTLA-4 blockade; heterogeneity within the human T-cell population.

T-cell co-stimulation delivered by the molecules B7-1 or B7-2 through CD28 has a positive effect on T-cell activation, whereas engagement of cytotoxic T-lymphocyte antigen 4 (CTLA-4) by these molecules inhibits activation. In vivo administration to mice of blocking monoclonal antibodies or Fab fragments against CTLA-4 can augment antigen-specific T-cell responses and, thus, therapy with monoclonal antibody against CTLA-4 has potential applications for tumor therapy and enhancement of vaccine immunization. The effects of B7-1 and B7-2 co-stimulation through CD28 depend on the strength of the signal delivered through the T-cell receptor (TCR) and the activation state of T cells during activation. Thus, we sought to determine whether these factors similarly influence the effect of B7-mediated signals delivered through CTLA-4 during T-cell activation. Using freshly isolated human T cells and Fab fragments of a monoclonal antibody against CTLA-4, we demonstrate here that CTLA-4 blockade can enhance or inhibit the clonal expansion of different T cells that respond to the same antigen, depending on both the T-cell activation state and the strength of the T-cell receptor signal delivered during T-cell stimulation. Thus, for whole T-cell populations, blocking a negative signal may paradoxically inhibit immune responses. These results provide a theoretical framework for clinical trials in which co-stimulatory signals are manipulated in an attempt to modulate the immune response in human disease.

Abatacept↗
PubMed2000

Vascular endothelial growth factor and basic fibroblast growth factor are found in resolving venous thrombi.

OBJECTIVE: Resolution of venous thrombi is accompanied by an ingrowth of capillaries, which appears to be analogous to angiogenesis in other tissues. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are major regulators of angiogenesis. The aim of this study was to determine the temporal changes and the location of VEGF and bFGF expression in a rat model of venous thrombus resolution. DESIGN AND METHODS: Thrombi were induced in the inferior venae cavae of rats by creating a stenosis to reduce blood flow by 80% to 90%. Thrombi, adjacent inferior vena cava wall, and systemic blood were collected at 1, 3, 7, 14, 21, and 28 days after thrombus generation (n = 9). Sham operations were performed (n = 5), and blood was collected at 1, 3, and 7 days. VEGF and bFGF were measured with specific immunoassays, and levels in tissues were expressed as picogram per milligram soluble protein. Tissues from two animals that were humanely killed 7 days after thrombus formation were prepared for histological examination. Immunohistochemistry was performed by the use of antibodies against VEGF, bFGF, and ED-1 (a monocyte/macrophage marker). RESULTS: Laminated thrombi were reliably produced with a median weight at 1 day of 39 mg (range, 23-63 mg). There was a significant increase in thrombus VEGF concentration between 1 day (median, 247; range, 0-514) and 7 days (median, 556; range, 254-1741) (P =.02). There was no difference between the seventh day and subsequent days. There was a positive linear correlation between thrombus bFGF concentration and time (R = 0.74, P <.0001), with a more than 300-fold increase in bFGF concentration over the 28 days of the study. VEGF and bFGF concentrations in the adjacent vena caval wall did not change significantly with time. The serum VEGF was significantly raised at 1 day (median, 5520 pg/mL; range, 4040-7912 pg/mL) and 3 days (median, 3880 pg/mL; range, 2564-7232 pg/mL) compared with 7 days (median, 1790 pg/mL; range, 232-3228 pg/mL) (P <.0001). Similar changes in the serum VEGF also developed in the sham-operated animals. The serum bFGF (day 1 median, 15.5 pg/mL; range, 1-42 pg/mL) did not change with time. Immunohistochemistry showed that the VEGF antigen was localized to monocytes, endothelial cells, and spindle-shaped cells within the thrombus. The bFGF antigen was localized to mononuclear cells and spindle-shaped cells and was also present in the extracellular matrix. CONCLUSION: VEGF and bFGF are found in organizing thrombi and have characteristic temporal expression patterns, which suggest that they have a role in thrombus resolution. Augmenting angiogenic growth factor expression may enhance thrombus recanalization, thus reducing long-term complications.

Animals↗
PubMed2000

Traceable calibration of ultraviolet meters used with broadband, extended sources.

A calibration system has been developed to provide increased accuracy in the measurement of the irradiance responsivity appropriate for UV meters used with broadband, extended sources of the type employed in phototherapy. The single wavelength responsivity of the test meter is obtained in the wavelength range 250-400 nm by intercomparison with a transfer standard meter in a narrow, monochromatic beam. Traceability to primary standard irradiance scales is provided via the National Measurement System with a best uncertainty of 7% (at 95% confidence). The effective responsivity of the test meter, when used with broadband extended sources, is calculated using the measured spectral and angular response of the meter and tabulated data on the spectral and spatial characteristics of the source radiance. The uncertainty in the effective responsivity, independent of the source variability, is estimated to be 10% (at 95% confidence). The advantages of this calibration system over existing approaches are discussed.

Calibration↗
PubMed2000

Evaluating 'Safe in the Sun', a curriculum programme for primary schools.

Eleven schools in the south of England took part in a trial of 'Safe in the Sun', a curriculum programme for primary school aged pupils. Case study methodology and the 'draw and write' technique were combined to evaluate changes in pupils' perceptions of the effects of the sun on their skin. Teachers were free to use the materials, consisting of a teacher's handbook and video, as they wished. Pupils in all schools showed higher levels of awareness of sun-safety measures in post-intervention studies compared with the levels recorded 4 months earlier. Chi-square analysis revealed that those pupils whose teachers had used the materials as recommended by the authors had significant increases in awareness and knowledge about keeping safe in the sun, compared with other levels of intervention. More pupils also appeared able to transfer their awareness to the context of the school playground, although the differences were not significant for any level of intervention. The discussion focuses on the value of the 'draw and write' technique as a tool for illuminative evaluation, on the factors which contributed to the pupils increased awareness of sun safety and on the importance of a whole school approach to sun safety.

Child↗
PubMed2000

Personnel exposure during gamma endovascular brachytherapy.

PURPOSE: The use of 192Ir brachytherapy for the treatment of in-stent restenosis of the coronary arteries has shown promising clinical results. This paper investigates the radiation exposure of catheterization laboratory staff associated with the performance of this procedure. METHODS AND MATERIALS: Cath lab staff were monitored using personal monitors (shielded against fluoroscopic x-rays) during the performance of eleven cases using nominal 10 GBq 192Ir sources. Staff positions in the lab were simultaneously tracked by video cameras. Direct measurements were also made using a survey meter. Treatments were administered in a conventional cardiac-catheterization-laboratory. RESULTS: The dosimeter readings were analyzed in combination with the radiation survey and time motion survey. Brachytherapy procedural times for the cardiologist, oncologist, physicist, and angiographic assistants were, respectively, 26 +/- 24, 401 +/- 132, 486 +/- 148, and 7 +/- 13 s per case (mean +/- standard deviation). Readings of the personnel monitors were low. Credible upper limits of the respective doses are estimated to be less than 10, 10, 7, and 5 microSv per procedure. Auxiliary shields reduced the dose to individuals located outside of the catheterization laboratory to less than 0.5 microSv per procedure. CONCLUSIONS: The average radiation dose received by laboratory personnel during a representative 192Ir endocoronary brachytherapy procedure is estimated to be less than 0.1% of the NCRP recommended annual radiation worker's Maximum Permissible Dose (1% of the general public's MPD). This level is justifiable as long as the use of 192Ir benefits patients by producing an improved clinical outcome relative to the use of a less penetrating radionuclide or the application of alternative therapies. Further optimization of the delivery procedure is expected to reduce staff dose.

Brachytherapy↗
PubMed2000

Effects of atovaquone and diospyrin-based drugs on the cellular ATP of Pneumocystis carinii f. sp. carinii.

Atovaquone (also called Mepron, or 566C80) is a napthoquinone used for the treatment of infections caused by pathogens such as Plasmodium spp. and Pneumocystis carinii. The mechanism of action against the malarial parasite is the inhibition of dihydroorotate dehydrogenase (DHOD), a consequence of blocking electron transport by the drug. As an analog of ubiquinone (coenzyme Q [CoQ]), atovaquone irreversibly binds to the mitochondrial cytochrome bc(1) complex; thus, electrons are not able to pass from dehydrogenase enzymes via CoQ to cytochrome c. Since DHOD is a critical enzyme in pyrimidine biosynthesis, and because the parasite cannot scavenge host pyrimidines, the drug is lethal to the organism. Oxygen consumption in P. carinii is inhibited by the drug; thus, electron transport has also been identified as the drug target in P. carinii. However, unlike Plasmodium DHOD, P. carinii DHOD is inhibited only at high atovaquone concentrations, suggesting that the organism may salvage host pyrimidines and that atovaquone exerts its primary effects on ATP biosynthesis. In the present study, the effect of atovaquone on ATP levels in P. carinii was measured directly from 1 to 6 h and then after 24, 48, and 72 h of exposure. The average 50% inhibitory concentration after 24 to 72 h of exposure was 1.5 microgram/ml (4.2 microM). The kinetics of ATP depletion were in contrast to those of another family of naphthoquinone compounds, diospyrin and two of its derivatives. Whereas atovaquone reduced ATP levels within 1 h of exposure, the diospyrins required at least 48 h. After 72 h, the diospyrins were able to decrease ATP levels of P. carinii at nanomolar concentrations. These data indicate that although naphthoquinones inhibit the electron transport chain, the molecular targets in a given organism are likely to be distinct among members of this class of compounds.

Adenosine Triphosphate↗
PubMed2000

Determinants of the variability in respiratory exchange ratio at rest and during exercise in trained athletes.

We examined the variability and determinants of the respiratory exchange ratio (RER) at rest and during exercise in 61 trained cyclists. Fasting (10-12 h) RER was measured at rest and during exercise at 25, 50, and 70% of peak power output (W(peak)), during which blood samples were drawn for [lactate] and [free fatty acid] ([FFA]). Before these measurements, training volume, dietary intake and muscle fiber composition, [substrate], and enzyme activities were determined. There was large interindividual variability in resting RER (0.718-0.927) that persisted during exercise of increasing intensity. The major determinants of resting RER included muscle glycogen content, training volume, proportion of type 1 fibers, [FFA] and [lactate], and %dietary fat intake (adjusted r(2) = 0.59, P < 0.001). Except for muscle fiber composition, these variables also predicted RER at 25, 50, and 70% W(peak) to different extents. The key determinant at 25% W(peak) was blood-borne [substrate], at 50% was muscle [substrate] and glycolytic enzyme activities, and at 70% was [lactate]. Resting RER was also a significant determinant of RER at 25 (r = 0.60) and 50% (r = 0.44) W(peak).

Adult↗
PubMed2000

Sexually dimorphic expression of glutamate decarboxylase mRNA in the hypothalamus of the deep sea armed grenadier, Coryphaenoides (Nematonurus) armatus.

Glutamate decarboxylase (GAD), is a key enzyme in the central nervous system (CNS) that synthesizes the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) from glutamate. Our previous phylogenetic studies on the evolution of this enzyme indicates that there are at least two distinct forms: GAD65 and GAD67. They are the products of separate genes and probably derive from a common ancestral GAD gene following gene duplication prior to the emergence of the teleosts more than 200 Myr ago. Furthermore, a third GAD-like molecule, GAD3, discovered in the armed grenadier, Coryphaenoides (Nematonurus) armatus, is equally divergent from both GAD65 and GAD67. Specimens of C. (N.) armatus were collected by trawl at a depth of 4,000 m in the Porcupine Seabight (Northeastern Atlantic), and brains dissected and frozen for RNA extraction. All three GAD forms are found in the cerebellum, telencephalon and hypothalamus. Semiquantitative PCR analysis showed that males and females have similar levels of expression of GAD67 and GAD3 in the tissues studied. Independent of the sex examined, the levels of expression of GAD65 and GAD67 in the cerebellum were approximately half that in the telencephalon. GAD3 levels were approximately 30% higher in the cerebellum than in either the telencephalon or hypothalamus. In contrast to GAD67 and GAD3, hypothalamic expression of GAD65 mRNA is 1.8 times higher (p < 0.05) in males than in females. These data indicate that the expression of GAD65, a key enzyme for the synthesis of GABA is sexually dimorphic in females and males of C. (N.) armatus.

Animals↗
PubMed2000

The population structure of ten Newfoundland outports.

Island populations are most informative in the study of the genetic structure of human aggregates. These populations are often of small size, thus violating the Hardy-Weinberg assumption of infinite size. Some geographically isolated island populations are further subdivided by religion, ethnicity, and socioeconomic factors, reducing their effective sizes and facilitating genetic changes due to stochastic processes. Because of extreme geographic and social isolation, fishing communities or outports of Newfoundland have been investigated for genetic microdifferentiation through the founder effect and genetic drift (Crawford et al. 1995). The purpose of this paper is to examine the population structure of 10 Newfoundland outports using the allelic frequencies derived from 12 red cell antigens. To achieve this goal, first we calculated gene frequencies using maximum-likelihood estimation procedures. Second, we used R-matrix methods to explore population differentiation. Third, we regressed mean per-locus heterozygosity on genetic distance from the gene frequency centroid to identify the most isolated populations. On the basis of this information, the three outports of Seal Cove, Island Harbor, and Tilting were found to be genetically differentiated from the other small populations. Moreover, religious and geographic subdivisions appear to explain the observed genetic variation.

Blood Group Antigens↗
PubMed1999

Complete sequence determination of the mouse and human CTLA4 gene loci: cross-species DNA sequence similarity beyond exon borders.

CTLA4 (CD152), a receptor for the B7 costimulatory molecules (CD80 and CD86), is considered a fundamental regulator of T-cell activation. In this paper, we present the complete primary structure of the mouse and human CTLA4 gene loci. Sequence comparison between the mouse and the human CTLA4 gene loci revealed a high degree of sequence conservation both for homologous noncoding regions (65-78% identity) and for coding regions (72-98% identity), with an overall score of 71% over the entire length of the two genes. Of the CTLA4 genomic regions aligned, five simple repetitive elements were found in the mouse locus, whereas two simple repetitive sequences were localized on the human locus. RNA blot analysis of mouse and human primary tissues indicated that both CTLA4 and T-cell receptor transcripts were found in most organs with generally higher levels in lymphoid tissues. The conservation of CTLA4 gene patterning raises the possibility that constrained gene evolution of CTLA4 may be linked to conserved transcriptional control of this locus.

Abatacept↗
PubMed1999

Cloning and characterization of the prostate-specific membrane antigen promoter.

Prostate-specific membrane antigen (PSMA) is a protein that is expressed predominantly in normal prostate epithelial cells and in most adenocarcinomas of the prostate (Cap) and in virtually all Cap metastases. In this article we describe the cloning of a 2-kb human genomic DNA fragment containing the 5' upstream untranslated region of the PSMA gene and present evidence that it provides promoter activity. When the DNA fragment was cloned into transient expression vectors to examine promoter activity, the vectors were functional in promoting expression in several prostate and nonprostate cell lines in transient transfection assays. A 614-bp fragment derived from the 3' end of the 2-kb fragment may represent the minimal PSMA promoter as determined by deletion mutagenesis. The 2-kb fragment compared with the 614-bp fragment provided higher expression levels when using prostate-derived cell lines (DU 145 and LNCaP). The increased transcription using the 2-kb fragment was not as great in non-prostate cell lines. Little or no transcription over basal levels was seen with a 232-bp promoter fragment. When the concentration of dihydrotestosterone was depleted or supplemented in the growth medium, no significant effect was seen on PSMA-promoted transient expression in LNCaP cells, a prostate cell line. J. Cell. Biochem. 74:395-405, 1999. Published 1999 Wiley-Liss, Inc.

Base Sequence↗
PubMed1999

A Phase II study of paclitaxel and ifosfamide for patients with advanced refractory carcinoma of the urothelium.

BACKGROUND: Cisplatin-based combination chemotherapy for patients with advanced transitional cell carcinoma (TCC) of the urothelium has limitations, and new therapies need to be evaluated. METHODS: Ifosfamide 1.0 gm/m2 on Days 1-4 and paclitaxel 135 mg/m2 by 24-hour infusion on Day 4 were administered to 26 patients with locally unresectable or metastatic TCC. Cycles were repeated every 21 days for a maximum of 6 cycles; dose escalation was dependent on whether Grade 3 or 4 toxicities occurred. RESULTS: There were 24 males and 2 females, with a median age of 66 years and a median Eastern Cooperative Oncology Group performance status of 0. The median number of cycles administered was 3. Twelve patients had Grade 3 or 4 hematologic toxicities, including 1 patient who died of a gastrointestinal hemorrhage while pancytopenic. There were no episodes of neutropenic fever. Two patients each had a complete response (CR) that lasted 5 and 28 months, respectively (response rate: 15%; 95% CI: 2-45%), among the 13 patients who had received prior chemotherapy. Of the 13 patients without prior chemotherapy, there were 3 with complete responses and 1 with a partial response ranging from 8 to 25+ months (RR: 30.7%; 95% CI: 9-61%). CONCLUSIONS: The combination of ifosfamide and paclitaxel is well tolerated and can produce objective responses in patients who are chemonaïve or have had prior therapy. For previously untreated patients, the addition of ifosfamide does not appear to result in a better response rate than single agent paclitaxel; and for previously treated patients, the addition of paclitaxel does not appear to result in a better response rate than single agent ifosfamide.

Adult↗
PubMed1999

JNK activation is not required for Fas-mediated apoptosis.

Fas ligation in the presence of cycloheximide induced Jun N-terminal kinase 1 (JNK1) and JNK2 phosphorylation, caspase activation and cell death in the IL-3-dependent cell line BAF3. Fas-mediated apoptosis was prevented by expression of dominant negative FADD but not inhibited by IL-3. To investigate the role of JNK activation in this process, we examined cells over-expressing a JNK-specific phosphatase M3/6. M3/6 prevented Fas stimulation of JNK, but did not affect Fas-mediated caspase activation or cell death, demonstrating that JNK activation is not required for these processes.

Animals↗