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Biomedical subjects

L Wilson

Publications and source records attributed to L Wilson.

At least 127 records · Page 7Linked to original sources
PubMed1998

Effect of pregnancy on the metabolic clearance rate and the volume of distribution of oxytocin in the baboon.

Pharmacokinetic parameters of oxytocin (OT) metabolism were determined during the last third of pregnancy and again 4-8 wk after delivery in the baboon. Animals were placed on a tether system with venous and arterial access and a continuous monitoring of uterine contractions during gestation. Two methods of determining OT pharmacokinetics were utilized (bolus injection vs. continuous infusion). The metabolic clearance rate of OT as determined during the bolus trials (n = 7) was 22.2 +/- 1.5 ml.min-1.kg-1 in pregnancy and 16.3 +/- 1.4 ml.min-1.kg-1 postpartum (P < 0.05), respectively, and 23.7 +/- 2.8 vs. 16.9 +/- 3.7 ml.min-1.kg-1 (P < 0.05), respectively, as determined during the 1-h infusion trials (n = 4). The initial dilution volume and the volume of distribution at steady state of OT after administration did not differ between pregnant and postpartum animals (P > 0.05). The mean residence time (MRT) of OT was shorter during pregnancy, 7.7 +/- 0.8 vs. 10.8 +/- 1.2 min postpartum (P < 0.05). In summary, OT metabolism during pregnancy in the baboon is characterized by 1) increased clearance rate (1.4-fold), 2) accelerated turnover due to the shorter MRT, and 3) unaltered distribution.

Animals↗
PubMed1998

Cardiopulmonary effects of inhaled nitric oxide in normal dogs and during E. coli pneumonia and sepsis.

We investigated the effect of inhaled nitric oxide (NO) at increasing fractional inspired O2 concentrations (FIO2) on hemodynamic and pulmonary function during Escherichia coli pneumonia. Thirty-eight conscious, spontaneously breathing, tracheotomized 2-yr-old beagles had intrabronchial inoculation with either 0.75 or 1.5 x 10(10) colony-forming units/kg of E. coli 0111:B4 (infected) or 0.9% saline (noninfected) in one or four pulmonary lobes. We found that neither the severity nor distribution (lobar vs. diffuse) of bacterial pneumonia altered the effects of NO. However, in infected animals, with increasing FIO2 (0.08, 0.21, 0.50, and 0.85), NO (80 parts/million) progressively increased arterial PO2 [-0.3 +/- 0.6, 3 +/- 1, 13 +/- 4, 10 +/- 9 (mean +/- SE) Torr, respectively] and decreased the mean arterial-alveolar O2 gradient (0.5 +/- 0.3, 4 +/- 2, -8 +/- 7, -10 +/- 9 Torr, respectively). In contrast, in noninfected animals, the effect of NO was significantly different and opposite; NO progressively decreased mean PO2 with increasing FIO2 (2 +/- 1, -5 +/- 3, -2 +/- 3, and -12 +/- 5 Torr, respectively; P < 0.05 compared with infected animals) and increased mean arterial-alveolar O2 gradient (0.3 +/- 0.04, 2 +/- 2, 1 +/- 3, 11 +/- 5 Torr; P < 0.05 compared with infected animals). In normal and infected animals alike, only at FIO2 < or = 0.21 did NO significantly lower mean pulmonary artery pressure, pulmonary artery occlusion pressure, and pulmonary vascular resistance index (all P < 0.01). However, inhaled NO had no significant effect on increases in mean pulmonary artery pressure associated with bacterial pneumonia. Thus, during bacterial pneumonia, inhaled NO had only modest effects on oxygenation dependent on high FIO2 and did not affect sepsis-induced pulmonary hypertension. These data do not support a role for inhaled NO in bacterial pneumonia. Further studies are necessary to determine whether, in combination with ventilatory support, NO may have more pronounced effects.

Administration, Inhalation↗
PubMed1998

The use of specialist palliative care services by patients with human immunodeficiency virus-related illness in the Yorkshire Deanery of the northern and Yorkshire region.

To examine the use of palliative care services by patients affected by human immunodeficiency virus (HIV) in hospices which do not specialize in the care of HIV patients, a tape-recorded, semistructured interview was carried out in 12 hospices in the UK. The interview explored concerns about such provision, as well as actual issues encountered. The study revealed that all 12 hospices accepted referrals for people affected by HIV and had clear working practices on infection control. between 1990 and 1996, 48 individuals affected by HIV had contact with the hospices. The number of referrals was not related to the size of the hospice. Thirty-nine individuals had a total of 655 days of inpatient care (range 1-35 days); mean length of stay 12.7 days. Twenty-four (62%) died during their first admission. Referrals came from disparate sources and this affected the amount and type of specialist HIV support available to the hospice. The paucity of referrals raised concerns in most of the units as to how to maintain skills. Issues about maintaining confidentiality of diagnosis in a multiprofessional team, and after death were highlighted. All units expressed concerns about the impact on fundraising of HIV-related admissions. Overall it was felt that the hospice units were failing to meet the palliative care needs of the majority of people affected by HIV or acquired immunodeficiency syndrome (AIDS) in the region. Possible reasons for this are given.

Advance Directives↗
PubMed1997

Mechanism of action of the unusually potent microtubule inhibitor cryptophycin 1.

Cryptophycin 1 is a remarkably potent antiproliferative compound that shows excellent antitumor activity against mammary, colon, and pancreatic adenocarcinomas in mouse xenographs. At picomolar concentrations, cryptophycin 1 blocks cells in the G2/M phase of the cell cycle by an apparent action on microtubules. The compound binds to tubulin, inhibits microtubule polymerization, and depolymerizes preformed microtubules in vitro. Its exceptionally powerful antitumor activity (many-fold greater than paclitaxel or the vinca alkaloids) raises important questions about its mechanism of action. By quantitative video microscopy, we examined the effects of cryptophycin 1 on the dynamics of individual microtubules assembled to steady state from bovine brain tubulin. At low nanomolar concentrations, in the absence of net microtubule depolymerization, cryptophycin 1 potently stabilized microtubule dynamics. It reduced the rate and extent of microtubule shortening and growing and increased the frequency of rescue. The results suggest that cryptophycin 1 exerts its antiproliferative and antimitotic activity by binding reversibly and with high affinity to the ends of microtubules, perhaps in the form of a tubulin-cryptophycin 1 complex, resulting in the most potent suppression of microtubule dynamics yet described.

Animals↗
PubMed1997

Stabilization of microtubule dynamics by estramustine by binding to a novel site in tubulin: a possible mechanistic basis for its antitumor action.

The cellular targets for estramustine, an antitumor drug used in the treatment of hormone-refractory prostate cancer, are believed to be the spindle microtubules responsible for chromosome separation at mitosis. Estramustine only weakly inhibits polymerization of purified tubulin into microtubules by binding to tubulin (Kd, approximately 30 microM) at a site distinct from the colchicine or the vinblastine binding sites. However, by video microscopy, we find that estramustine strongly stabilizes growing and shortening dynamics at plus ends of bovine brain microtubules devoid of microtubule-associated proteins at concentrations substantially below those required to inhibit polymerization of the microtubules. Estramustine strongly reduced the rate and extent both of shortening and growing, increased the percentage of time the microtubules spent in an attenuated state, neither growing nor shortening detectably, and reduced the overall dynamicity of the microtubules. Significantly, the combined suppressive effects of vinblastine and estramustine on the rate and extent of shortening and dynamicity were additive. Thus, like the antimitotic mechanisms of action of the antitumor drugs vinblastine and taxol, the antimitotic mechanism of action of estramustine may be due to kinetic stabilization of spindle microtubule dynamics. The results may explain the mechanistic basis for the benefit derived from combined use of estramustine with vinblastine or taxol, two other drugs that target microtubules, in the treatment of hormone-refractory prostate cancer.

Animals↗
PubMed1997

Antigen processing and presentation by human trophoblast-derived cell lines.

The trophoblast-derived choriocarcinoma cell lines JEG-3 and JAR express the nonclassical MHC class I molecules HLA-G (JEG-3) or, at a low level, HLA-E (JAR), but lack expression of the classical MHC class I molecules HLA-A and HLA-B. Expression of these nonclassical MHC class I genes was found to coincide with expression of the genes encoding the peptide transporter associated with Ag processing (TAP). In immunoprecipitation studies, a physical interaction between the TAP complex and HLA-G or HLA-E could be demonstrated. To investigate whether trophoblast-derived cell lines were capable of peptide processing, transport, and loading of MHC class I molecules, HLA-A*0201-expressing transfectants of JEG-3 and JAR were used for functional studies. These transfectants were recognized by both allospecific cytotoxic T cell clones and, after viral infection, by an influenza A matrix peptide-specific cytotoxic T cell clone, indicating that these trophoblast-derived cell lines were capable of presenting endogenously derived peptides in the context of HLA-A*0201. From these observations, it can be inferred that the TAP complex and other molecules involved in Ag processing and presentation by MHC class I molecules are functionally active in these trophoblast-derived cell lines. This implies that trophoblasts are able to provide antigenic peptides for presentation by nonclassical MHC class I molecules that are naturally expressed by this cell type.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Taxol differentially modulates the dynamics of microtubules assembled from unfractionated and purified beta-tubulin isotypes.

Substoichiometric binding of taxol to tubulin in microtubules potently suppresses microtubule dynamics, which appears to be the most sensitive antiproliferative mechanism of taxol. To determine whether the beta-tubulin isotype composition of a microtubule can modulate sensitivity to taxol, we measured the effects of substoichiometric ratios of taxol bound to tubulin in microtubules on the dynamics of microtubules composed of purified alphabeta(II)-, alphabeta(III)-, or alphabeta(IV)-tubulin isotypes and compared the results with the effects of taxol on microtubules assembled from unfractionated tubulin. Substoichiometric ratios of bound taxol in microtubules assembled from purified beta-tubulin isotypes or unfractionated tubulin potently suppressed the shortening rates and the lengths shortened per shortening event. Correlation of the suppression of the shortening rate with the stoichiometry of bound taxol revealed that microtubules composed of purified alphabeta(II)-, alphabeta(III)-, and alphabeta(IV)-tubulin were, respectively, 1.6-, 7.4-, and 7.2-fold less sensitive to the effects of bound taxol than microtubules assembled from unfractionated tubulin. These results indicate that taxol differentially modulates microtubule dynamics depending upon the beta-tubulin isotype composition. The results are consistent with recent studies correlating taxol resistance in tumor cells with increased levels of beta(III0- and beta(IV)-tubulin expression and suggest that altered cellular expression of beta-tubulin isotypes can be an important mechanism by which tumor cells develop resistance to taxol.

Animals↗
PubMed1997

Suppression of microtubule dynamics by LY290181. A potential mechanism for its antiproliferative action.

LY290181, 2-amino-4-(3-pyridyl)-4H-naphtho(1,2-b)pyran-3-carbonitrile, is a potent antiproliferative compound that blocks cells in the G2/M phase of the cell cycle by an apparent action on microtubules. In the present work we found that LY290181 bound to tubulin with high affinity (1 mol of LY290181 per mol of tubulin dimer; Ka, 3.8 x 10(5) M-1) and that it did not appear to bind at the colchicine or vinblastine-binding sites. LY290181 strongly stabilized microtubule dynamics as determined by video microscopy. It reduced the rate and extent of growing and shortening, reduced the catastrophe frequency and increased the rescue frequency, and increased the percentage of time the microtubules spent in an attenuated state. At the lowest effective LY290181 concentrations (0.1-0.3 microM), suppression of dynamics occurred with little reduction in polymer mass. However, at higher concentrations, LY290181 strongly reduced the polymer mass with half-maximal inhibition at a concentration of 0.75 microM. We suggest that LY290181 may exert its antiproliferative activity by stabilizing spindle microtubule dynamics by binding to tubulin at a novel site.

Anilino Naphthalenesulfonates↗
PubMed1997

Treatment of recurrent pelvic and selected primary gynecologic malignancies with 241Am.

The purpose of this study was to update the experience and demonstrate the effectiveness and limitations of 241Am applicators for previously irradiated patients and for selected patients with primary gynecologic malignancies. Between October 1986 and May 1994, 30 patients were treated with 241Am. The median patient age was 68 years, ranging from 41 to 91 years. Patients were retrospectively categorized by treatment intent, i.e., palliative vs. curative. Patients undergoing curative therapy were further classified as to whether 241Am brachytherapy was directed at microscopic residua after surgery or to gross primary tumor. Of the 30 patients, 18 had recurrent pelvic malignancies from various primary sites and were reirradiated with 241Am for palliation. Six patients had microscopic disease after surgical resection and were managed with postoperative radiotherapy (RT) that included 241Am. Six patients had gynecologic cancers managed with primary RT that included treatment with 241Am. Overall, 50% (9/18) of the patients with recurrent pelvic malignancies were locally controlled after reirradiation with 241Am. Including surgical salvage, the ultimate local control rate was 61% (11/18). Postoperative 241Am with or without external beam radiation therapy (XRT) was effective in 83% (5/6) of the patients with microscopic disease. Including surgical salvage, 100% (6/6) of the patients were ultimately free of disease. Fifty percent (3/6) of the patients treated with primary RT that included 241Am brachytherapy experienced local control. Including surgical salvage, 67% (4/6) of the patients were ultimately controlled with 241Am. In conclusion, reirradiation utilizing 241Am was effective in palliating patients with recurrent pelvic malignancies. 241Am was effective in 83% (5/6) of the patients with microscopic disease managed with postoperative RT. 241Am was of marginal benefit in patients with gynecologic tumors managed with primary RT.

Aged↗
PubMed1997

SH3 domain-mediated interactions involving the phox components of the NADPH oxidase.

OBJECTIVE AND DESIGN: To derive a model describing the SH3 domain-mediated assembly of the activated NADPH oxidase. MATERIALS: Recombinant SH3 domain and Pro-rich fusion proteins were used to investigate potential co-associations. METHODS: Interactions were assessed using biotinylated overlay assays and the yeast two hybrid system. Association with p47phox from cell lysates was examined by immunoblot analysis. RESULTS: The association between p47- and p22phox involves the SH3 domains of p47phox functioning in tandem. The Prorich motif in p47phox interacts with both p40phox and the COOH-terminal SH3 domain of p67phox. CONCLUSIONS: In the resting cell, the Pro-rich motif of p47phox interacts with the SH3 domain of p40phox, which in turn associates with p67phox. Upon activation, the p47-p40phox regulatory complex dissociates, permitting the association of p47phox with the COOH-terminal SH3 domain of p67phox. This complex translocates to the plasma membrane and associates with cytochrome b558, via interaction of the tandem SH3 domains of p47phox with the p22phox Pro-rich motif.

Binding, Competitive↗
PubMed1997

Late disruption of Dacron aortic grafts.

Aneurysmal degeneration, or complete disruption of Dacron grafts (as opposed to anastomotic complications such as pseudoaneurysms), are not expected by vascular surgeons. We have noted two such cases. A 65-year-old male who had an aortobifemoral, double-velour Dacron graft in 1980, presented in 1995 with a large, pulsatile mass in the right lower quadrant, caused by disruption of the mid-portion of the right limb of the Dacron graft. In a second case, a 68-year-old man had a Dacron aortobifemoral graft placed in 1968 which developed diffuse aneurysmal defects, noted clinically in 1987. Both patients had successful graft replacement. A review of the literature indicates that this complication, although unusual, has been noted periodically. Between 1970 and 1996, we identified 11 case reports of aortic Dacron graft rupture, including knitted Dacron (4), double velour (3), woven (1), knitted thin wall (1), and unspecified Dacron grafts (2). An inquiry to the FDA disclosed another 68 cases of Dacron graft failure in addition to those reported in the surgical literature. We present these cases to alert vascular surgeons of the possibility of Dacron graft degeneration, as late as 19 years after implantation. Diagnosis of the complication is readily apparent by clinical examination and imaging studies, which display an aneurysm of the graft remote from the anastomoses.

Aged↗
PubMed1997

Lycra garments designed for patients with upper limb spasticity: mechanical effects in normal subjects.

OBJECTIVE: To assess the stretch of pronator muscles produced by a specifically designed upper-limb Lycra garment that could have a better acceptability than rigid splints in treating upper-limb spasticity. DESIGN: Double-blind comparison among three garments. They were designed to produce a supinating, a pronating, and no torsional force, and were individually manufactured and tested in 10 healthy volunteers. MAIN OUTCOME MEASURE: Angular position and passive rotational stiffness of the forearm were measured with and without each of the garments immediately after the garment was fitted and every hour for 6 hours. RESULTS: When put on by a trained person, the supinator garment supinated the forearm in all subjects (mean, 17 degrees; p < .01; range, 5 degrees to 44 degrees) while the pronator garment pronated the forearm in 8 of 10 subjects (mean, 5 degrees; p < .01). These effects gradually decayed over 6 hours, as garment position was not readjusted. Passive rotational stiffness of the forearm increased by about 30% with each type of garment. The garments designed to produce no torsional force exerted no intrinsic rotational effect. CONCLUSION: Individually made Lycra garments can produce continuous stretch of muscles for several hours and may be useful in the treatment of spasticity. The garments, however, must be put on by a trained person and their position adjusted when necessary.

Adult↗
PubMed1997

Cost-of-illness of scleroderma: the case for rare diseases.

OBJECTIVE: To determine the societal costs of scleroderma (SSc), a rare chronic connective tissue disease that affects approximately 98,000 Americans. Lack of reliable national databases limit rare disease cost studies, and this study suggests methods of using multiple data sources to assess the costs of rare diseases. METHODS: Primary and secondary data sources were used to calculate direct and indirect costs of SSc, including discounted lifetime mortality and morbidity costs. A prevalence-based, human capital approach was used. Sensitivity analyses were used to vary parameters that are uncertain, such as prevalence, mortality, and labor costs. RESULTS: Annual direct and indirect costs of SSc in the United States are $1.5 billion. Morbidity represents the major cost burden, with costs of $819 million (56%) of total costs. The current value of lifetime earnings lost was $179 million (12%) or $300,000 per death. Direct costs were $462 million (32%) or $4,731 per person annually, indicating that costs are spread over the long disease duration. CONCLUSIONS: This study provides one model for the assessment of rare disease costs. Triangulation of data sources and sensitivity analyses are important for determining the costs of rare diseases. The high cost of SSc, despite its low prevalence, suggests that the burden of rare chronic diseases can be high. The high morbidity costs reflect the young age of onset of the disease as well as the need for treatments to decrease morbidity costs. Local shared databases and national surveys are needed to improve cost estimates of rare diseases.

Adolescent↗
PubMed1997

Prenatal diagnosis in merosin-deficient congenital muscular dystrophy.

Prenatal diagnosis was carried out in five merosin-deficient congenital muscular dystrophy (CMD) families. We studied both laminin-alpha 2 chain expression in trophoblast using immunocytochemistry and linkage analysis to the LAMA2 locus. In four families there was good agreement between the immunocytochemistry and linkage analysis results: in one case the trophoblast was negative for LAMA2 expression and haplotype analysis suggested the foetus was affected; in the other three cases the laminin-alpha 2 chain expression was normal and foetuses were found to be carriers. In the remaining family, a case of partial laminin-alpha 2 chain expression, the immunostaining of the trophoblast was weaker compared to the control. Linkage analysis, however, could not be performed because of maternal DNA contamination. After termination of pregnancy, the foetal muscle was studied and suggested weak laminin-alpha 2 chain expression. The haplotype analysis however showed that the foetus was probably a carrier, unless a double recombinant event had occurred. We conclude that a combination of immunocytochemistry and linkage analysis can be used for the prenatal diagnosis of merosin deficient CMD. The results are easy to interpret in families with total absence of the protein, while caution is required when dealing with families where partial expression occurs.

Antibodies, Monoclonal↗
PubMed1997

Functional interactions between the proline-rich and repeat regions of tau enhance microtubule binding and assembly.

Tau is a neuronal microtubule-associated protein that promotes microtubule assembly, stability, and bundling in axons. Two distinct regions of tau are important for the tau-microtubule interaction, a relatively well-characterized "repeat region" in the carboxyl terminus (containing either three or four imperfect 18-amino acid repeats separated by 13- or 14-amino acid long inter-repeats) and a more centrally located, relatively poorly characterized proline-rich region. By using amino-terminal truncation analyses of tau, we have localized the microtubule binding activity of the proline-rich region to Lys215-Asn246 and identified a small sequence within this region, 215KKVAVVR221, that exerts a strong influence on microtubule binding and assembly in both three- and four-repeat tau isoforms. Site-directed mutagenesis experiments indicate that these capabilities are derived largely from Lys215/Lys216 and Arg221. In marked contrast to synthetic peptides corresponding to the repeat region, peptides corresponding to Lys215-Asn246 and Lys215-Thr222 alone possess little or no ability to promote microtubule assembly, and the peptide Lys215-Thr222 does not effectively suppress in vitro microtubule dynamics. However, combining the proline-rich region sequences (Lys215-Asn246) with their adjacent repeat region sequences within a single peptide (Lys215-Lys272) enhances microtubule assembly by 10-fold, suggesting intramolecular interactions between the proline-rich and repeat regions. Structural complexity in this region of tau also is suggested by sequential amino-terminal deletions through the proline-rich and repeat regions, which reveal an unusual pattern of loss and gain of function. Thus, these data lead to a model in which efficient microtubule binding and assembly activities by tau require intramolecular interactions between its repeat and proline-rich regions. This model, invoking structural complexity for the microtubule-bound conformation of tau, is fundamentally different from previous models of tau structure and function, which viewed tau as a simple linear array of independently acting tubulin-binding sites.

Amino Acid Sequence↗
PubMed1997

The relationship between nonorganic signs and centralization of symptoms in the prediction of return to work for patients with low back pain.

BACKGROUND AND PURPOSE: The purpose of this study was to assess the relationship between the nonorganic signs (Waddell scores) of patients with low back pain, their response to repetitive end-range lumbar spine test movements (centralization of symptoms), and the rate of return to work at a 6-month follow-up. SUBJECTS: Patients were assessed at five locations of the Canadian Back Institute. A consecutive sample of 126 patients with low back pain, with or without referred leg pain, was selected and reviewed. METHODS: Physical therapists assessed patients' responses to repetitive test movements (centralization), as described by McKenzie, and tested the patients for nonorganic signs (Waddell scores). Therapists completed a data sheet that classified patients as either those who centralize their symptoms or those who do not centralize their symptoms and recorded their Waddell scores. Although the patients were classified at assessment, they remained in treatment. All patients followed a structured Canadian Back Institute protocol of active exercise, regardless of centralization status or Waddell score. RESULTS: The inability to centralize symptoms indicated a decreased likelihood of returning to work, regardless of the Waddell score. A high Waddell score predicted a poor chance of returning to work, regardless of the patients' ability to centralize symptoms. CONCLUSION AND DISCUSSION: A high Waddell score appears to be the best predictor of outcome, as indicated by return to work.

Adult↗