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Biomedical subjects

J Warner

Publications and source records attributed to J Warner.

At least 19 recordsLinked to original sources
PubMed1997

Anti-vector immunoglobulin induced by retroviral vectors.

Replication-incompetent retroviruses have been employed as gene therapy vectors in experimental settings for more than a decade. More recently, these vectors have been tested in the clinic as immunotherapeutic agents and anticancer agents. One potential problem with the use of such vectors is the possible development of immune responses directed against the vector particles themselves. Here, we examine immunoglobulin (Ig) responses specific for retroviral vectors derived from murine leukemia virus (MLV). Anti-MLV Ig is seen following intramuscular (i.m.) administration of retroviral vectors in mice, and in nonhuman primates; as expected, these responses are dependent upon the vector dose delivered. Furthermore, serum from vector-treated animals is capable of partially neutralizing vector-mediated transduction of target cells in an in vitro assay. Nevertheless, even in the presence of significant levels of anti-vector Ig in vivo, i.m. administration of retroviral vector is still capable of driving both Ig and cytotoxic T lymphocyte (CTL) responses specific for vector-encoded gene products. This work suggests that although retroviral vectors may readily induce immune responses directed against the vector particles themselves, such responses will not significantly affect the efficiency of these vectors in an immunotherapeutic protocol.

Animals↗
PubMed1997

Comparison of human tissues and mechanical prostheses for aortic valve replacement in children.

BACKGROUND: Aortic valve replacement in children is problematic because of complications of mechanical valves and uncertain outcomes associated with human valves. The results of pediatric aortic valve replacements over 5 years were reviewed. METHODS AND RESULTS: Mechanical valves were used exclusively during the first part of this series (n = 26). Thereafter, 25 consecutive aortic valve replacements were performed with autografts (n = 19) or allografts (n = 6). Allografts were used for Marfan's syndrome patients or those with unusable pulmonary valves. Among autograft/allograft recipients, 16 patients underwent 27 prior operations. In the mechanical group, 18 patients underwent 19 previous operations. Three patients in each group underwent a previous mechanical aortic valve replacement. Operative complications included two mild strokes and one pacemaker in the autograft/allograft group and three deaths and two pacemakers in the mechanical group. One autograft recipient required reoperation for pulmonary allograft stenosis. In the mechanical group, late complications included six cases of nonstructural degeneration and two cases of endocarditis, with three reoperations. Reoperation-free survival was 96% at 2 years in the autograft/allograft group and 80% at 2 years and 75% at 3 years in the mechanical group. Event-free survival was 96% at 2 years in the autograft/allograft group compared with 67% at 2 years and 49% at 3 years in the mechanical group (P < .05). CONCLUSIONS: The frequency of reoperations for mechanical aortic valve replacement has been surprisingly high. Aortic valve replacement in children with only autografts or allografts achieves good early results.

Adolescent↗
PubMed1997

The effect of intravenous administration of a chimeric anti-IgE antibody on serum IgE levels in atopic subjects: efficacy, safety, and pharmacokinetics.

CGP 51901 is a non-anaphylactogenic mouse/human chimeric anti-human IgE antibody that binds to free IgE and surface IgE of IgE-expressing B cells but not to IgE bound to high affinity IgE receptors (Fc epsilonR1) on mast cells and basophils or low affinity IgE receptors (Fc epsilonR2) on other cells. A phase 1 double-blind, placebo-controlled, single dose study with doses of 3, 10, 30, and 100 mg of CGP 51901 was conducted in 33 pollen-sensitive subjects who had raised levels of serum IgE and received either intravenous CGP 51901 or placebo. The administration of CGP 51901 was well tolerated and resulted in a decrease of serum free IgE levels in a dose-dependent manner, with suppression after 100 mg of CGP 51901 reaching > 96%. Time of recovery to 50% of baseline IgE correlated with the dose of administered antibody and ranged from a mean of 1.3 d for the 3 mg to 39 d for the 100 mg dose. Total IgE, comprised of free and complexed IgE, increased as stored and newly synthesized IgE bound to CGP 51901. Complexed IgE was eliminated at a rate comparable with the terminal half-life of free CGP 51901 (11-13 d at all doses). Only one subject showed a weak antibody response against CGP 51901. We conclude that the use of anti-human IgE antibody is safe and effective in reducing serum IgE levels in atopic individuals and provides a potential therapeutic approach to the treatment of atopic diseases.

Adolescent↗
PubMed1997

Bedtime rituals of nursing home residents: a study.

This article explores the bedtime rituals espoused by a sample of elderly residents' in a nursing home and the extent to which care assistants meet individual needs. Residents perceptions of choice, status and dependency are identified as important factors. The author suggests that care assistants could be given more information and responsibility for residents' bedtime care. The accompanying commentary highlights the importance of choice and individual care.

Aged↗
PubMed1997

Structural features and biochemical properties of TNF-alpha converting enzyme (TACE).

Tumor necrosis factor-alpha is a potent cytokine, secreted primarily by activated monocytes and macrophages, that possesses a broad range of immunomodulating properties. Involvement of this cytokine has been validated in disease states such as arthritis and Crohn's disease and implicated in diverse neuroimmunological pathologies such as multiple sclerosis, Alzheimers and stroke. TNF-alpha is initially synthesized as a 26 kDa precursor molecule that is subsequently processed to the mature form by cleavage of the Ala76 Val77 bond. The 17 kDa carboxy-terminal protein is then secreted to function in a paracrine manner. The enzyme that processes precursor TNF-alpha has previously been identified as a microsomal metalloprotease called TNF-alpha converting enzyme (TACE). We have now purified and partially cloned the enzyme. TACE represents a novel target for therapeutic intervention in a variety of inflammatory and neuroimmunological diseases.

ADAM Proteins↗
PubMed1997

The sanctuary of sobriety: the emergence of temperance as a feminine virtue in Tudor and Stuart England.

This study examines the reasons why temperance was viewed as an appropriate virtue for women in sixteenth- and seventeenth-century England. It makes use of contemporary literature to document shifts in attitudes toward women who drank in a public and conspicuous fashion, and examines the economic and cultural changes that contributed to those shifts. The literature consulted in this study would suggest that up until the first decades of the sixteenth century men and women both enjoyed considerable freedom as to where and when they might consume alcohol, and would further suggest that it was only during the economic and social crises of the early modern period that two distinct drinking cultures started to emerge, one centred in the home and exclusive of men, the other centred outside the home and exclusive of women. The emergence of temperance as a virtue specific to women happened to occur at a time when real wages were in sharp decline, and effectively sanctioned the redistribution of household income in favour of men, whose right to drink was never seriously challenged. Criticism of women who drank in a public and conspicuous fashion also happened to coincide with the rediscovery of classical texts commending the supposed temperance of the women of early Rome.

England↗
PubMed1995

Molecular analysis of the TK locus in L5178Y large and small colony mouse lymphoma cell mutants induced by hycanthone methanesulfonate.

Mouse lymphoma cells of the L5178Y TK + /-3.7.2C line were exposed to varying concentrations of the anti-schistosomal drug hycanthone methanesulfonate. The trifluorothymidine (TFT)-resistant cells fell into two classes based on colony size. Southern blot analyses were performed using NcoI-digested DNA from a number of large and small mutant colonies from each treatment group. Two different restriction fragment banding patterns were identified in these analyses, those colonies that contained the 6.4 kb NcoI restriction fragment and those that did not. A total of 471 mutant colonies were analyzed and 84.5% (398) of these colonies did not exhibit the 6.4 kb fragment. There did not appear to be a hycanthone methanesulfonate dose response effect in the number of colonies that did not contain the 6.4 kb fragment among the treated groups. In addition, 82% (154 out of 188) of spontaneous mutants did not contain the 6.4 kb fragment. The results imply that greater than 80% of all spontaneous mutations found in the mouse lymphoma assay regardless of colony size do not contain the 6.4 kb fragment and each may be considered to be a large scale mutation. In addition, greater than 80% of the hycanthone induced mutations in the mouse lymphoma assay do not contain the 6.4 kb fragment and thus may be considered to be a large scale mutation.

Animals↗
PubMed1995

Simultaneous initiation of degranulation and inhibition of leukotriene release by soman in human basophils.

Previous studies noted that the serine esterase inhibitor, soman, could induce histamine release from human basophils. To investigate the mechanisms by which soman causes histamine release (a preformed mediator), we also examined its ability to induce leukotriene release (a newly synthesized mediator) from basophils. We found that no leukotriene release followed activation with soman, while histamine release was usually greater than 70%. In addition, soman and diisopropyl-fluorophosphate were found actively to suppress low level spontaneous leukotriene release as well as ongoing leukotriene release induced by anti-IgE antibody. Soman (0.3 mM) was able to stop leukotriene release as rapidly as the calcium chelator, EDTA. In a series of control experiments, it was noted that soman did not influence the metabolism of LTC4 to LTD4 or LTE4 (for which little metabolism occurred), eliminating the possibility that reduced LTC4 release could have resulted from its enhanced metabolism. Therefore, using one compound (soman), basophils could be simultaneously activated to degranulate while having the pathway leading to leukotriene release actively suppressed. These results provide further evidence that histamine and leukotriene release are independent pathways resulting from the activation of basophils.

Basophil Degranulation Test↗
PubMed1995

Inhibitory motor seizures: correlation with centroparietal structural and functional abnormalities.

Six adults and 2 children with focal inhibitory motor seizures (ictal paralysis) were evaluated during a 4-year period. Paresthesias at seizure onset occurred during some seizures in all patients, and focal clonic activity followed paralysis in 4. EEG-CCTV recordings of the seizures in 2 patients showed that ictal paralysis coincided with an ictal discharge starting in one centroparietal area. MRI showed centroparietal structural lesions in six patients. One patient with a normal MRI scan had right centroparietal hypometabolism on PET. Inhibitory motor seizures must be differentiated from transient ischemic attacks and migraine. In our patients a centroparietal epileptogenic focus was suggested by neuroimaging studies, and in 2 instances by ictal EEG.

Adolescent↗
PubMed1995

Role of elevated plasma soluble ICAM-1 and bronchial lavage fluid IL-8 levels as markers of chronic lung disease in premature infants.

BACKGROUND: Pulmonary neutrophilia characterises both the relatively transient inflammation associated with infant respiratory distress syndrome (IRDS) and the persistent inflammation of chronic lung disease. The possibility that persistently raised markers of inflammation indicate the development of chronic lung disease in low birth weight (< 1730 g) preterm (< 31 weeks) infants was therefore investigated. METHODS: Soluble ICAM-1 (sICAM-1) levels in plasma, and interleukin (IL)-8 and myeloperoxidase (MPO) levels in bronchial lavage fluid (BLF) obtained from 17 infants on days 1, 5, and 14 following birth were measured and correlations with the number of neutrophils in BLF sought. Peripheral neutrophils were isolated on Polymorphoprep and chemotactic responsiveness to IL-8 was assessed using micro Boyden chambers. RESULTS: Sixteen infants developed IRDS and, of these, 10 infants subsequently developed chronic lung disease. Levels of IL-8 in BLF at 14 days of age correlated with the long term requirement for intermittent positive pressure ventilation (IPPV). Interleukin 8 levels in BLF correlated with neutrophil numbers and MPO concentration, suggesting both recruitment and activation in response to this cytokine. Antibody depletion studies showed that approximately 50% of total neutrophil chemotactic activity in BLF was due to IL-8. No difference in peripheral neutrophil chemotactic responsiveness at any age was observed for infants with IRDS or chronic lung disease. Plasma soluble intercellular adhesion molecule (sICAM-1) was higher at 14 days of age in infants who developed chronic lung disease than in those with resolving IRDS, and correlated with severity of disease, as indicated by duration of IPPV. CONCLUSIONS: The results indicate that high levels of plasma sICAM-1 and IL-8 in BLF at day 14 correlate with the development of chronic lung disease and indicate the severity of disease.

Biomarkers↗
PubMed1994

Results of conservative management of clinically localized prostate cancer.

BACKGROUND: The selection of treatment for patients with localized prostate cancer requires reliable information about the outcome of conservative management. Previous studies of this question are generally considered unreliable because they were uncontrolled and nonrandomized. METHODS: We performed a pooled analysis of 828 case records from six nonrandomized studies, published since 1985, of men treated conservatively (with observation and delayed hormone therapy but no radical surgery or irradiation) for clinically localized prostate cancer. A Cox regression analysis was performed to determine which factors influenced survival among patients who did not die of causes other than prostate cancer (disease-specific survival). Kaplan-Meier curves for overall and metastasis-free survival among such patients were compared with use of the log-rank method and the Mantel-Haenszel test. RESULTS: Factors that had a significant effect on disease-specific survival were grade 3 tumors (risk ratio, 10.04), residence in Israel (risk ratio, 2.48) or New York (risk ratio, 0.37), and age under 61 years (risk ratio, 0.32). Ten years after diagnosis, disease-specific survival (with data on men who died from causes other than prostate cancer censored) was 87 percent for men with grade 1 or 2 tumors and 34 percent for those with grade 3 tumors; metastasis-free survival among men who had not died of other causes was 81 percent for grade 1, 58 percent for grade 2, and 26 percent for grade 3 disease. These findings were not affected by the inclusion of men who had early-stage cancer, were older, had worse-than-average health, or underwent delayed radiation therapy or radical prostatectomy. CONCLUSIONS: The strategy of initial conservative management and delayed hormone therapy is a reasonable choice for some men with grade 1 or 2 clinically localized prostate cancer, particularly for those who have an average life expectancy of 10 years or less. New treatment strategies are needed for men with grade 3 prostate cancer.

Aged↗
PubMed1994

Expectant management of clinically localized prostatic cancer.

Among approximately 4,000 prostatic cancer registrations 75 patients with clinical stage B histologically proved prostatic cancer receiving no therapy for at least 1 year after diagnosis were identified and managed expectantly. Of the patients 29 had stage B1, 37 stage B2 and 9 stage B3 lesions. Eight patients ultimately elected definitive radiation treatment. First evidence of tumor progression was local in more than 90% of the cases. Overall median intervals were 78 months to local progression, 186 months to metastasis, 108 months to initiation of any treatment and 156 months to death. The rate of tumor progression was often consistent with protracted survival. Prostatic cancer and co-morbidity were each significant forces of mortality.

Aged↗