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Biomedical subjects

C Carson

Publications and source records attributed to C Carson.

At least 19 recordsLinked to original sources
PubMed2004

The 'effectiveness' scale--therapeutic outcome of pharmacologic therapies for ED: an international consensus panel report.

Despite availability of outcome measures and scales for assessing erectile dysfunction (ED) treatment efficacy, guidelines are not available for assessing broader therapeutic outcomes or defining treatment failure in ED. An International Consensus Advisory Panel was convened to develop guidelines, definitions and a new algorithm for evaluating treatment effectiveness in ED. These new guidelines are recommended for use in both research and clinical practice. A multidisciplinary, international panel, consisting of 11 senior researchers and clinicians, was convened to address pertinent issues concerning therapeutic outcome assessment for ED. The panel utilized a modified Delphi method of consensus development and proposed a new model for outcomes assessment. This model is inherently testable, using existing instruments and current methods of assessment. Following a comprehensive literature review and discussion, the Panel recommended adoption of a new treatment effectiveness conceptual framework or theoretical model for assessing therapeutic outcomes in ED. Treatment effectiveness is presumed to be a combined function of two other factors, treatment response and treatment satisfaction. Treatment response is based on the combined assessment of efficacy and tolerability, and treatment satisfaction on the combined assessment of patient and partner satisfaction. Taken together, these two domains define an overall domain of treatment effectiveness. This therapeutic index would be derived by independently assessing treatment efficacy and satisfaction by means of event logs, questionnaires or the more typical patient interview methods. In conclusion, the Ad Hoc Advisory Consensus Panel recommends adoption of a new framework or conceptual model for conducting ED outcome trials or clinical research. The concept of 'treatment effectiveness' is proposed as a new 'umbrella concept' or distal outcome to be evaluated.

Consensus Statements as Topic↗
PubMed2003

Mapping the initial DNA breaks in apoptotic Jurkat cells using ligation-mediated PCR.

Apoptotic DNA degradation could be initiated by the accumulation of single-strand (ss) breaks in vulnerable chromatin regions, such as base unpairing regions (BURs), which might be preferentially targeted for degradation by both proteases and nucleases. We tested this hypothesis in anti-Fas-treated apoptotic Jurkat cells. Several nuclear proteins known for their association with both MARs and the nuclear matrix, that is, PARP, NuMA, lamin B and SATB1, were degraded, but the morphological rearrangement of the BUR-binding SATB1 protein was one of the earliest detected changes. Subsequently, we have identified several genes containing sequences homologous to the 25 bp BUR element of the IgH gene, a known SATB1-binding site, and examined the integrity of genomic DNA in their vicinity. Multiple ss breaks were found in close proximity to these sites relative to adjacent regions of DNA. Consistent with our prediction, the results indicated that the initiation of DNA cleavage in anti-Fas-treated Jurkat cells occurred within the BUR sites, which likely became accessible to endonucleases due to the degradation of BUR-binding proteins.

Base Sequence↗
PubMed2001

Establishment and maintenance of a longitudinal study of bovine spongiform encephalopathy (the ULiSES scheme).

This paper addresses the issues of tracing and compliance encountered in setting up and maintaining a UK-wide 5-year observational study of beef cattle. The 5-year prospective study was initiated in 1997 to investigate the occurrence of bovine spongiform encephalopathy (BSE) in a single herd of pedigree Aberdeen Angus cattle, in which BSE had been detected at low prevalence. The study was given the acronym ULiSES (University of Liverpool Spongiform Encephalopathy Scheme). All cattle present on the farm at the start of the scheme were registered as members of the study population (n=320), as were all calves subsequently born on the farm (n=350). Animals that were sold (n=291) were traced and monitored at destination farms. Farmers were requested to give advance notification of slaughter of any ULiSES animal and an attempt was made to collect post-mortem samples of nervous tissue, peripheral lymphoid tissue and striated muscle from all animals in the scheme at the time of slaughter, death or euthanasia. Sections of medulla were examined (by standard histopathological techniques) for the presence of spongiform change. Remaining samples were stored at -70 degrees C for future investigation by alternative tests. At the halfway point of the scheme in October 1999, 75.2% (506/673) of the study population was still alive; 42% (284) of the population was still alive on the study farm and 33% (222) was distributed on other farms throughout the UK. Complete sets of specimens had been recovered from 77% (129/167) of dead animals. All brainstem sections were negative by histopathological examination. No suspect cases of BSE were reported in ULiSES animals. Failure to recover specimens occurred principally in animals which had left the study farm. The main cause of specimen loss was a failure of compliance in a small number of individuals who had purchased large numbers of ULiSES animals, and subsequently slaughtered them without contacting the University. Despite this, farmer compliance was generally high. The ULiSES scheme shows the feasibility of a country-wide longitudinal observational study spanning a period of several years and indicates the large impact of small numbers of non-compliant individuals.

Animals↗
PubMed2001

Vasomax for the treatment of male erectile dysfunction.

This paper reviews laboratory and clinical data concerning oral phentolamine mesylate, Vasomax, an alpha-1, alpha-2 adrenergic receptor antagonist developed specifically for treatment of erectile dysfunction. A contemporary view of the neurovascular mechanisms in penile erection includes the effects of both smooth muscle relaxation and contraction. Contraction of the cavernosal arteries and trabecular smooth muscle appears to be predominantly under the control of alpha-adrenergic innervation. Conversely, adrenergic blockade of alpha-1 and alpha-2 receptors has been shown to facilitate penile erection in both animal and human models. The pharmacokinetic profile of Vasomax appears well suited for an oral erectogenic agent. Vasomax is rapidly absorbed and eliminated in normal males. Peak plasma concentrations are achieved in 30-60 min, and the half-life approximates 5-7 h. Food decreases the rate, but not the extent of bioavailability. Vasomax has low protein binding and is excreted primarily via urine and feces. There is a strong dose-response relationship in maximum plasma concentration (Cmax) and area under the curve (AUC), and there are no clear age-related differences in absorption or elimination rates. Efficacy of Vasomax has been systematically evaluated in two (ZON300, ZON301) large-scale, placebo-controlled trials, in addition to two long-term open-label studies. In both studies, Vasomax was associated with significant improvements in the erectile function domain scores of the International Index of Erectile Function (IIEF). Further improvements were noted as the duration of treatment and dose level were increased. The percentage of successful penetration attempts was also significantly improved with Vasomax compared to placebo. For patients who continued in open-label treatment with Vasomax, efficacy was generally well maintained. Vasomax was well tolerated by the majority of patients. The most common side effects observed were nasal congestion (10%), headache (3%), dizziness (3%), tachycardia (3%) and nausea (1%). Side effects were generally dose-related and in the mild-to-moderate range in all three studies. Furthermore, side effects seldom resulted in treatment discontinuation. Very few serious adverse events were observed in these trials. In summary, Vasomax appears to be effective in the treatment of male erectile dysfunction and well-tolerated by the majority of patients. The drug has a satisfactory side effect profile, without significant risk of cardiovascular effects. Results of clinical trials with Vasomax support the concept of adrenergic-blockade as a clinically relevant mechanism in the control of penile erection.

Adrenergic alpha-Antagonists↗
PubMed2000

Effects of neoplastic transformation and teniposide (VM26) on protein kinase C isoform expression in rodent fibroblasts.

This study examined changes in protein kinase C (PKC) isoforms in rodent fibroblasts (rat F111 and mouse NIH3T3), transformed by the polyoma virus middle T antigen (mT) and undergoing apoptosis in response to teniposide (VM26). The mT-transformed cells up-regulated PKC delta and down-regulated both PKC epsilon and PKC lambda expression, and were more sensitive to the drug than their non-transformed counterparts. The drug treatment further lowered the expression of PKC epsilon, triggered nuclear translocation of PKC delta and its site-specific proteolysis, consistent with the notion that changes in specific PKC isoforms play a role not only in the neoplastic transformation of fibroblasts, but also in their apoptotic response.

3T3 Cells↗
PubMed1999

Neither caspase-3 nor DNA fragmentation factor is required for high molecular weight DNA degradation in apoptosis.

In this paper, we show that there is a two-step process of DNA fragmentation in apoptosis; DNA is first cleaved to large fragments of 50-300 kb that are subsequently cleaved to smaller oligonucleosomes in some, but not all cells. Significantly, only the first stage is considered essential for cell death since some cells, for example human MCF7 breast carcinoma cells and human NT2 neuronal cells, do not show this behavior but still display normal nuclear morphological apoptotic changes. In cells that usually produce small fragments blocking the second (internucleosomal) stage of DNA fragmentation prevents neither nuclear condensation nor apoptosis. We are beginning to understand why the extent of DNA fragmentation during apoptosis varies enormously and why it appears to be a function of the cell type not the inducer. Presumably, this reflects the content of not only endonuclease activit(ies) but also on the ability of the cells to activate caspases, particularly caspase-3, and other proteases that may be involved in endonuclease activation. Since NT2 cells activate caspase-3, but do not correctly process DFF45, other factors must also impinge on the inevitability of that process.

Adenocarcinoma↗
PubMed1999

Interleukin 2 gene therapy of colorectal carcinoma with autologous irradiated tumor cells and genetically engineered fibroblasts: a Phase I study.

The purpose of this study was to determine the safety, toxicity, and antitumor immune response following S.C. immunizations with a mixture of irradiated, autologous tumor cells and autologous fibroblasts that were genetically modified to express the gene for interleukin 2 (IL-2) in patients with colorectal carcinoma. Ten patients were treated with a fixed dose of tumor cells (10(7)) and escalating doses of fibroblasts secreting IL-2 (per 24 h): 100 units (three patients), 200 units (three patients), 400 units (three patients), and 800 units (one patient). Pre- and posttreatment peripheral blood mononuclear cells were evaluated for evidence of antitumor immune responses. Fatigue and/or flu-like symptoms were experienced by seven patients and delayed-type hypersensitivity-like skin reactions were observed at the sites of the second or subsequent vaccinations in five patients. Low frequencies of tumor cytotoxic T-cell precursors (range, 1/190,000-1/1,320,000 peripheral blood mononuclear cells) were detected prior to therapy in four of seven patients. There was a 5-fold increase following treatment in the frequency of tumor cytotoxic T-cell precursors in two of six evaluable patients. Some patients with colorectal cancer have low frequencies of tumor cytotoxic T-cell precursors that may be increased by this well-tolerated form of IL-2 gene therapy, which warrants continued clinical evaluation.

Cancer Vaccines↗
PubMed1998

Genome scan of human systemic lupus erythematosus: evidence for linkage on chromosome 1q in African-American pedigrees.

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by production of autoantibodies against intracellular antigens including DNA, ribosomal P, Ro (SS-A), La (SS-B), and the spliceosome. Etiology is suspected to involve genetic and environmental factors. Evidence of genetic involvement includes: associations with HLA-DR3, HLA-DR2, Fcgamma receptors (FcgammaR) IIA and IIIA, and hereditary complement component deficiencies, as well as familial aggregation, monozygotic twin concordance >20%, lambdas > 10, purported linkage at 1q41-42, and inbred mouse strains that consistently develop lupus. We have completed a genome scan in 94 extended multiplex pedigrees by using model-based linkage analysis. Potential [log10 of the odds for linkage (lod) > 2.0] SLE loci have been identified at chromosomes 1q41, 1q23, and 11q14-23 in African-Americans; 14q11, 4p15, 11q25, 2q32, 19q13, 6q26-27, and 12p12-11 in European-Americans; and 1q23, 13q32, 20q13, and 1q31 in all pedigrees combined. An effect for the FcgammaRIIA candidate polymorphism) at 1q23 (lod = 3.37 in African-Americans) is syntenic with linkage in a murine model of lupus. Sib-pair and multipoint nonparametric analyses also support linkage (P < 0.05) at nine loci detected by using two-point lod score analysis (lod > 2.0). Our results are consistent with the presumed complexity of genetic susceptibility to SLE and illustrate racial origin is likely to influence the specific nature of these genetic effects.

Animals↗
PubMed1997

Jun and JNK kinase are activated in thymocytes in response to VM26 and radiation but not glucocorticoids.

In order to establish what role members of the activating protein-1 (AP-1) gene families, i.e., c-fos, c-jun, junB, and junD, play in thymic apoptosis, we have analyzed changes in their expression in response to three different agents: a glucocorticoid analog dexamethasone, an inhibitor of topoisomerase II teniposide VM26, and gamma radiation. All three agents induced thymic death at a similar rate and with the same morphological and biochemical features. There was a rapid and transient increase in the steady-state mRNA level of junB and c-fos genes in all treatments, including control cultures, reminiscent rather of cellular stress response to the environmental changes than to the apoptotic stimuli. On the other hand, treatments with the DNA-damaging agents, VM26 and gamma radiation, resulted in superinduction of the c-jun mRNA and in the activation of the stress response signaling pathway of c-Jun N-terminal kinase. Gene transcription ceased completely in cells with fragmented DNA and the down-regulation of genes such as junD and tubulin was reflective of the thymocytes' commitment to apoptosis. The DNA-binding activities of the serum response factors, cyclic AMP response element binding proteins, and AP-1 factors, indicative of their transcriptional competence, were compromised shortly after induction of apoptosis regardless of the agent employed, consistent with previously reported enhancement in cellular proteolysis which is an essential component of the apoptotic cell death.

Animals↗
PubMed1997

Induction of apoptosis in neoplastic cells by depletion of vitamin B12.

Methionine synthase, a critical enzyme in deoxyribonucleotide biosynthesis for DNA replication, requires vitamin B12 as a cofactor. We have tested the hypothesis that depletion of cells of vitamin B12 would block growth of neoplastic cells and divert them into apoptosis and could form the basis of a new therapeutic strategy for cancer treatment. Using nitrous oxide to inactivate vitamin B12 we show that, in a variety of cell lines in vitro, methionine synthase is rapidly inhibited, the cells cease proliferation and undergo apoptosis. The kinetics of cell death, once started, are similar to those observed following methotrexate treatment or serum withdrawal. This is the first observation of apoptosis being induced following depletion of an essential metabolite as opposed to the more conventional strategy of adding a toxic drug to damage cells thereby triggering apoptosis. Moreover, vitamin B12 depletion has no effect on the nonproliferating cell population.

Journal Article↗
PubMed1996

Laparoscopic complications in markedly obese urologic patients (a multi-institutional review)

OBJECTIVES: Significant obesity is considered to be a relative contraindication to laparoscopic surgery. This study reviews the complications encountered in massively obese patients undergoing urologic laparoscopic surgery. METHODS: Body mass index (BMI) was used as an objective index to indicate massive obesity. Eleven institutions compiled retrospective data on 125 patients having a BMI greater than 30. Procedures performed included 76 pelvic lymph node dissections, 14 nephrectomies, 7 bladder neck suspensions, and 28 miscellaneous procedures. RESULTS: For the group as a whole, the mean BMI was 35.1 (range 30.1 to 57.2). Mean operative time was 202 minutes (range 60 to 480). Conversion to open surgery occurred in 15 of the 125 patients (12%). Complication rates (minor and major) were 22% (27 occurrences in 125 patients) intraoperatively and 26% (33 occurrences in 125 patients) postoperatively. The major complications included 2 trocar injuries to abdominal wall vessels, 1 bladder injury, 3 peripheral nerve injuries, 1 dysrhythmia, 1 deep vein thrombosis, 1 wound seroma, 1 nephrocutaneous fistula, 1 incisional hernia, and 1 death. CONCLUSIONS: In this review, complication rates for urologic laparoscopic surgery on massively obese patients were higher than in the general population undergoing laparoscopic surgery (0.3% to 21%).

Adolescent↗
PubMed1996

Management of splenic injuries in a Canadian trauma centre.

OBJECTIVES: To document the current practice pattern for the treatment of splenic injuries in one Canadian trauma centre and to identify factors that determined which method was employed. DESIGN: A cohort study. SETTING: A Canadian lead trauma centre. PATIENTS: A cohort of 100 patients with splenic injury treated at one trauma hospital over 5 years was identified from a prospective trauma database. MAIN OUTCOME MEASURES: The success rate and failure rate for splenic salvage by splenectomy, splenorrhaphy or observation. Volume of blood transfused, injury severity score (ISS) and method of diagnosis. RESULTS: The median ISS for the cohort was 34 (36 for splenectomy, 38 for splenorrhaphy and 35 for observation). A blunt mechanism of injury was present in 96%. The diagnosis was made by computed tomography (CT) in 55%. Splenic salvage was accomplished in 51 patients; of these, 44 (86%) were in the observation group, and the success rate was 90% (within the range reported in the literature). Only seven patients underwent splenorrhaphy. CT was performed more frequently in the observation group than in the splenectomy group (82% v. 25%, p < 0.0001). The splenectomy group had more blood transfused than the successful observation group (mean units 15 v. 3, p = 0.0001) and had a higher median ISS (36 v. 29, p = 0.02). Multivariate analysis revealed that the method of diagnosis (CT v. diagnostic peritoneal lavage) was the strongest factor associated with how the splenic injury was treated. CONCLUSIONS: The finding in this report of an increase in observational treatment of splenic injuries represents a shift in practice from a previous Canadian report and is in keeping with recent published trends from the United States. Future studies are needed to assess whether any strong regional practice pattern variations in the management of blunt splenic injuries exists in other trauma centres across Canada.

Adult↗
PubMed1995

Interleukin-2 gene therapy in a patient with glioblastoma.

A patient with glioblastoma multiforme (GBM) who had failed conventional therapy was treated with IL-2 gene therapy. The patient received 10 subcutaneous immunizations with autologous tumor cells and fibroblasts genetically modified to secrete IL-2 by retroviral gene transfer. An antitumor immune response mediated in part by CD8+ cytotoxic T cells was demonstrated with the patient's peripheral blood mononuclear cells. A magnetic resonance imaging (MRI) scan performed 4 weeks after the highest treatment dose revealed marked tumor necrosis. These results support the evaluation of this form of IL-2 gene therapy in additional patients with glioblastoma.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

Structural features of the maize sus1 gene and protein.

Genomic clones, cDNA clones, and protein of the maize (Zea mays L.) Suc synthase1 (sus1) gene were isolated and sequenced. Termini (5' and 3') of the transcribed unit were identified. The SUS1 protein was purified from tissue culture cells as a phosphorylated protein. The overall structure of sus1 is virtually identical with that of the paralogous gene, shrunken1 (sh1); however, the last intron of sh1 is missing in sus1. This intron bears much sequence similarity with the adjacent exon, suggesting that the intron arose from an internal duplication. Although the placement of the other 14 introns is identical in both genes, the introns exhibit markedly greater differences in size and sequence relative to that shown by the exons. An explanation for the differential rate of divergence of exons and introns is selection pressure for gene function. Additionally, comparisons of coding regions of plant sucrose synthases show that sh1-like and sus1-like genes can be found in all monocots so far analyzed. These latter observations point to an important role played by both genes in this group of plants.

Base Sequence↗
PubMed1989

Digital respirosonography. New images of lung sounds.

We used tape recordings from normal subjects and from patients with lung disease to generate spectrographic images of respiratory sounds on a personal computer. These digital respirosonograms presented timing and frequency content of lung sounds, with the sound intensities displayed on a color scale. Respiratory sounds during inspiration and expiration could be recognized by their association with concurrent respiration curves. Contributions of low-frequency cardiac sounds were visually identified by their relationship to simultaneously recorded ECGs. Typical characteristics of normal and adventitious lung sounds were documented and displayed both in the time and the frequency domain. Digital respirosonography provides an easy way to assess lung sound amplitudes, frequencies and timing over several breaths.

Adolescent↗