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Biomedical subjects

R Gilbert

Publications and source records attributed to R Gilbert.

At least 73 records · Page 4Linked to original sources
PubMed1997

Effective treatment of B16 melanoma by direct delivery of bleomycin using electrochemotherapy.

Electrochemotherapy (ECT), chemotherapy administered in combination with electric fields, has the potential to be an effective localized treatment for cutaneous malignancies. Bleomycin's cytotoxicity was enhanced by exposing tumour cells to electrical fields following intravenous injection of the chemotherapeutic agent. Two issues associated with this procedure are the existence of a narrow but optimal time-window for effective treatment and the fact that a systemic drug dose is administered for a localized therapy. In order to address these issues, a study was initiated to examine the effectiveness of administering bleomycin by intratumoural injection. A dose-response relationship for intratumoural injection was determined. In addition, the minimal effective field strength necessary for ECT was established. Results of this study indicated drastic reductions in tumour volume for ECT-treated groups. In addition, ECT-treated groups showed increased survival over control groups. The minimum effective dose for the ECT intratumour bleomycin group was 0.025 units. The minimum effective field strength was found to be 1250 V/cm. The results demonstrate that intratumoural injection of bleomycin in combination with electric pulses is effective, and this information will be used to initiate clinical trials.

Animals↗
PubMed1997

Gene therapy research for Duchenne and Becker muscular dystrophies.

Gene therapy is a promising option for the definitive treatment of Duchenne and Becker muscular dystrophies. Presently, gene therapy for Duchenne and Becker muscular dystrophies is still in the preclinical stage with dystrophin-deficient animals (the mdx mouse and a golden retriever dog strain) serving as convenient models. The thrust of research during the past 18 months has focused on two approaches: adenovirus-mediated dystrophin gene transfer and upregulation of a natural dystrophin analogue, utrophin. In the area of adenovirus-mediated gene transfer, substantial progress has been made in characterizing and mitigating the deleterious immune responses to the vector and transgene proteins. Furthermore, new adenovirus vectors have been created with reduced immunogenicity and increased insert gene capacity, which enhance the longevity of the transgene expression. Additional efforts are underway to develop safe and efficient routes of administration of the adenovirus vector carrying the dystrophin expression cassette. The prospects of utrophin upregulation as an attractive strategy for treatment of Duchenne and Becker muscular dystrophies was greatly enhanced by the demonstration of a substantial mitigation of the dystrophic phenotype of the transgenic mdx mouse overexpressing utrophin.

Animals↗
PubMed1997

Is selective neck dissection sufficient treatment for the N0/Np+ neck?

OBJECTIVE: The purpose of this study was to evaluate the therapeutic role of selective neck dissection performed electively in the N0 patient. METHOD: Fifty-four patients with squamous cell carcinoma of the oral cavity, pharynx, and larynx, without clinical evidence of lymph node metastases, underwent 72 selective neck dissections over a 6-year period. The preoperative tumour and patient data were recorded in all patients. Mean follow-up was 59 months. Outcome data pertaining to pathologic nodal status, tumour recurrence, and survival were recorded on all patients. RESULTS: Eighty-one percent of patients were histologically and clinically node negative. Seven percent of N0/Np0 patients failed in the neck compared to 50% of patients with occult nodal metastases (N0/Np+). Salvage treatment following nodal recurrence was successful in only one patient. CONCLUSION: Selective neck dissection does not compromise survival and may minimize surgical morbidity in the N0/Np+ population.

Adult↗
PubMed1996

In vivo gene electroinjection and expression in rat liver.

In vivo targeted gene transfer by non-viral vectors is subjected to anatomical constraints depending on the route of administration. Transfection efficiency and gene expression in vivo using non-viral vectors is also relatively low. We report that in vivo electropermeabilization of the liver tissue of rats in the presence of genes encoding luciferase or beta-galactosidase resulted in the strong expression of these genetic markers in rat liver cells. About 30-40% of the rat liver cells electroporated expressed the beta-galactosidase genetic marker 48 h after electroporation. The marker expression was also detected at least 21 days after transfection at about 5% of the level 48 h after electroporation. The results indicate that gene transfer by electroporation in vivo may avoid anatomical constraints and low transfection efficiency.

Animals↗
PubMed1996

Enhanced effects of multiple treatment electrochemotherapy.

Electrochemotherapy has been demonstrated to be an effective treatment for cutaneous cancers. The treatment includes administering a chemotherapeutic agent followed by electric pulses which are applied directly to the tumour. The pulses facilitate delivery of drug through the plasma membrane. Enhanced delivery is restricted to the area that has been electrically treated. Currently, electrochemotherapy is administered as a single treatment. Complete response rates are high; however, partial responses are obtained in a fraction of the treated tumours. An issue associated with this is whether or not multiple treatments would result in an improved therapy for these partially responding tumours. A multiple treatment electrochemotherapy study was implemented in order to address this issue. The study utilized subcutaneously induced murine B16 melanoma tumours in C57B1/6 mice. Results showed large tumour volume reductions in multiple treatment groups. In addition, a twofold increase in tumour doubling time and greater percentages of complete responses were found as a result of multiple treatment. These results will be utilized to augment existing clinical trials with respect to retreating tumours that have partially responded to a single electrochemotherapy treatment.

Animals↗
PubMed1996

Atrial natriuretic peptide and plasma renin levels in assessment of mineralocorticoid replacement in Addison's disease.

Assessment of mineralocorticoid replacement therapy in Addison's disease relies on clinical features and laboratory measurements, including plasma renin and potassium. Previous studies have questioned the value of measuring the plasma renin concentration (PRC), particularly in the setting of fludrocortisone overreplacement. The aim of this study was to evaluate the usefulness of plasma atrial natriuretic peptide (ANP) measurements as a marker of sodium and volume status in Addison's disease. Fourteen patients with Addison's disease receiving their usual glucocorticoid doses were placed on various doses of fludrocortisone (FC; 0 mg, 0.05 mg, 0.1 mg and 0.2 mg) in random order for four 2-week periods. At the end of each period, blood pressure and clinical symptoms were assessed, and blood was drawn for measurement of PRC and ANP levels. PRC was significantly elevated in patients receiving placebo (54.2 +/- 57.9 ng/mL x h) compared with PRC in those receiving baseline FC (24.7 +/- 42.4 ng/mL x h), 0.1 mg FC (15.2 +/- 25.9 ng/mL x h), and 0.2 mg FC (5.5 +/- 5.7 ng/mL x h). ANP levels were measured by either an extraction method (ANP(ext)) or directly from plasma (ANP(dir)). ANP(dir) was significantly elevated at 0.2 mg FC (87.1 +/- 20.1 pg/mL) compared with baseline (63.3 +/- 8.1 pg/mL), placebo (56.1 +/- 5.5 pg/mL), 0.05 mg FC (60.5 +/- 16.0 pg/mL), and 0.1 mg FC (65.4 +/- 13.7 pg/mL) values. ANP(ext) was elevated in patients receiving 0.2 mg FC (42.7 +/- 41.8 pg/mL) compared with that in patients receiving placebo (7.9 +/- 5.4 pg/mL), 0.05 mg FC (16.2 +/- 11.2 pg/mL), or 0.1 mg FC (19.7 +/- 11.1 pg/mL). Our data suggest that PRC is of value in determining mineralocorticoid underreplacement, whereas ANP is a more sensitive index of FC overreplacement. ANP levels may, therefore, be complementary to PRC in adjustment of mineralocorticoid doses in the upper dose range, where clinical symptoms and signs appear to be of little value.

Addison Disease↗
PubMed1996

The carboxyl terminus of myosin binding protein C (MyBP-C, C-protein) specifies incorporation into the A-band of striated muscle.

Myosin binding protein-C (MyBP-C), also known as C-protein, is a major constituent of the thick filaments of vertebrate striated muscles. The protein, approximately 130 kDa, consists of a series of 10 globular motifs (numbered I to X) each of approximately 90-100 amino acids, bearing resemblance to the C2-set of immunoglobins (Ig C2) and to the fibronectin type III (FnIII) motifs. Using pure preparations of myosin and MyBP-C, it has been demonstrated that the major myosin binding domain of MyBP-C resides within the C-terminal Ig C2 motif (motif X). However, in the context of the in vivo thick filament, it is uncertain if the latter domain is sufficient to target MyBP-C correctly to the A-band or if other regions of the molecule are required for this process. To answer this question, cultures of skeletal muscle myoblasts were transfected with expression plasmids encoding seven truncation mutants of MyBP-C, and their targeting to the A-band investigated by immunofluorescence microscopy. To distinguish the recombinant proteins from endogenous MyBP-C, a myc epitope was inserted at each amino terminus. Recombinant MyBP-C exhibited an identical distribution in the sarcomere to that of native MyBP-C; i.e. it was found exclusively in the C-zone of the A-band. A mutant encoding the C-terminal 372 amino acids, but lacking motifs I-VI (termed delta 1-6), also targeted correctly to the A-band. This fragment, which is composed of two Ig C2 and two FnIII motifs, was the minimal protein fragment required for correct A-band incorporation. Larger amino-terminal deletions or deletion of motif X, the myosin binding domain, abolished all localization to the A-band. One construct (delta 10) lacking only motif X strongly inhibited myofibril assembly. We conclude that the myosin binding domain of MyBP-C, although essential, is not sufficient for correct incorporation into the A-band and that motifs VII to IX are required for this process. The data suggest a topological model in which MyBP-C is associated with the thick filament through its C terminus.

Animals↗
PubMed1995

Matrix metalloproteinases and processing of pro-TNF-alpha.

Tumor necrosis factor-alpha (TNF-alpha) is released from a cell membrane-anchored precursor by proteolytic cleavage. We have shown that broad spectrum synthetic inhibitors of matrix metalloproteinases (MMPs) prevent the processing of the TNF precursor but do not inhibit the release of other cytokines. Purified MMPs, stromelysin, matrilysin, collagenase, and the gelatinases can all cleave a recombinant pro-TNF substrate to yield mature TNF. MMP inhibitors prevent the rise in blood levels of TNF after endotoxin administration in rats and are effective in animal models of inflammatory disease such as adjuvant arthritis. Drugs that inhibit MMP action and TNF release show great promise for the treatment of autoimmune inflammatory diseases.

Amino Acid Sequence↗
PubMed1995

Sleep-related violence.

We hypothesized that sleep-related violent behavior associated with parasomnias occurs as the result of a diathesis and is precipitated by stressors and mediated by disturbed nonrapid eye movement (NREM) sleep physiology. Sixty-four consecutive adult patients (mean age 30 years) who were investigated for sleepwalking or sleep terrors were categorized according to clinical history into three groups: serious violence during sleep to other people or to property or self (n = 26); harmful, but not destructive behavior (n = 12); and nonviolent behavior (n = 26). Log linear analysis showed that a diathesis (childhood parasomnia and/or family history of parasomnia) and a stressor (psychologic distress, substance abuse and sleep schedule disorder) predicted the presence of sleepwalking or night terror. Serious violent acts were more likely to occur with males (p < 0.004) who showed sleep schedule disorder (p < 0.03). Both harmful and serious violent sleep behavior occurred with drug abuse (p < 0.009). In comparison to all other groups, those who were violent to other people were males who experienced more stressors (p < 0.02), drank excessive caffeinated beverages, abused drugs (p < 0.03) and showed less stage 4 sleep (p < 0.02) and less alpha (7.5-11 Hz) electroencephalogram NREM sleep (p < 0.02) on polysomnography. Being male and having < 2% stage 4 sleep provided 89% sensitivity, 80% specificity and 81% diagnostic accuracy for individuals who were violent to others. The forensic implications of these findings are discussed.

Adolescent↗
PubMed1995

The effect of velocity and gender on load range during knee extension and flexion exercise on an isokinetic device.

Limb acceleration and deceleration during exercise on an isokinetic device encounter no machine-offered resistance. The purpose of this study was to quantify the relationship between velocity and range of motion that is sustained at a predetermined isokinetic velocity, termed load range, during concentric knee extension and flexion exercise. Nine male and nine female subjects performed three maximal concentric reciprocal knee extension and flexion repetitions at 60, 120, 180, 240, 360, and 450 degrees/sec. Extension and flexion results revealed a significant (p < 0.05) increase in acceleration and deceleration range of motion while load range significantly decreased with increasing velocity. Males exhibited greater load range and less acceleration range of motion than females at 240, 360, and 450 degrees/sec, while deceleration range of motion was not different between genders at any speed. These results demonstrate an inverse relationship between isokinetic velocity and load range and suggest a need to carefully consider velocity selection when performing exercise on an isokinetic device.

Adult↗
PubMed1994

SIDS: risk reduction measures.

Increasing public awareness of the prone sleeping position, maternal smoking and overheating as potentially avoidable risk factors for the sudden infant death syndrome (SIDS) has been accompanied by a dramatic reduction in mortality. The results of two population based studies of SIDS in Avon are compared; the first one occurred before these risk factors were widely known and during the second study there was a gradual increase in publicity. Between the studies the prevalence of prone sleeping in the control populations fell significantly from 60% to 28% and almost all of the reduction in SIDS mortality (3.5 to 1.7 per thousand live births) could be attributed to this change. Other changes were also found: the seasonal pattern of incidence was lost, the proportion of expreterm babies increased and the male predominance was accentuated. The relative importance of smoking and bottle feeding appeared to increase whereas the odds ratios for heavy wrapping and overnight heating were no longer significantly elevated. Small numbers limit the significance of these individual variations but demonstrate that changes are occurring. Local and national public health campaigns have been launched in the UK and abroad to encourage infant care practices that reduce the risk of SIDS. Monitoring the effectiveness of these campaigns is important and may allow new risk factors to be identified which could in turn be targeted in future preventative campaigns. Significant reductions in mortality have followed these initial campaigns but in order to maintain them the message must be regularly renewed using an appropriate approach and effective channels of communication to target high risk families within the community.

Bottle Feeding↗
PubMed1994

Processing of tumour necrosis factor-alpha precursor by metalloproteinases.

Tumour necrosis factor-alpha (TNF-alpha) is a potent pro-inflammatory and immunomodulatory cytokine implicated in inflammatory conditions such as rheumatoid arthritis, Crohn's disease, multiple sclerosis and the cachexia associated with cancer or human immunodeficiency virus infection. TNF-alpha is initially expressed as a 233-amino-acid membrane-anchored precursor which is proteolytically processed to yield the mature, 157-amino-acid cytokine. The processing enzyme(s) which cleave TNF-alpha are unknown. Here we show that the release of mature TNF-alpha from leukocytes cultured in vitro is specifically prevented by synthetic hydroxamic acid-based metalloproteinase inhibitors, which also prevent the release of TNF-alpha into the circulation of endotoxin challenged rats. A recombinant, truncated TNF-alpha precursor is cleaved to biologically active, mature TNF-alpha by several matrix metalloproteinase enzymes. These results indicate that processing of the TNF-alpha precursor is dependent on at least one matrix metalloproteinase-like enzyme, inhibition of which represents a novel therapeutic mechanism for interfering with TNF-alpha production.

Animals↗
PubMed1994

Microalbuminuria in diabetes.

This statement summarises current understanding of the role of microalbuminuria in diabetic nephropathy and describes its natural history and clinical relevance. It outlines core facts and makes recommendations for the management of patients with persistent microalbuminuria.

Albuminuria↗