Search PubMed⌕ Search

Biomedical subjects

M J Gardner

Publications and source records attributed to M J Gardner.

At least 73 records · Page 4Linked to original sources
PubMed1996

DNA vaccines against malaria: immunogenicity and protection in a rodent model.

Since the first demonstration of the technology a few years ago, DNA vaccines have emerged as a promising method of vaccination. In a variety of experimental systems, DNA vaccines have been shown not only to induce potent immune responses, but also to offer many advantages in terms of ease of construction, testing, and production. In this article we summarize the progress achieved in development of DNA vaccines that can protect mice from infection by the rodent malaria parasite Plasmodium yoelii, describe initial studies of immunogenicity of a malaria DNA vaccine in a primate model, and outline the strategies being employed to design the next generation of malaria DNA vaccines.

Animals↗
PubMed1996

Is computed tomography a useful adjunct to the clinical examination for the diagnosis of pediatric gastrointestinal perforation from blunt abdominal trauma in children?

Perforations of the gastrointestinal (GI) tract, compared to solid organ injuries, are a relatively infrequent sequela of blunt abdominal trauma in children. The purpose of this study is to review retrospectively the diagnostic modalities used in 30 children with proven traumatic intestinal perforations treated at one institution. Since computed tomography with intravenous and oral GI contrast is commonly used in the diagnosis of suspected solid organ injury from blunt abdominal trauma, we evaluated retrospectively the computed tomographic (CT) scan findings in these children in an attempt to accurately predict or suggest GI perforation. Between January 1987 and December 1993, 5,795 children were admitted. Three hundred fifty suffered blunt abdominal trauma of which 30 patients (8.5%) required surgery for a GI perforation and formed the basis for this study. Data collected were mechanisms of injury, results of admission and serial clinical examinations, results of radiologic imaging, associated injuries, operative findings, and outcome. Follow-up was obtained on all patients and averaged 2.5 years. Blows to the abdomen (handlebars, cars, kicks) were the most common cause of perforation, followed by seatbelt injuries. Eleven patients underwent immediate laparotomy an average of 0.75 hours after admission. The indication for surgery was shock (three), clinically apparent peritonitis (five), and free air on plain abdominal radiograph (three). Nineteen patients underwent "later" laparotomy, an average of 3.4 hours after admission, all because of the eventual development of peritonitis. Retrospective review of these CT scans revealed free air anterior to the liver in three, and the remaining 16 had CT findings suggestive of GI injury such as free fluid, focal fluid-filled thick-walled bowel loops, and mesenteric infiltration. There were five (26%) false negative CT scans performed an average of 5.0 hours after injury. We believe serial physical examinations are the gold standard for diagnosing pediatric GI perforation from blunt abdominal trauma. The CT scan may be a useful adjunct to the diagnosis of an intestinal perforation in patients who have no immediate indication for surgery. Presently, the only CT finding that is an absolute indication for laparotomy is free air (in the absence of pulmonary/mediastinal injury or barotrauma). The other CT "findings" need to be validated prospectively.

Abdominal Injuries↗
PubMed1996

More informative abstracts revisited.

Following proposals in 1987 and 1988, several medical journals have provided more informative abstracts ("structured abstracts") for articles of clinical interest. Structured abstracts for original studies require authors to systematically disclose the objective, basic research design, clinical setting, participants, interventions (if any), main outcome measurements, results, and conclusions; and for literature reviews the objective, data sources, methods of study selection, data extraction and synthesis, and conclusions. More informative abstracts of this kind can facilitate peer review before publication, assist clinical readers to find articles that are both scientifically sound and applicable to their practices, and allow more precise computerized literature searches. We review the feasibility, acceptability, and dissemination of structured abstracts, reassess the underlying strategy, and describe modifications of the approach. This innovation can aid communication from scientists to clinicians, and other clinical journals are invited to join this effort.

Abstracting and Indexing↗
PubMed1995

Spatial features in body-surface potential maps can identify patients with a history of sustained ventricular tachycardia.

BACKGROUND: Regional disparities of ventricular primary-repolarization properties contribute to an electrophysiological substrate for arrhythmias. Such disparities can be assessed from body-surface distributions of ECG QRST areas. Our objective was to isolate and test those features of QRST-area distributions that would be suitable for identifying patients at risk for life-threatening ventricular arrhythmias. METHODS AND RESULTS: We recorded ECGs simultaneously from 120 leads during sinus rhythm for 204 patients taking no antiarrhythmic drugs: half had had sustained ventricular tachycardia (VT); the other half, a myocardial infarction but no history of VT. For each patient, we calculated the QRST area in each lead and, using Karhunen-Loeve (K-L) expansion, reduced these data to 16 coefficients (each relating to one spatial feature, an eigenvector, derived from the total set of 204 QRST-area maps). Using stepwise discriminant analysis, we selected feature subsets that best discriminated between the two groups, and we estimated by a bootstrap procedure using 1000 trials how these subsets would perform on a prospective patient population. The mean diagnostic performance of the classifier for 1000 randomly selected training sets (n = 102 in each, with both groups equally represented) increased monotonically with the number of features used for classification. The initial trend for the corresponding test sets (n = 102 in each) was the same but reversed when the number of features exceeded eight. For an optimal set of eight spatial features, the sensitivity and specificity of the classifier for detecting patients with VT in 1000 test sets were (mean +/- SD) 90.3 +/- 4.3% and 78.0 +/- 6.1%, and its positive and negative predictive accuracies were 80.7 +/- 4.2% and 89.2 +/- 4.2%, respectively. Use of QRS duration as a supplementary feature to eight K-L coefficients can, in the test sets, increase specificity to 80.9 +/- 5.4% and positive predictive accuracy to 82.8 +/- 3.9% compared with the results for the optimal number of eight K-L features alone. CONCLUSIONS: Multiple body-surface ECGs contain valuable spatial features that can identify the presence of an arrhythmogenic substrate in the myocardium of patients at risk for ventricular arrhythmias. Our results compare very favorably with those achieved by any other known test, invasive or noninvasive, for arrhythmogenicity.

Body Surface Potential Mapping↗
PubMed1995

Expression of cell adhesion molecules on ovarian tumour cell lines and mesothelial cells, in relation to ovarian cancer metastasis.

A major route for the spread of ovarian cancer is by the attachment of tumour cells to the mesothelium lining in the peritoneal cavity. The expression of various adhesion molecules has been measured on freshly-prepared mesothelial cells, two mesothelial cells lines and 13 established ovarian tumour cell lines. The integrins beta 1 and beta 3, ICAM-1, and CD44 were detected on all mesothelial preparations and on many or all of the tumour lines. VCAM-I was expressed exclusively on the mesothelial cells and Lewis x was expressed on half of the tumour lines. There was low or no expression of sialyl Le(x), sialyl Le(a), integrins alpha 4, beta 1, beta 4, or E and P selectins. Only CD44 expression was significantly affected by trypsin treatment. From the known interactions of adhesion molecules, the results suggest that CD44, and beta 1 and beta 3 integrins may be important in tumour/mesothelial interactions.

Carrier Proteins↗
PubMed1995

Hyaluronic acid secreted by mesothelial cells: a natural barrier to ovarian cancer cell adhesion.

The adhesion to mesothelial monolayers of eight cultured ovarian tumour cell lines was studied in multiwell plates as a model for some of the interactions of ovarian cancer in the peritoneal cavity. When only the upper half of the conditioned medium (CM) from a confluent mesothelial cell culture was aspirated, the adhesion of the tumour cells was low (3.5%-36%). When the medium was removed completely the adhesion increased. The tumour cell lines showing the greatest enhancement of adhesion were those which had previously been shown to express the highest amounts of CD44. By adding erythrocyte suspensions to mesothelial cells it was shown that there was a pericellular coat around the mesothelial cells that could be destroyed by aspirating the medium, or by treating the medium with hyaluronidase (Hase). Treatment of the CM with Hase also considerably increased tumour cell adhesion. Furthermore, CM was shown to contain high amounts of hyaluronic acid (HA). HA blocked adhesion in the absence of CM, but the effect was not as large as that produced by the pericellular coat. It is proposed that pericellular HA produced by mesothelial cells has an important role in the invasion of ovarian tumour cells in the peritoneal cavity.

Cell Adhesion↗
PubMed1995

Laryngotracheal disruption from blunt pediatric neck injuries: impact of early recognition and intervention on outcome.

Blunt and penetrating neck injuries are an infrequent cause of morbidity and mortality in the pediatric population. Although less common than penetrating injuries, blunt pediatric neck injuries are more often life-threatening because of associated laryngotracheal disruption. The authors reviewed their experience with pediatric neck injuries over the past 5 years. There were nine blunt and 14 penetrating injuries, representing 0.5% of the trauma admissions. There was no significant difference in age or gender distribution between the two groups. Blunt pediatric neck injuries were more often associated with frank respiratory distress at the time of presentation. Massive subcutaneous emphysema and hoarseness were the most common symptoms encountered. All patients with blunt injury underwent direct laryngoscopy and bronchoscopy (DL & B) and esophagoscopy. DL & B results were positive for eight patients; seven patients underwent neck exploration and successful repair of the laryngotracheal injuries. There were two deaths; one of these patients had laryngeal transection, which was not recognized at the time of DL & B. The other death resulted from associated tracheobronchial disruption secondary to massive blunt chest trauma. The patients with penetrating neck injuries were more likely to be treated nonoperatively, to have a shorter stay in the hospital and intensive care unit, and to have a lower injury severity score. There were no deaths in this group. The authors conclude that all patients with blunt neck trauma should undergo emergent and meticulous DL & B. Visualization of laryngotracheal disruption mandates immediate neck exploration and primary repair.

Adolescent↗
PubMed1995

Blunt urogenital trauma in prepubescent female patients: more than meets the eye!

Blunt traumatic injury to the urogenital region in the prepubescent girl is commonly evaluated in pediatric emergency departments (ED). The purpose of this study is: 1) to establish recommendations for an accurate, painless (both physically and psychologically), and timely diagnosis, and 2) to determine whether the ED examination can accurately determine the extent of the injury. Over a 24-month period (January 1991 through December 1992), 22 girls with blunt trauma to the urogenital region (mean age 5.7 years, range 2-9 years) were retrospectively evaluated. Initial ED evaluations were by both an emergency physician and a pediatric surgeon. All 22 patients underwent an examination under anesthesia (EUA) in the operating room to evaluate the extent of the injury and to repair the injury as needed. Follow-up was obtained in all patients and averaged 18 months. The findings at EUA demonstrated a significant disagreement with the preoperative ED evaluation. In only five patients was there agreement between the preoperative ED assessment and the findings during the EUA (24% concurrence). Thus, 16 patients (76%) had injuries of greater extent than was appreciated during the preoperative examination in the ED. Partial or complete disruption of the perianal sphincters occurred in six patients (27%) and was unrecognized preoperatively in each. Twenty-one of the 22 patients required suture repair of lacerations, the remaining patient did not require surgical therapy. Three patients had contusions or lacerations to the urethral area requiring repair and/or prolonged bladder catheter drainage for two to 14 days (average seven days). The average hospital stay was 19.3 hours. There were three minor wound complications following surgery: two required repeat EUA with suturing or cauterization, and one required no further therapy. This study clearly demonstrates that the ED examination, by both emergency physicians and pediatric surgeons, of young girls who have suffered blunt urogenital trauma grossly underestimates the severity of injuries when compared to the EUA in the operating room. EUA is safe and allows early discharge with minimal psychologic sequelae. Recommendations for mandatory EUA are made.

Accidents↗
PubMed1995

The effects of age and gender on the pharmacokinetics of tenidap sodium in patients with rheumatoid arthritis and osteoarthritis.

1. This open-label study was conducted to evaluate the effects of age and gender on the pharmacokinetics of tenidap sodium in patients with either rheumatoid arthritis (RA) or osteoarthritis (OA). 2. A total of 145 male and female patients, 80 with RA (aged 22-91 years) and 65 with OA (aged 45-83 years) each received a single dose of 120 mg tenidap sodium. Pharmacokinetic parameters were estimated from individual tenidap plasma concentration-time curves determined up to 120 h post-dose. Tenidap plasma protein binding was determined in the youngest and oldest age groups for both RA and OA patients. 3. In RA patients, age and gender did not significantly affect the disposition of tenidap or the percentage of unbound tenidap in plasma. Only for tmax were statistically significant effects in the analysis of covariance observed and these were attributed to very high tmax values in two female patients. Likewise, in patients with OA, age and gender did not significantly affect the pharmacokinetics of tenidap, although patients with larger body weights had lower Cmax values. 4. Pharmacokinetic parameters were not significantly different between RA and OA patients, except for t1/2, where two outlier RA patients had low values that caused the mean value to be significantly lower in RA (24 h) than in OA (26 h) patients. Pharmacokinetic parameters for pooled values from RA and OA patients were as follows: t1/2 = 25 h, AUC = 538.4 micrograms ml-1 h, Cmax = 21.9 micrograms ml-1, tmax = 3.2 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Single and multiple dose pharmacokinetics of tenidap sodium in healthy subjects.

1. The absorption, protein binding, clearance and absolute bioavailability of tenidap sodium were studied after single and multiple dosing. 2. Thirteen healthy male volunteers received a single 120 mg oral dose of tenidap sodium and a 20 mg intravenous infusion of deuterated tenidap ([D3]-tenidap) on day 1. This was followed by a 6-day washout period (days 2-7) and then further daily doses of oral tenidap sodium 120 mg for 21 consecutive days (days 8-28) with an additional 20 mg intravenous infusion of [D3]-tenidap on day 28. Twelve subjects were eligible for pharmacokinetic evaluation. 3. Following multiple oral doses, the half-life of tenidap is approximately 23 h. 4. Following single and multiple dose administration, the absolute bioavailability is 85%. 5. Systemic clearance of [D3]-tenidap was 29% greater on day 28 than on day 1 indicating a significant increase in intrinsic clearance (CLint) of tenidap since protein binding of tenidap in plasma did not change during the study. Consistent with the increase in systemic clearance, the half-life of [D3]-tenidap decreased and the ratio of AUC(0,24h) day 28/AUC day 1 following oral dosing was less than one. Tenidap is subject to extensive hepatic metabolism, so the increase in CLint may indicate that tenidap induces its own metabolism. 6. Steady-state was achieved by the eleventh day of dosing. Since numerous studies in patients with rheumatoid arthritis have shown that multiple dosing with tenidap is clinically efficacious, this suggests that the pharmacokinetic differences observed between the first and twenty-first day of multiple tenidap dosing do not influence the clinical response.

Adult↗
PubMed1995

Cimetidine does not alter the clearance or plasma binding of tenidap in healthy male volunteers.

1. An open-label, placebo-controlled study was conducted to examine the effect of cimetidine on the steady-state pharmacokinetics of tenidap. 2. Twenty-four healthy volunteers received tenidap sodium (120 mg) each morning throughout the study. On day 14 plasma levels of tenidap had reached steady state; half of the subjects were treated concomitantly with cimetidine 800 mg at night, while the other half received placebo. Allocation of cimetidine or placebo was randomised. Plasma profiles of tenidap were measured on days 14 and 16. 3. The addition of cimetidine did not significantly affect the Cmax, tmax, or lambda z of tenidap. The AUC(0,24h) increased by 4% between days 14 and 16 in the cimetidine treatment group, compared with a decrease of 2% in the placebo group. This small difference is statistically significant (P = 0.047), but it is not considered to be clinically relevant. 4. It is concluded that concomitant administration of cimetidine does not significantly affect the pharmacokinetics of tenidap at steady state.

Adolescent↗
PubMed1995

The effect of tenidap sodium on the disposition and plasma protein binding of phenytoin in healthy male volunteers.

1. The effects of tenidap sodium 120 mg day-1 at steady state and placebo on the plasma protein binding and pharmacokinetics of phenytoin were compared in this randomised, double-blind, placebo-controlled, parallel-group study, involving 12 healthy young men, conducted over 34 days. 2. Single oral doses of phenytoin 200 mg were given on days 1-3 and 29-31, and intravenous phenytoin, 250 mg infused over 20 min, was given on days 4 and 32. Tenidap (120 mg day-1), or matching placebo, was administered as single oral daily doses from days 8 to 34 inclusive. 3. The plasma protein binding of phenytoin was determined immediately before oral phenytoin administration on days 1 and 29. Pharmacokinetic parameters were estimated from the serum phenytoin concentration-time curves derived on days 4 and 32 following the phenytoin infusions. The differences between the pre- and post-treatment mean percentage of unbound plasma phenytoin and mean pharmacokinetic parameters were compared between treatment groups. 4. Tenidap sodium 120 mg day-1, at steady state, increased the percentage of unbound phenytoin in plasma by approximately 25%, but did not significantly affect AUC(0,48h) or Cmax. 5. Since tenidap increases the percentage of unbound phenytoin in plasma, when monitoring phenytoin plasma concentrations free concentrations of phenytoin should be considered. 6. Tenidap was well tolerated throughout the study.

Adult↗
PubMed1995

Tenidap sodium does not alter the clearance or plasma protein binding of tolbutamide in healthy male volunteers.

1. This randomised, double-blind, parallel group study in 12 healthy young men compared the effects of tenidap sodium 120 mg day-1, at steady state, with placebo on the plasma protein binding and clearance of tolbutamide. 2. Each subject received a 1000 mg intravenous infusion of tolbutamide given over 5 min on day 1 of the study, and again on day 30 following 22 days of successive tenidap or placebo administration. 3. The percentage of unbound tolbutamide in plasma was determined immediately before each infusion. Mean pharmacokinetic parameters (system plasma clearance, terminal phase rate constant, apparent volume of distribution at steady state) of tolbutamide were derived from individual tolbutamide plasma concentration-time curves generated after infusion. The within group day 30 minus day 1 differences were compared between treatment groups. 4. Tenidap was shown to have no statistically or clinically significant effects on any of the parameters assessed. These results indicate that tenidap does not induce or inhibit the P450IIC9 isozyme which metabolises tolbutamide and that tenidap does not displace tolbutamide from plasma protein binding sites. 5. Both tenidap and tolbutamide were well tolerated. No severe treatment-related adverse events were reported, no subject withdrew from the study, and there were no reports of treatment-related laboratory abnormalities, or significant variations in vital signs.

Adult↗
PubMed1994

A precise, rapid and sensitive in vitro assay to measure the adhesion of ovarian tumour cells to peritoneal mesothelial cells.

Ovarian cancer is the second most common gynaecological cancer in the UK, causing 2000 deaths per year. It spreads by shedding cells which attach to the mesothelial lining of the peritoneal cavity. In order to quantitatively study this interaction, a model system was developed in which mesothelial cells were cultured as monolayers in multiwell plates, and ovarian tumour cells were added that had been pre-labelled with a fluorescent dye (calcein). Synchronous interaction between the two populations was achieved by brief centrifugation at low g and the degree of attachment was measured on an automated fluorimeter after washing away the unbound cells. Using this procedure it was possible to measure tumour cell adhesion in 96 wells in 3-4 h. The reproducibility of the method was high even after short incubation times and the background absorbance was so low that the adhesion of less than a 1000 cells could be easily detected. The method works equally well for all ovarian tumour cell lines so far studied, and in preliminary experiments, it was shown that it can be used to screen for the effects of various blocking agents.

Cell Adhesion↗
PubMed1994

The evolutionary origin of the 35 kb circular DNA of Plasmodium falciparum: new evidence supports a possible rhodophyte ancestry.

In common with other Apicomplexan parasites, Plasmodium falciparum carries two extrachromosomal DNAs, one of which, the 6 kb element, is undoubtedly mitochondrial. The second, generally referred to as the 35 kb circle, is of unknown provenance, but the nature and organization of its genetic content makes a mitochondrial association unlikely and the molecule has features reminiscent of plastid genomes. We now report the occurrence on the circle of an open reading frame specifying a predicted 470 amino acid protein that shares more than 50% identity with a gene currently known only on the plastome of red algae. This high degree of conservation confirms the 35 kb circle's plastid ancestry, and we speculate that it may have originated from the rhodoplast of an ancient red algal endosymbiont in the progenitor of the Apicomplexa.

Amino Acid Sequence↗