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Biomedical subjects

J D Gilbert

Publications and source records attributed to J D Gilbert.

At least 37 records · Page 2Linked to original sources
PubMed2000

Unexpected death in association with an occult posterior lingual abscess.

An 82 year old woman was found unexpectedly dead in bed on the day of admission to hospital for the investigation of difficulty breathing. During a barium swallow examination after admission she was thought to have aspirated contrast material. At autopsy a large posterior lingual abscess was found, with barium in the airways. Death was attributed to a combination of upper airway narrowing associated with the abscess, chronic lung disease and possible aspiration of barium. This case demonstrates an unusual sequence of events associated with localised upper airway sepsis. It also confirms the importance of careful examination of the upper aerodigestive tract at autopsy in individuals of all ages.

Journal Article↗
PubMed2000

Volatile substance use in sexual asphyxia.

A 38-year-old man was found dead in bed dressed in female clothing with a mouth gag, handcuffs and bindings around the genitals and limbs. A respirator was also covering the mouth and nose. There were no suspicious circumstances and a diagnosis of death due to sexual asphyxia was made. Following the subsequent discovery of bottles of chloroform in the bedroom, head space analysis of blood confirmed the presence of chloroform, with a blood level of 33 mg/L. Death was, therefore, attributed to a combination of chloroform toxicity and upper-airway obstruction. Headspace analysis with follow-up quantitation may, therefore, be a useful adjunct to the investigation of such cases when devices such as respirators or gas masks are found with the body.

Journal Article↗
PubMed2000

Fractures of the hyoid bone and laryngeal cartilages in suicidal hanging.

A prospective study of neck trauma associated with suicidal hanging was undertaken at the Forensic Science Centre, Adelaide over a 3-year period from July 1996 to June 1999. There were a total of 40 cases of suicidal hanging with an age range of 17-74 years (average = 35 years; M:F = 33:7). Fractures of neck structures were identified in 19 cases (47.5%) and were more common in older victims and males. Nine victims had only thyroid cartilage fractures (22.5%), four victims had only fractures of the hyoid bone (10%), and six victims had fractures of both the hyoid bone and thyroid cartilage (15%). No fractures of the cricoid cartilage or cervical spine were demonstrated. Potentially confusing issues encountered in the assessment of possible fractures of neck structures included cases where there was congenital absence of the greater horn of the thyroid cartilage, where accessory nodules of cartilage were present in the posterior margin of the thyrohyoid membrane, and where there had not yet been bony fusion of the cartilaginous joints between the greater horns and body of the hyoid bone.

Journal Article↗
PubMed2000

Forensic studies of a stabbed infant bottlenose dolphin.

A 4-6-week-old male bottlenose dolphin (Tursiops truncatus) was found freshly dead on a beach. He belonged to a nearby dolphin group that was known to have considerable curiosity about human activity and to frequently approach pleasure craft. An autopsy revealed an otherwise healthy animal with death due to a stab wound that had passed completely through the body, incising the aorta. Careful assessment of the wounds indicated that the blade of the weapon had been at least 190 mm in length and 22 mm in width, with a single edge. This report demonstrates that standard forensic techniques may be extremely useful in determining the cause of death in animals, in documenting injuries to assist in the investigation of such cases, and in providing facts to aid in the successful prosecution of those guilty of killing or injuring animals.

Journal Article↗
PubMed2000

Pathologic features of childhood pedestrian fatalities.

A retrospective analysis of 68 cases of fatal childhood pedestrian accidents in South Australia that occurred over a 20-year period from January 1977 to December 1996 was undertaken. The age range was 12 months to 16 years (average, 7.6 years), with a male to female ratio of 41:27. The most common site of significant injury was the head (91.2%), followed by the abdomen (50%), chest (47.1%), and neck (38.2%). The most frequently encountered significant injury combinations involved the head, chest, and abdomen (14.7%); the head and chest (11.8%); and the head, neck, and abdomen (11.8%). Injuries were severe, consisting of extensive compound and comminuted skull fractures, neck fractures, and massive intraparenchymal brain and internal organ damage with avulsions and fragmentation. Non-life-threatening limb injuries occurred in 88% of cases. A distinct subgroup involved infants and younger children playing in driveways at home who were hit by reversing vehicles. The injuries were often of such a severe nature that death was instantaneous and with no possibility of successful medical intervention. More deaths occurred during the winter than summer months.

Abdominal Injuries↗
PubMed2000

Pathologic features of fatal shark attacks.

To examine the pattern of injuries in cases of fatal shark attack in South Australian waters, the authors examined the files of their institution for all cases of shark attack in which full autopsies had been performed over the past 25 years, from 1974 to 1998. Of the seven deaths attributed to shark attack during this period, full autopsies were performed in only two cases. In the remaining five cases, bodies either had not been found or were incomplete. Case 1 was a 27-year-old male surfer who had been attacked by a shark. At autopsy, the main areas of injury involved the right thigh, which displayed characteristic teeth marks, extensive soft tissue damage, and incision of the femoral artery. There were also incised wounds of the right wrist. Bony injury was minimal, and no shark teeth were recovered. Case 2 was a 26-year-old male diver who had been attacked by a shark. At autopsy, the main areas of injury involved the left thigh and lower leg, which displayed characteristic teeth marks, extensive soft tissue damage, and incised wounds of the femoral artery and vein. There was also soft tissue trauma to the left wrist, with transection of the radial artery and vein. Bony injury was minimal, and no shark teeth were recovered. In both cases, death resulted from exsanguination following a similar pattern of soft tissue and vascular damage to a leg and arm. This type of injury is in keeping with predator attack from underneath or behind, with the most severe injuries involving one leg. Less severe injuries to the arms may have occurred during the ensuing struggle. Reconstruction of the damaged limb in case 2 by sewing together skin, soft tissue, and muscle bundles not only revealed that no soft tissue was missing but also gave a clearer picture of the pattern of teeth marks, direction of the attack, and species of predator.

Adult↗
PubMed2000

Methadone maintenance programs--a two-edged sword?

Retrospective review was undertaken of all autopsies in which methadone was detected at the Forensic Science Centre, South Australia, during a 3-year period from July 1996 to June 1999. Thirty-five cases were found in which methadone had either caused or contributed to death (age range = 14-54 years; average = 31 years; M:F = 3.4:1). Ten victims were participating in a methadone maintenance program, of whom four died within a week of enrollment. Eight victims (23%) not enrolled in a methadone maintenance program were found who had died after the use of "diverted" methadone (i.e., prescribed for someone else) (age range = 14-34 years; average = 25 years; M:F = 6:2). Deaths were directly attributable to methadone toxicity in seven of the eight cases, with additional drugs or alcohol being found in seven cases. Prevention of ongoing deaths caused by methadone diversion could be achieved by allowing only daily releases of methadone, with the addict having to consume the drug under close supervision.

Adolescent↗
PubMed2000

Predictors of torsades de pointes in rabbit ventricles perfused with sedating and nonsedating histamine H1-receptor antagonists.

Several nonsedating histamine H1-receptor antagonists are associated with torsades de pointes ventricular tachycardia. The objectives of this study were to: (i) compare electrocardiographic, monophasic action potential, and arrhythmogenic effects of sedating and nonsedating H1-receptor antagonists, and (ii) identify correlates of drug-induced torsades de pointes in an isolated ventricle model. Isolated, electrically paced (1-3 Hz) rabbit ventricles were Langendorff-perfused with either drug-free Tyrode's solution or one of the following: (i) the sedating H1-receptor antagonist hydroxyzine (0.1-30 microM), (ii) cetirizine, a nonsedating metabolite of hydroxyzine (1-300 microM), and (iii) the nonsedating, putatively arrhythmogenic H1-receptor antagonist astemizole (0.1-30 microM). Volume conducted electrocardiographic signals and monophasic action potentials from the periapical left ventricular endocardium and epicardium were recorded. There were no apparent changes in control (n = 15) or hydroxyzine-perfused (n = 7) hearts. Cetirizine (n = 13) produced a mild biphasic electrocardiographic QT interval prolongation and was associated with early afterdepolarizations, but not with torsades de pointes. Astemizole (n = 11) lengthened QT intervals, and at high concentration (30 microM) induced torsades de pointes in 10 of 11 hearts (P < 0.001 vs. all other groups). These findings are consistent with previously reported repolarizing current inhibition by cetirizine, but may additionally indicate "compensatory" inhibition of inward currents at higher concentrations. By contrast, astemizole-induced changes are consistent with unopposed repolarizing current inhibition.

Action Potentials↗
PubMed1999

Medicolegal complications of pseudologia fantastica.

A 46-year-old woman allegedly on a witness protection scheme who died under unusual circumstances with a factitious history of two previous homicide attempts and multiple medical problems including paraplegia and lung carcinoma is presented to demonstrate difficulties that may arise in the medicolegal investigation of such cases. A diagnosis of pseudologia fantastica was made once no corroboration of the presenting history or medical illnesses could be made. Death was due to haemorrhage from a self-inflicted incised wound to the arm.

Journal Article↗
PubMed1999

Efficacy of adenovirus-mediated CD/5-FC and HSV-1 thymidine kinase/ganciclovir suicide gene therapies concomitant with p53 gene therapy.

Recent evidence has suggested that tumor cells having a wild-type p53 status are more sensitive to chemotherapeutic agents and radiation than cells that lack functional p53. The heightened sensitivity of wild-type p53 cells is thought to be attributable to their propensity to undergo p53-mediated apoptosis after insult. Given that suicide gene therapy is essentially tumor-targeted chemotherapy, we examined the hypothesis that coexpression of wild-type p53 could enhance the efficacy of adenovirus-mediated suicide gene therapy. Human Hep3B and SK-OV-3 cells, which are null for p53, were infected with a pair of replication-deficient adenoviruses that expressed a cytosine deaminase/herpes simplex virus thymidine kinase (CD/HSV-1 TK) fusion gene without (fusion gene nonreplicative adenovirus, FGNR) or with (FGNRp53) the wild-type human p53 gene. The sensitivity of cells to the CD/5-fluorocytosine (CD/5-FC) and HSV-1 TK/ ganciclovir (GCV) enzyme/prodrug systems was determined in vitro and in vivo. Coexpression of p53 did not enhance the cytotoxicity of either the CD/5-FC or HSV-1 TK/GCV system in vitro. The failure to observe an effect of p53 could not be explained on the basis of insufficient or transient p53 expression, because FGNRp53-infected cells growth arrested in G1, induced Bax, and underwent apoptosis at an increased rate after prodrug treatment, particularly when the adenovirus E1A protein was present. Intratumoral injection of FGNRp53 concomitant with single or double pro-drug therapy resulted in a tumor growth delay that was equal to or less than that observed with the FGNR virus. Our results indicate that coexpression of p53 may not necessarily improve the efficacy of adenovirus-mediated CD/ 5-FC and HSV-1 TK/GCV suicide gene therapies in vivo.

Adenoviridae↗
PubMed1998

Human translocation liposarcoma-CCAAT/enhancer binding protein (C/EBP) homologous protein (TLS-CHOP) oncoprotein prevents adipocyte differentiation by directly interfering with C/EBPbeta function.

Human translocation liposarcoma (TLS)-CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP) is a fusion oncoprotein found specifically in a malignant tumor of adipose tissue and results from a t(12;16) translocation that fuses the amino-terminal part of TLS to the entire coding region of CHOP. Being that CHOP is a member of the C/EBP transcription factor family, proteins that comprise part of the adipocyte differentiation machinery, we examined whether TLS-CHOP blocked adipocyte differentiation by directly interfering with C/EBP function. Using a single-step retroviral infection protocol, either wild-type or mutant TLS-CHOP were co-expressed along with C/EBPbeta in naïve NIH3T3 cells, and their ability to inhibit C/EBPbeta-driven adipogenesis was determined. TLS-CHOP was extremely effective at blocking adipocyte differentiation when expressed at a level comparable to that observed in human myxoid liposarcoma. This effect of TLS-CHOP required a functional leucine zipper domain and correlated with its ability to heterodimerize with C/EBPbeta and inhibit C/EBPbeta DNA binding and transactivation activity in situ. In contrast, the TLS-CHOP basic region was dispensable, making it unlikely that the inhibitory effect of TLS-CHOP is attributable to unscheduled gene expression resulting from TLS-CHOP's putative transactivation activity. Another adipogenic transcription factor, PPARgamma2, was able to rescue TLS-CHOP-inhibited cells, indicating that TLS-CHOP interferes primarily with C/EBPbeta-driven adipogenesis and not with other requisite events of the adipocyte differentiation program. Together, the results demonstrate that TLS-CHOP blocks adipocyte differentiation by directly preventing C/EBPbeta from binding to and transactivating its target genes. Moreover, they provide strong support for the thesis that a blockade to normal differentiation is an important aspect of the cancer process.

3T3 Cells↗
PubMed1998

A novel three-pronged approach to kill cancer cells selectively: concomitant viral, double suicide gene, and radiotherapy.

Two obstacles limiting the efficacy of nearly all cancer gene therapy trials are low gene transduction efficiencies and the lack of tumor specificity. Recently, a replication-competent, E1B-attenuated adenovirus (ONYX-015) was developed that could overcome these limitations, because it was capable of efficiently and selectively destroying tumor cells lacking functional p53. In an attempt to improve both the efficacy and safety of this approach, we constructed a similar adenovirus (FGR) containing a cytosine deaminase (CD)/herpes simplex virus type-1 thymidine kinase (HSV-1 TK) fusion gene, thereby allowing for the utilization of double-suicide gene therapy, which has previously been demonstrated to produce significant antitumor effects and potentiate the therapeutic effects of radiation. The FGR virus exhibited the same tumor cell specificity and replication kinetics as the ONYX-015 virus in vitro. Importantly, both the CD/5-FC and HSV-1 TK/GCV suicide gene systems markedly enhanced the tumor cell-specific cytopathic effect of the virus, and, as expected, sensitized tumor cells to radiation. By contrast, neither the FGR virus nor either suicide gene system showed significant toxicity to normal human cells. Both suicide gene systems could be used to suppress viral replication effectively, thereby providing a means to control viral spread. The results support the thesis that the three-pronged approach of viral therapy, suicide gene therapy, and radiotherapy may represent a powerful and safe means of selectively destroying tumor cells in vivo.

Adenoviridae↗
PubMed1998

The use of stable isotope labeling and liquid chromatography-tandem mass spectrometry techniques to simultaneously determine the oral and ophthalmic bioavailability of timolol in dogs.

Assays have been established for the quantitation of timolol and its 13C3- and 2H9-stable-isotope-labeled analogs in plasma and urine using liquid chromatography with atmospheric-pressure chemical-ionization tandem mass spectrometry. For the analysis of urine, underivatized timolol and its labeled analogs are monitored while timolol in plasma is assayed down to concentrations of 0.2 ng/mL after derivatization with phosgene. The great power of this technique is illustrated by simultaneously assaying three different species of timolol in plasma and urine obtained from dogs receiving simultaneous ophthalmic, oral, and intravenous doses of unlabeled and [2H9]- and [13C3]-labeled timolol. Thus, the ophthalmic and oral bioavailabilities of timolol are measured in a single experiment rather than as a three-phase crossover experiment. This approach yields accurate and precise analytical data, obviates intrasubject variability, and saves both analytical and animal resources.

Administration, Oral↗
PubMed1997

The simultaneous determination of mixtures of drug candidates by liquid chromatography/atmospheric pressure chemical ionization mass spectrometry as an in vivo drug screening procedure.

Liquid chromatography, combined with tandem mass spectrometry (LC/MS/MS) has been rapidly embraced by the pharmaceutical industry as the definitive method for the determination of drug levels in biological fluids obtained from pharmacokinetic and toxicological studies. This technique has proved to be reliable, accurate and precise for the determination of drugs and related substances (e.g. metabolites and isotope-labeled compounds) in support of preclinical and clinical studies. Our group has recently expanded the use of quantitative LC/MS/MS into the area of discovering new substances as potential drug candidates. When used as an accurate mass detector, triple quadrupole instruments have the ability to simultaneously and specifically detect minute quantities of closely-related drug substances in the extracts of biological fluids. Analytical procedures have been developed and validated that simultaneously determine plasma concentrations of up to 12 drug candidates over a concentration range of 1-1000 ng mL-1 in single analytical occasions. This approach is used to support drug discovery by rapidly providing pharmacokinetic data to a wide range of compounds following either the administration of multiple compounds to single animals, or by increasing the speed and efficiency of analyzing samples following the administration of single compounds to multiple animals. Currently, we have screened over 400 compounds in two different target classes in a period of 24 weeks. A standard operating procedure defining the acceptability of quality control data obtained during such screening experiments is described.

Animals↗
PubMed1997

Use of LC-MS/MS to cross-validate a radioimmunoassay for the fibrinogen receptor antagonist, Aggrastat (tirofiban hydrochloride) in human plasma.

A method based on LC-MS/MS was developed for the determination of the fibrinogen-receptor antagonist Aggrastat in human plasma. The drug is isolated from plasma by liquid extraction and converted into its N-trifluoroacetyl derivative prior to analysis by HPLC with atmospheric pressure negative chemical ionization MS/MS detection. A structural analog is used as the internal standard and the lower quantifiable limit of the assay is 0.4 ng ml-1 with a relative standard deviation of 7%. This assay was used to cross-validate the existing immunoassay by analysis of plasma from patients receiving the drug. The specificity of the immunoassay was thereby confirmed.

Calibration↗
PubMed1997

A direct technique for the simultaneous determination of 10 drug candidates in plasma by liquid chromatography-atmospheric pressure chemical ionization mass spectrometry interfaced to a Prospekt solid-phase extraction system.

New drug candidates are being synthesized at an ever increasing rate and, until recently, the pharmacokinetics of only a few of these could be evaluated. Our laboratory is taking a novel approach to rapid multiple pharmacokinetic screening of potential drug candidates in which mixtures of new substances are co-administered to animals and analyzed simultaneously in plasma using liquid chromatography with tandem MS/MS detection in conjunction with a Prospekt automated on-line solid-phase extraction system. Plasma is sampled via an autosampler and extracted by the Prospekt with the eluent being introduced directly via a reverse phase HPLC column and a heated nebulizer interface to the mass spectrometer. Generic extraction and chromatographic conditions generally give good recoveries. The chromatographic run-times are less than 8 min. The accuracy and precision of these assays are carefully controlled with recoveries generally in the range 80-120% and coefficients of variation less than 20%. Lower quantifiable limits range from 2.5 to 5 ng ml-1. This approach considerably reduces the number of animals needed to screen drug candidates and its power is illustrated by determination of the pharmacokinetics of 10 substances after their simultaneous administration to dogs.

Animals↗
PubMed1997

D-glucose stimulates mesangial cell GLUT1 expression and basal and IGF-I-sensitive glucose uptake in rat mesangial cells: implications for diabetic nephropathy.

The complications of diabetes arise in part from abnormally high cellular glucose uptake and metabolism. To determine whether altered glucose transporter expression may be involved in the pathogenesis of diabetic nephropathy, we investigated the effects of elevated extracellular glucose concentrations on facilitative glucose transporter (GLUT) expression in rat mesangial cells. GLUT1 was the only transporter isoform detected. Cells exposed to 20 mmol/l glucose medium for 3 days demonstrated increases in GLUT1 mRNA (134%, P < 0.002), GLUT1 protein (68%, P < 0.02), and V(max) (50%, P < 0.05) for uptake of the glucose analog [3H]2-deoxyglucose (3H2-DOG), when compared to cells chronically adapted to physiologic glucose concentrations (8 mmol/l). The increase in GLUT1 protein was sustained at 3 months, the latest time point tested (77% above control, P < 0.01). In contrast, hypertonic mannitol had no effect on GLUT1 protein levels. Insulin-like growth factor I (IGF-I; 30 ng/ml) increased the uptake of 3H2-DOG by 28% in 8 mmol/l glucose-treated cells (P < 0.05) and by 75% in cells switched to 20 mmol/l glucose for 3 days (P < 0.005). These increases in 3H2-DOG uptake occurred despite a lack of effect of IGF-I on GLUT1 protein levels (P > 0.5 vs. control). Therefore, hyperglycemia and IGF-I treatment both lead to increases in mesangial cell glucose uptake, and hyperglycemia induces increased GLUT1 expression, which can directly lead to the pathological changes of diabetic nephropathy. The effects of high glucose and of IGF-I to stimulate 3H2-DOG uptake also appear to be additive.

Animals↗