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Biomedical subjects

M Goddard

Publications and source records attributed to M Goddard.

At least 37 records · Page 2Linked to original sources
PubMed1998

Orthotopic heart transplantation in a transgenic pig-to-primate model.

BACKGROUND: Previous studies demonstrated that hearts from transgenic pigs expressing human decay-accelerating factor (hDAF) were not hyperacutely rejected when transplanted heterotopically into the abdomen of cynomolgus monkeys. This study examines orthotopic transplantation of hDAF transgenic pig hearts into baboon recipients. METHODS: Orthotopic xenogeneic heart transplantation was performed using piglets, transgenic for hDAF, as donors. Ten baboons were used as recipients and were immunosuppressed with a combination of cyclophosphamide, cyclosporine, and steroids. RESULTS: Five grafts failed within 18 hr without any histological signs of hyperacute rejection. Pulmonary artery thrombosis induced by a size mismatch was observed in two of these animals. The other three recipients died because of failure to produce even a low cardiac output and/or dysrhythmia. The remaining five animals survived between four and nine days. One animal died of bronchopneumonia on day 4. Three xenografts stopped beating on day 5 due to acute vascular rejection. The longest survivor was killed on day 9 with a beating, histologically normal xenograft, because of pancytopenia. CONCLUSIONS: The results reported here demonstrate that hDAF transgenic pig hearts are not hyperacutely rejected when transplanted into baboon recipients. Orthotopically transplanted transgenic pig hearts are capable of maintaining cardiac output in baboons. An optimum immunosuppressive regimen is the subject of ongoing research.

Animals↗
PubMed1998

Performance indicators. All quiet on the front line.

Managers interviewed in hospital trusts, health authorities and regional offices believed performance indicators to be broadly helpful. But our study found evidence that the role of the current performance indicators is distinctly limited. The indicators are primarily used to highlight instances of exceptionally poor performance. Frontline staff, such as junior doctors, are often largely unaware of performance indicators. Performance indicators have led to misrepresentation and manipulation of data.

Attitude of Health Personnel↗
PubMed1998

From competition to co-operation: new economic relationships in the National Health Service.

The Labour government has outlined its plans to 'replace' the competitive internal market with a more collaborative system based on partnership. Agreement amongst purchasers and providers is to be based on co-operation rather than competition. Longer term agreements covering periods of 3-5 years are to replace annual contracts within this new environment. The aim of this paper is to explore the potential economic implications of these policy changes by drawing on the economics of co-operation and the transaction costs approach to longer term contracting. Issues surrounding the role of trust in contractual relationships are explored and the relevance of experience and evidence from non-health care sectors is considered in the context of the NHS. It is concluded that both theory and empirical evidence suggest that co-operation and trust can play a central role in the efficient organisation of contractual arrangements in circumstances similar to those under which the NHS operates. However, we warn against the expectation that the policy changes will produce automatically the scale of benefits predicted by the Labour government, especially as they will have to find a way of extracting reasonable performance from providers under a system of collaboration and long term agreements. They may find they need to tread a fine line between competition and co-operation in order to reap the benefits of both.

Contract Services↗
PubMed1998

High-resolution computed tomographic appearance of MALToma of the lung.

MALToma of the lung is rare and advances in molecular techniques have only recently allowed accurate diagnostic classification of the previously termed "pseudolymphomas" by demonstrating that many are monoclonal B-cell proliferations of MALT tissue and therefore true low-grade lymphomas. No significant previous contribution was found in the literature regarding the high-resolution CT appearance (HRCT) of these tumours. We describe the high-resolution CT appearances in five cases presenting to our institution from 1994 to 1997. The HRCT scans (1-mm sections at 10- to 15-mm intervals) were performed as the opacities seen radiographically were thought to be part of a diffuse lung process. In one patient a spiral sequence was performed through the main airway. Multifocal, ill-defined nodules containing air bronchograms were seen in four cases and focal lobar consolidation in one case. Interlobular septal thickening, centrilobular micronodules and bronchial wall thickening were seen in two cases. Mediastinal lymphadenopathy and pleural reaction do not appear to be characteristic features. The appearance of multifocal consolidation is similar to that seen in bronchoalveolar cell carcinoma and cryptogenic organising pneumonia.

Adenocarcinoma, Bronchiolo-Alveolar↗
PubMed1998

Improving surgical resection rate in lung cancer.

BACKGROUND: Surgical resection is the recognised treatment of choice for patients with stage I or II non-small cell lung cancer (NSCLC). In the UK surgical resection rates have remained far lower (< 10%) than those achieved in Europe and the USA (> 20%), despite the recent introduction of fast access investigation units. It remains unclear therefore why UK surgical resection rates lag so far behind those of other countries. METHODS: A new quick access two stop investigation service was established at Papworth in November 1995 to investigate all patients presenting to any of three surrounding health districts with suspected lung cancer. Once staging was complete, all patients with confirmed lung cancer were reviewed by a multidisciplinary team which included an oncologist and a thoracic surgeon. Time from presentation to definitive treatment and surgical resection rates were reviewed. RESULTS: Two hundred and nine (76%) of a total of 275 consecutive patients investigated had confirmed lung cancer (28 small cell, 181 non-small cell). Of the remainder, eight patients (2%) had metastatic disease, four (1%) had other thoracic malignancy (thymoma, mesothelioma), four patients (1%) had benign thoracic tumours, and 50 (18%) had other non-malignant diseases. Of the 181 patients with non-small cell primary lung cancer, 47 (25%) underwent successful surgical resection, of whom 59% had stage I and 21% stage II disease. The failed thoracotomy rate was 11%. Median time from presentation at the peripheral clinic to surgical resection was 5 weeks (range 1-13). CONCLUSION: Quick access investigation, high histological confirmation rates, routine CT scanning, and review of every patient with confirmed lung cancer by a thoracic surgeon led to a substantial increase in the successful surgical resection rate. These results support the growing concern that many patients with operable tumours are being denied the chance of curative surgery in our present system.

Aged↗
PubMed1997

Barrier durability of latex and vinyl medical gloves in clinical settings.

This study evaluated changes in the tensile strength and barrier integrity of medical gloves during hospital clinical use. Nonsterile vinyl, sterile vinyl, and nonsterile natural rubber latex gloves were collected after use in a clinical setting and then tested for tensile strength, elongation, and water leakage. Tensile properties of vinyl gloves did not change during use, whereas changes in latex depended on the brand evaluated. New gloves, regardless of material of manufacture, were found to have leakage rates of 2% or less. Two brands of nonsterile vinyl gloves were found to have an average rate of leakage after use of 24 to 28% (average 26%), three brands of latex gloves of 6 to 10% (average 8%), and one brand of sterile vinyl gloves of 3%. Low-protein powderless latex gloves leaked slightly less than the powdered brands. The high rates of leakage observed for nonsterile vinyl gloves indicate that they provide less barrier protection than latex in typical hospital use. The low leakage rate observed for sterile vinyl gloves indicates that barrier durability is not solely a function of the generic polymer composition of the barrier.

Equipment Failure↗
PubMed1997

Hypernatraemia.

Explore the source record for details and available documents.

Aged↗
PubMed1997

The effect of 60-Hz magnetic fields on co-promotion of chemically induced skin tumors on SENCAR mice: a discussion of three studies.

Three independent experiments involving a total of 288 SENCAR mice were used to study the effects of 60-Hz magnetic fields on the growth and development of skin tumors. Given the constraints imposed by the experimental design, the results did not support a role for magnetic fields as a tumor co-promoter. This negative finding could also be interpreted to mean that the SENCAR mouse skin tumor model was not sensitive enough to detect the action of a weak co-promoter. The two-stage (initiation/promotion) model was used to assess the genotoxic potential of magnetic fields because it had been widely used to evaluate chemical carcinogens. This model, however, lacks the sensitivity to detect all but the most potent direct-acting carcinogens, and the tumor response to the action of low doses of promoter results in large random fluctuations in tumor incidence, yield, and multiplicity. The need to limit tumor incidence in the sham is a necessary condition to ensure that a magnetic field-induced effect on tumorigenesis would have a reasonable chance of being detected. This requirement, and the variability in tumor development between and within experiments, increases the level of uncertainty in the system and makes a weak response to the magnetic field difficult to detect and interpret.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1996

Gene therapy for amyotrophic lateral sclerosis (ALS) using a polymer encapsulated xenogenic cell line engineered to secrete hCNTF.

The gene therapy approach presented in this protocol employs a polymer encapsulated, xenogenic, transfected cell line to release human ciliary neurotrophic factor (hCNTF) for the treatment of Amyotrophic Lateral Sclerosis (ALS). A tethered device, containing around 10(6) genetically modified cells surrounded by a semipermeable membrane, is implanted intrathecally; it provides for slow continuous release of hCNTF at a rate of 0.25 to 1.0 micrograms/24 hours. The semipermeable membrane prevents immunologic rejection of the cells and interposes a physical, virally impermeable barrier between cells and host. Moreover, the device and the cells it contains may be retrieved in the event of side effects. A vector containing the human CNTF gene was transfected into a line of baby hamster kidney cells (BHK) with calcium phosphate using a dihydrofolate reductase-based selection vector with a SV40 promoter and contains a HSV-tk killer gene. hCNTF is a potent neurotrophic factor which may have utility for the treatment of ALS. Systemic delivery of hCNTF in humans has been frustrated by peripheral side effects, the molecule's short half life, and its inability to cross the blood-brain barrier. The gene therapy approach described in this protocol is expected to mitigate such difficulties by local intrathecal delivery of a known quantity of continuously-synthesized hCNTF from a retrievable implant.

Amyotrophic Lateral Sclerosis↗
PubMed1996

Intrathecal delivery of CNTF using encapsulated genetically modified xenogeneic cells in amyotrophic lateral sclerosis patients.

Neuronal growth factors hold promise for providing therapeutic benefits in various neurological disorders. As a means of ensuring adequate central nervous system delivery of growth factors and minimizing significant adverse side effects associated with systemic delivery methods, we have developed an ex vivo gene therapy approach for protein delivery using encapsulated genetically modified xenogeneic cells. Ciliary neurotrophic factor (CNTF) has been shown in various rodent models to reduce the motor neuron cell death similar to that seen in amyotrophic lateral sclerosis (ALS). The initial trials focusing on the systemic administration of CNTF for ALS have been discontinued as a result of major side effects, thus preventing determination of the potential efficacy of the molecule. In order to deliver CNTF directly to the nervous system, we conducted a phase I study in which six ALS patients were implanted with polymer capsules containing genetically engineered baby hamster kidney cells releasing approximately 0.5 microgram of human CNTF per day in vitro. The CNTF-releasing implants were surgically placed within the lumbar intrathecal space. Nanogram levels of CNTF were measured within the patients' cerebrospinal fluid (CSF) for at least 17 weeks post-transplantation, whereas it was undetectable before implantation. Intrathecal delivery of CNTF was not associated with the limiting side effects observed with systemic delivery. These results demonstrate that neurotrophic factors can be continuously delivered within the CSF of humans by an ex vivo gene therapy approach, opening new avenues for the treatment of neurological diseases.

Amyotrophic Lateral Sclerosis↗
PubMed1996

Immunoisolated xenogenic chromaffin cell therapy for chronic pain. Initial clinical experience.

BACKGROUND: Chromaffin cells from the adrenal gland secrete a mixture of compounds that have a strong analgesic effect, especially when administered intrathecally. Many studies in animal models have shown that discordant xenogeneic cell isolates, including chromaffin cells, can survive and have biologic effects when transplanted within a semipermeable membrane capsule. METHODS: To evaluate the clinical potential of encapsulated cell therapy, a human-scale implant containing bovine chromaffin cells was developed, characterized, and implanted in the subarachnoid space of seven patients with severe chronic pain not satisfactorily managed with conventional therapies. Patients received no pharmacologic immunosuppression. Cell devices were implanted during minimally invasive surgery, and device design allowed retrieval. All devices were recovered after implant periods of 41 to 176 days. RESULTS: Postexplant histologic analysis, immunostaining, and secretory function all confirmed survival and biochemical function of the encapsulated cells. Reductions in morphine intake and improvement in pain ratings were observed in several patients. CONCLUSIONS: This study represents the first successful trial of encapsulated xenogeneic cells in humans. The preliminary findings of pain reduction warrant the initiation of a randomized, double-blind phase II study to evaluate the potential efficacy of the procedure.

Adult↗
PubMed1995

A 60-Hz magnetic field increases the incidence of squamous cell carcinomas in mice previously exposed to chemical carcinogens.

The exposure of tumor-bearing SENCAR mice to a magnetic field of 2 mT at a frequency of 60 Hz for 52 weeks, was found to increase the rate of malignant conversion in chemically-induced dorsal skin papillomas. Detailed histopathology revealed the presence of squamous cell papillomas and squamous cell carcinomas in both sham and magnetic field exposed mice at week 52. However, of the nine mice assessed as having squamous cell carcinomas, eight came from the group exposed to magnetic fields, a difference which is statistically significant at P = 0.03.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1995

Comparison of the up-and-down, conventional LD50, and fixed-dose acute toxicity procedures.

The up-and-down procedure (UDP), fixed-dose procedure (FDP) and conventional LD50 tests were compared to determine their consistency in chemical hazard classification for acute oral toxicity according to the European Economic Community (EEC) system. There was consistent classification for 23 out of 25 cases between the UDP and the conventional LD50 results, in 16 out of 20 cases between the FDP and the conventional LD50, and in seven out of 10 cases between the UDP and the FDP. The UDP needed only between six and 10 animals of one sex (fewer than either the LD50 or the FDP). Available literature indicates that the sexes are usually similar in their acute toxicity responses and that of females are often more sensitive than males when acute toxicity differences do exist, thus obviating the need for both sexes to be tested in most cases. Unlike the FDP, the UDP also estimates an LD50, thus providing data directly applicable to all current hazard classification systems based on acute oral toxicity.

Animals↗
PubMed1994

Functional recovery in hemiparkinsonian primates transplanted with polymer-encapsulated PC12 cells.

Cross-species neural grafting of cell lines immunoisolated by a permselective polymer membrane represents a promising source of neuroactive molecules for the treatment of neurodegenerative diseases. Utilization of a cell line of xenogeneic origin is advantageous since the transplanted cells will be rejected by the host immune system in case of breakage of the immunoisolating envelope. Polymer-encapsulated PC12 cells, a dopaminergic cell line derived from a rat pheochromocytoma, were transplanted in five Macaca fascicularis monkeys which had been previously rendered hemiparkinsonian by a unilateral carotid injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Well-preserved, tyrosine hydroxylase positive encapsulated PC12 cells were observed in the lesioned striatum for up to 5 months after implantation. Four out of five monkeys which received polymer-encapsulated PC12 cells showed significant behavioral improvement, whereas three monkeys implanted with either encapsulated bovine chromaffin cells or empty polymer envelopes showed no amelioration.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1993

A hypertonic infusion in the treatment of experimental shock in calves and clinical shock in dogs and cats.

A novel composite hypertonic solution for intravenous use was tested in two experimental models, one of endotoxic shock and one of shock linked with dehydration, both in anaesthetised calves. Endotoxic shock was induced with Escherichia coli lipopolysaccharide and was characterised by a low cardiac output, hypoxaemia, acidosis and anuria. Treatment with a small volume of the solution increased cardiac output, improved oxygen carriage, corrected acidosis and stimulated renal function. Experimental dehydration in calves was induced by intraperitoneal mannitol and frusemide diuresis, and was characterised by reduced circulating plasma volume, acidosis and poor peripheral perfusion. Treatment with the new solution corrected the acidosis and stimulated peripheral circulation significantly better than treatment with hypertonic or isotonic saline alone, and also expanded the calves' plasma volume. The new solution was also compared with conventional fluid therapy in clinical small animal practice. Twenty cats and dogs with clinical shock were treated with either small volumes of the hypertonic solution or large volumes of isotonic fluids. The animals treated with small volumes of the hypertonic solution responded better than the animals treated with large volumes of isotonic fluid.

Animals↗