Biomedical subjects

M Goddard

Publications and source records attributed to M Goddard.

At least 19 recordsLinked to original sources

PubMed2000

Neuroprotective gene therapy for Huntington's disease using a polymer encapsulated BHK cell line engineered to secrete human CNTF.

Huntington's disease (HD) is an autosomal dominant genetic disease with devastating clinical effects on cognitive, psychological, and motor functions. These clinical symptoms primarily relate to the progressive loss of medium-spiny GABA-ergic neurons of the striatum. There is no known treatment to date. Several neurotrophic factors have, however, demonstrated the capacity to protect striatal neurons in various experimental models of HD. This includes the ciliary neurotrophic factor (CNTF), the substance examined in this protocol. An ex vivo gene therapy approach based on encapsulated genetically modified BHK cells will be used for the continuous and long-term intracerebral delivery of CNTF. A device, containing up to 106 human CNTF-producing BHK cells surrounded by a semipermeable membrane, will be implanted into the right lateral ventricle of 6 patients. Capsules releasing 0.15-0.5 microg CNTF/day will be used. In this phase I study, the principal goal will be the evaluation of the safety and tolerability of the procedure. As a secondary goal, HD symptoms will be analyzed using a large battery of neuropsychological, motor, neurological, and neurophysiological tests and the striatal pathology monitored using MRI and PET-scan imaging. It is expected that the gene therapy approach described in this protocol will mitigate the side effects associated with the peripheral administration of recombinant hCNTF and allow a well-tolerated, continuous intracerebroventricular delivery of the neuroprotective factor.

Animals↗

PubMed2000

Long-term survival of nonhuman primates receiving life-supporting transgenic porcine kidney xenografts.

BACKGROUND: Recently, there has been a resumed interest in clinical xenotransplantation using pig organs. However, no data are available yet regarding the capacity of porcine organs to sustain the life of a primate beyond the first month. We have attempted to obtain long-term survival of nonhuman primates using human decay-accelerating factor (hDAF) transgenic pig organs and an immunosuppressive strategy particularly aimed at neutralizing the humoral component of the immune response. METHODS: hDAF transgenic or control kidneys were transplanted into 14 bilaterally nephrectomized cynomolgus monkeys (Macaca fascicularis) that underwent splenectomy and were immunosuppressed with cyclosporine A, cyclophosphamide, and steroids. All animals also received recombinant erythropoietin. Postoperatively, the primates were monitored daily. Laboratory evaluations included serum biochemistry, hematology, and measurements of hemolytic antipig antibodies. To assess the role of splenectomy in the control of humoral response, historical data were also used from a group of monkeys (n=7) that received the same immunosuppressive regimen and an hDAF transgenic porcine kidney but did not have splenectomy or receive recombinant erythropoietin. RESULTS: This immunosuppressive approach obtained the longest survival time (78 days) described to date of a primate receiving a life-supporting porcine renal xenograft. Furthermore, four of nine animals in this series survived for 50 days or more. Most biochemical measurements in this study (including plasma urea, creatinine, sodium, and potassium concentrations) remained within normal ranges for several weeks in all of the longest-surviving animals. CONCLUSIONS: Normalization of renal function (urea and creatinine) in primate recipients of porcine renal xenografts suggests that pig kidneys may be suitable for future clinical xenotransplantation. Additional immunosuppressive approaches, specifically designed to prevent humorally mediated immunological damage, should be explored to further prolong survival of primates that have received porcine xenografts.

Animals↗

PubMed2000

Enhancing performance in health care: a theoretical perspective on agency and the role of information.

This paper examines the role of information in securing control of health care systems. The discussion focuses on the impact of the proposed 'Performance Framework', which entails a significant increase in the importance attached to formal performance indicators in the management of the UK National Health Service. The paper starts with a discussion of the role of performance data in securing organizational control within health care systems and summarizes recent research into the behavioural consequences of seeking to control health care agents using such information. A theoretical principal/agent model is then used to illustrate the incentives that exist for dysfunctional behaviour within health care when only imperfect information systems are available. The theoretical results are then examined in the context of a qualitative empirical study, which elicited the perceptions of managers and health care professionals connected with eight NHS hospitals. The study confirmed the existence and importance of serious dysfunctional consequences arising from the use of information as a means of control, and concludes that the Performance Framework will be successful only if it is used in careful conjunction with other means of control.

Delivery of Health Care↗

PubMed2000

Clinical versus actual outcome in cardiac surgery: a post-mortem study.

BACKGROUND: Clinical attribution of the cause of death can be misleading, with the only true outcome measure being post-mortem analysis. Despite this there is very little published data on post-mortems following cardiac surgery. METHODS: Prospective consecutive post-mortem data were collected on 167 patients (84.4% of all in-hospital cardiac surgical deaths) in a single institution. Clinical diagnoses were compared with post-mortem findings. RESULTS: The mean age at death was 69.8 with 67.6% male. The proportion undergoing coronary artery bypass graft (CABG) alone was 52.1%, valve surgery 18.6%, valve+CABG 19.2% and other procedures 10.1%. The mean time to death was 7.9 days (range 0-87). The causes of death were cardiac 67.7%, gastrointestinal 9.6%, respiratory 8.4%, haemorrhage/technical failure 4.8%, stroke (cerebrovascular accident) 3.6%, multiorgan failure 3.0%, sepsis 1.8%, malignancy 0. 6% and trauma 0.6%. Post-mortem revealed an unsuspected cause of death in 19 (11.4%). These were gastrointestinal (infarction nine, perforation two), cardiac three, adult respiratory distress syndrome two, technical two and pulmonary embolus one. In addition, an unsuspected lung cancer was found in 1 patient who died of cardiac causes. When cardiac deaths were compared with non-cardiac causes the Parsonnet score was higher 20.0 (+/-1.4) vs. 15.3 (+/-1.6), P=0. 07; and a greater proportion tended to have poor ejection fractions (34 vs. 15%), P=0.12. There was no significant difference between the groups in terms of age, sex, operation, hypertension, diabetes, creatinine and body mass. CONCLUSIONS: Post-mortem can determine unsuspected diagnoses in a significant proportion of cases. Pre-operative risk factors do not correlate with eventual cause of death. Post-mortem still has an important role to play in cardiac surgery.

Aged↗

PubMed2000

Life supporting function for over one month of a transgenic porcine heart in a baboon.

BACKGROUND: Inhibition of hyperacute rejection (HAR) and sustained graft survival have been demonstrated in a pig-to-primate model of heterotopic cardiac xenotransplantation using pigs transgenic for human Decay Accelerating Factor (hDAF). Building on this work, an orthotopic model has been developed. This case records 39-day cardiac xenograft function in a life-supporting capacity with clinically applicable immunosuppression. METHODS: Using a heart from an hDAF transgenic pig, an orthotopic cardiac transplant was performed on an adult baboon. The immunosuppressive regimen consisted of induction with a short course of cyclophosphamide, followed by maintenance therapy with cyclosporine A, mycophenolate mofetil and a tapering course of corticosteroids. Post-operative monitoring included daily anti-pig hemolytic antibody titer surveillance and endomyocardial biopsy. RESULTS: The animal survived 39 days and was active and energetic throughout its postoperative course, remaining free of signs of cardiopulmonary failure. Endomyocardial biopsy performed on post-operative Day 36 revealed only patches of sub-endocardial fibrosis with no signs of active rejection. The baboon succumbed to an acute cardiopulmonary decompensation immediately following administration of medication via oral gavage. Post-mortem histopathology demonstrated well-preserved myocardial architecture with small foci of mild humoral rejection. CONCLUSIONS: This case documents the longest survival recorded to date of a discordant orthotopic cardiac xenograft and illustrates that the hDAF transgene combined with a clinically acceptable maintenance immunosuppressive regimen enables sustained, life-supporting function of porcine cardiac xenografts in non-human primates. The inhibition of hyperacute rejection and the subsequent control of humoral and cellular rejection for over 1 month demonstrated in this experiment represent significant progress in the development of a viable strategy for clinical xenotransplantation.

Animals↗

PubMed1999

Long-term contracts in the NHS: a solution in search of a problem?

Purchasers and providers in the National Health Service (NHS) are now required to move from annual contracting cycles to longer-term contracts. The benefits are expected to include more efficient investment and improved sharing of financial risk. This paper argues that the economic analysis of longer-term contracts has assumed implicitly that agents operate in the private sector. Once the constraints of the public sector are introduced, the apparent economic benefits of longer-term contracts become doubtful. The paper explores these issues using evidence collected from analysis of the contracts of a sample of Health Authorities and from semi-structured interviews with individuals involved in the contracting process. We conclude that with the property rights and financial structure of the public sector, the move from short- to long-term contracts is unlikely to produce the improvements in performance expected by the government.

Contract Services↗

PubMed1999

Evolution of acute cytomegalovirus gastritis to chronic gastrointestinal dysmotility in a nonimmunocompromised adult.

A 30-year-old nonimmunocompromised woman developed chronic gastrointestinal dysmotility as a consequence of acute cytomegalovirus infection. The acute nature of the infection was documented by high immunoglobulin M antibody titer to cytomegalovirus (CMV); the chronicity of the infection was shown by persistence of CMV in biopsy specimens of her gastrointestinal tract over a 21/2-year period. Gastrointestinal dysmotility was confirmed by delayed emptying on gastric nuclear scintigraphy, by retrograde propagation of migrating myoelectric complexes on small intestinal manometry, and by presence of tachygastria on cutaneous electrogastrography. The patient's nausea, vomiting, abdominal pain, and early satiety resolved after a short course of treatment with leuprolide acetate but returned after medication was discontinued. Her symptoms persisted despite clearance of CMV from the gastrointestinal tract after a course of treatment with ganciclovir. These observations show that acute CMV infection can cause gastrointestinal dysmotility in nonimmunocompromised individuals and that the disturbance in gastrointestinal motor function may persist for years after viral infection of the gastrointestinal tract has been eradicated.

Acute Disease↗

PubMed1999

Assessing the performance of NHS hospital trusts: the role of 'hard' and 'soft' information.

Formal performance measurement systems have become a prominent feature throughout most of the public sector. The NHS is no exception and the government is developing and expanding on existing performance data to produce a new national framework which is to be at the heart of the 'performance-led' NHS. The success of formal performance measurement systems depends in part on the degree to which they can capture adequately relevant information within a quantitative framework. In this paper, we explore the use of formal, quantitative 'hard' information and informal, subjective 'soft' information in the assessment of the performance of NHS hospital Trusts by external organisations. Our empirical work is summarised into 3 main themes: (i) the use of 'soft' information as a complement to 'hard' information; (ii) the use of 'soft' information as a substitute for 'hard' information; and (iii) the use of 'hard' information as a safety net in the assessment of performance. We argue that 'soft' information plays a valuable role in the assessment of performance of NHS Trusts and note that this is also reflected in current practice in the private sector. We argue that one of the main functions of 'hard' information in performance assessment is to act as a safety net in order to identify laggards by highlighting poor performance. Rarely is it used as a means to encourage good performance or to identify best practice. Whilst the safety net function may indeed be useful, if the new national performance framework is to achieve its aim of promoting good performance, the limitations of formal systems will have to be taken into account. We argue that the advantages of 'soft' information in the NHS should be acknowledged, rather than trying to force it into a formal framework where the benefits may be nullified. However, we also warn against excessive reliance on 'soft' information and suggest that a balanced system which allows both 'hard' and 'soft' information to flourish is the optimal solution to performance assessment in the NHS.

Efficiency, Organizational↗

PubMed1999

Mesothelioma--VATS biopsy and lung mobilization improves diagnosis and palliation.

OBJECTIVES: Mesothelioma is an increasingly frequent malignancy in which diagnosis is often delayed and disease diagnosed at an advanced stage. Earlier diagnosis and therapeutic intervention that can control recurrent pleural effusion may improve outlook and survival. METHODS: A prospective series of 25 patients in whom mesothelioma was suspected was referred for histological diagnosis by video assisted-thoracoscopy (VAT) after failure of other methods. At the same operative procedure drainage of pleural effusion, cytoreductive pleurectomy and lung mobilization was performed where possible. Complete follow-up was obtained. RESULTS: All patients had a histological diagnosis (100%) from the material sent for biopsy. In 23 patients this was mesothelioma, in two patients chronic empyema. All patients undergoing drainage of effusion, cytoreductive pleurectomy and lung mobilization subsequently were diagnosed of having mesothelioma stages III to IV. Fifteen out of 21 who underwent lung mobilization had closure of the pleural space. Post operative air leak in this group was a mean of 5 days (2-12 days). Recurrent effusion occurred in only one patient. Eleven patients remain alive at 1-2 years post operation with no hospital admissions for recurrent pleural effusion. In the six out of 21 who did not have closure of the pleural space, one remained alive 9 months post surgery. Five died within 1-6 months of the procedure. The average number of further hospital admissions for repeat drainage of effusion was 3 (1-6). CONCLUSIONS: VATs provides adequate tissue for histological diagnosis where other methods fail. At the same operative sitting it provides a therapeutic intervention that allows drainage of effusion cytoreductive pleurectomy and lung mobilization in a significant number of cases. Where the pleural space can be closed this results in significantly fewer hospital admissions and appears to improve quality of life and length of survival. The price is a longer hospital stay due to prolonged air leak.

Adult↗

PubMed1999

Contracting for quality: does length matter?

OBJECTIVES: To examine whether longer-term contracts for health services will shift attention away from concern for finance and activity levels and towards the achievement of better quality services. METHODS: Analysis of 288 contracts from the British National Health Service (NHS) and 12 semi-structured interviews with staff from provider (NHS hospital trusts) and purchaser (health authorities) organisations. RESULTS: No relationship was found between the duration of a contract and the duration of service specifications or quality frameworks. The annual contracting cycle is concerned largely with ensuring that all parties stay within activity targets and financial constraints, and this is unlikely to be affected by a shift to longer-term contracts. The setting of standards and initiatives to improve quality is largely independent of the contracting process and the duration of contracts, and relies on relationships rather than contracts. CONCLUSIONS: It is optimistic to expect longer-term contracts automatically to produce a greater focus on quality and the incentives needed to ensure that improvements in quality are delivered. However, this may not matter as issues of quality are being addressed more appropriately in the British NHS through a variety of other routes.

Contract Services↗

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

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↗