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Biomedical subjects

J Dunning

Publications and source records attributed to J Dunning.

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

An oral vaccine against NMDAR1 with efficacy in experimental stroke and epilepsy.

The brain is generally considered immunoprivileged, although increasing examples of immunological responses to brain antigens, neuronal expression of major histocompatibility class I genes, and neurological autoimmunity have been recognized. An adeno-associated virus (AAV) vaccine generated autoantibodies that targeted a specific brain protein, the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor. After peroral administration of the AAV vaccine, transgene expression persisted for at least 5 months and was associated with a robust humoral response in the absence of a significant cell-mediated response. This single-dose vaccine was associated with strong anti-epileptic and neuroprotective activity in rats for both a kainate-induced seizure model and also a middle cerebral artery occlusion stroke model at 1 to 5 months following vaccination. Thus, a vaccination strategy targeting brain proteins is feasible and may have therapeutic potential for neurological disorders.

Administration, Oral↗
PubMed2000

Pharmacokinetics and pulmonary extraction of clevidipine, a new vasodilating ultrashort-acting dihydropyridine, during cardiopulmonary bypass.

Clevidipine is a new vascular-selective, calcium channel antagonist of the dihydropyridine type with an ester side chain susceptible to esterase metabolism. In healthy volunteers, it has high clearance (0.069 litres min-1 kg-1) with a small volume of distribution at steady state (0.19 litres kg-1). The half-lives of the two initial rapid phases, accounting for approximately 95% of the area under the curve after an i.v. bolus, are 0.7 and 2.3 min, respectively. The aims of this study were to determine the pharmacokinetics and the pulmonary extraction ratio of clevidipine in patients undergoing cardiac surgery. Seventeen patients received clevidipine as an i.v. infusion before cardiopulmonary bypass (CPB), and eight of these patients were also given clevidipine during hypothermic CPB. Mixed venous and arterial blood samples were taken for pharmacokinetic analysis and calculation of pulmonary extraction ratio. A two-compartment pharmacokinetic model with zero-order input was used to describe the pharmacokinetics of clevidipine before and during CPB. Virtually identical concentrations in mixed venous and arterial blood suggest negligible pulmonary metabolism of clevidipine. The total blood clearance of clevidipine is extremely high (0.055 litres min-1 kg-1). During CPB, clearance of clevidipine was significantly reduced, to 0.03 litres min-1 kg-1 (P < 0.005), probably as a consequence of reduced body temperature.

Adult↗
PubMed1998

Calorie restriction, stress and the ubiquitin-dependent pathway in mouse livers.

Calorie restriction (R) is the only known method to delay the aging process and extend mean and maximal lifespan in rodents. R has been shown to delay the age-related accumulation of damaged proteins and to protect organisms from various stresses which can produce damaged proteins. Such stresses include irradiation, heat shock, and oxidative stress. The ubiquitin- and ATP-dependent proteolytic pathway (UPP) has been associated with the degradation of abnormal and/or damaged proteins. We examined the effect of diet and oxidative stress on activities of the UPP in supernatants from livers taken from 23-month-old Emory mice which had been exposed to an in-vivo injection of paraquat. Paraquat induces oxidative stress by generating superoxide radicals. In livers from non-stressed animals, steady-state levels of endogenous ubiquitin conjugates, de novo conjugate formation, and E1 and E2 activities were significantly lower in R animals than in control (C) animals. However, after exposure to paraquat, levels of endogenous ubiquitin conjugates were significantly higher in R versus C animals, and de novo conjugate formation and E1 and E2 activities in R animals rose to levels which were indistinguishable from levels of these activities noted in C animals. R was associated with an increased ability to degrade beta-lactoglobulin by the UPP after an oxidative stress was imposed. Ability to degrade beta-lactoglobulin by the C or R livers in non-stressed animals was not significantly different. Taken together, these data indicate that oxidative stress in R animals is associated with enhanced levels of ubiquitin conjugates and that this enhancement may be due to an increase in UPP activity. These data also indicate that the ability to form ubiquitin conjugates and the UPP system does not change with oxidative stress in C animals. The latter is consistent with prior reports that suggests that older C animals may already be in a state of enhanced oxidative stress and that activities of the UPP provide a sensitive indicator of levels of cellular redox status.

Adenosine Triphosphate↗
PubMed1998

Aging, calorie restriction and ubiquitin-dependent proteolysis in the livers of Emory mice.

Calorie restriction (R), the only known method to delay the aging process and extend mean and maximal lifespan, has been shown to delay the age-related decline in protein degradation. There are several proteolytic pathways. The ubiquitin- and ATP-dependent proteolytic pathway (UPP) is frequently associated with degradation of damaged abnormal and/or regulatory proteins. We examined the effect of aging and R on supernatants of livers taken from young (4.5 months) and old (23 months) Emory mice. Aging was associated with increased levels of endogenous ubiquitin conjugates, enhanced ability to form high molecular weight conjugates and ubiquitin activating (E1) and ubiquitin conjugating (E2) activity in the control (C) liver supernatants. The age-related increase in levels of endogenous ubiquitin conjugates in liver appears to be primarily due to increased E1 and E2 activities. R prevented the age-related increase in E1 and E2 activity, and thus prevented the age-related increase in levels of ubiquitin conjugates. In spite of the age-related increase in ubiquitin conjugates, no age-related changes in ubiquitin-dependent proteolytic pathway were observed in the C animals. R was associated with an enhanced ability (130%) to degrade beta-lactoglobulin by the ubiquitin-dependent proteolytic pathway in livers from 4.5-month-old animals relative to age-matched C livers. However, rates of the ubiquitin-dependent degradation of beta-lactoglobulin in the 23-month-old C and R animals were indistinguishable. There were no age- or diet-related differences in the ability to degrade another substrate, oxidized ribonuclease (RNase).

Adenosine Triphosphate↗
PubMed1998

Life-supporting pig-to-baboon heart xenotransplantation.

BACKGROUND: The aim of this study was to investigate the effect of the expression of human decay-accelerating factor in transgenic pigs on hyperacute rejection in a pig-to-baboon heterotopic heart transplantation model and to assess the ability of such transgenic pig hearts in supporting the life of a primate when transplanted orthotopically. METHODS: Hearts from pigs transgenic for human decay-accelerating factor were transplanted heterotopically (n = 3) and orthotopically (n = 5) into the baboon. All animals received cyclosporine, steroids, and cyclophosphamide. Blood was sampled regularly for total antipig antibody titers, trough cyclosporine levels, full blood count, electrolytes, and creatinine. Rejection of the heterotopic hearts was defined as the absence of palpable cardiac pulsation. Explanted hearts were examined histologically with hematoxylin and eosin and with immunochemistry for complement components C3, C4, C9, and immunoglobulin M. RESULTS: None of the hearts were hyperacutely rejected. In the heterotopic group one heart underwent acute vascular rejection on day 13, and the remaining two recipients with beating xenografts were killed on days 2 and 21. In the orthotopic group, one recipient with a life-supporting xenograft was killed on day 9 because of poor general condition. Histologic examination demonstrated no evidence of rejection. Two xenografts stopped beating on day 5, and histologic study showed acute vascular rejection in both. There were also two graft failures for technical reasons in this group. CONCLUSIONS: Hyperacute rejection is abrogated in pig-to-baboon heart xenotransplantation with the expression of the human decay-accelerating factor transgene. The human decay-accelerating factor transgenic pig heart is able to support primate life for a prolonged period.

Animals↗
PubMed1997

Artificial heart transplants.

The use of a mechanical device to support a failing heart is one of the greatest challenges in cardiothoracic practice. Many different approaches are being considered, but they share the use of many advanced engineering principles. Power supplies and the interface between artificial surfaces and the blood remain areas of difficulty. The accent is moving from console driven devices with drive lines which must cross the body wall to reach the pump, towards smaller control packs, with inductive coupling to fully contained pumps. More attention is focused on the use of axial pumps lying within the lumena of the great vessels and the ventricles. Despite the wideheld belief that mechanical pumps must confer survival advantage to the recipients, there has been no prospective study demonstrating any advantage over medical management of the failing heart. Economic considerations must be taken into account if the technology is to be available to everyone with heart failure.

Equipment Design↗
PubMed1997

The retrieval of thoracic organs: donor assessment and management.

The optimal management of the multi-organ donor is critical to the successful outcome of transplantation. It is a complex challenge demanding careful attention to detail, and requiring a shift in emphasis, since the pathophysiological processes have far reaching effects which many clinicians do not see on a day-to-day basis. The optimal management of haemodynamic and respiratory status is essential in order to maximise the yield of suitable thoracic donor organs, yet this process will also improve the condition of other organs at the time of procurement and thus enable prompt recovery of function following hepatic and renal transplantation. The process commences when a potential donor is identified, and is only complete after successful transplantation of all possible organs. In order to achieve this end, a dedicated, multi-disciplinary team is necessary, consisting not only of medical staff, but also support workers who organise logistics, and who play their own part in vital areas, such as transport of the donor team and organs. The co-ordinator's role is pivotal in bringing together, in harmony, teams from different centres. It is important to remember that the effort of every person involved in the management and procurement of donor organs is primarily directed towards maximisation of the donor pool, and that our main responsibility is to the recipients on our waiting lists.

Brain Death↗
PubMed1996

Carpal tunnel syndrome: evaluation of a new method of assessing median nerve conduction at the wrist.

OBJECTIVE: To compare median nerve conduction velocity measured using a new, portable electroneurometer with measurements made using conventional hospital nerve conduction apparatus. METHODS: Twenty five patients were studied who were consecutively referred to a hospital neurophysiology department with a clinical diagnosis of carpal tunnel syndrome. Sensory and motor latencies for the median nerve at the wrist were measured bilaterally using the portable electroneurometer and a Medilec MS 92 hospital apparatus operated by a trained technician. RESULTS: There was strong agreement between motor latency values obtained by the two techniques (r = 0.89, p < 0.001; mean difference -0.03 ms, limits of agreement -0.33 to 0.27 ms). Sensory latencies were less easy to detect with the electroneurometer, and correlated less well with the hospital apparatus (r = 0.78, p < 0.001; mean difference -0.16 ms, limits of agreement -0.50 to 0.18 ms). CONCLUSION: The portable electroneurometer provides a convenient, rapid, and inexpensive means of assessing median nerve conduction velocity at the wrist. Measurements of motor latency obtained with this new instrument agree more strongly with those made by conventional apparatus than do measurements of sensory latency. Although the utility of the instrument in clinical practice will be limited, it provides a helpful tool in epidemiological studies of carpal tunnel syndrome.

Adult↗
PubMed1996

Heart-lung-liver transplantation.

We report three patients with cystic fibrosis and one patient with primary biliary cirrhosis and plexogenic pulmonary hypertension who have undergone heart-lung-liver transplantation as a combined procedure. Liver transplantation was necessary in the three patients with cystic fibrosis because of portal hypertension secondary to either hepatic fibrosis or established cirrhosis in addition to their advanced lung disease. Three of the four patients were alive at 20, 50, and 100 months after transplantation (one patient with cystic fibrosis died on day 16 of pneumonia) with well-preserved pulmonary function (forced expiratory volume in 1 second 110%, 49%, and 100% predicted, respectively), normal hepatic function and New York Heart Association class 1 performance status. Heart-lung and concurrent liver transplantation is a feasible and successful procedure with a satisfactory long-term outcome in selected patients with advanced pulmonary and hepatic disease.

Adult↗
PubMed1994

Aprotinin and bleeding in profoundly hypothermic perfusion.

Clinical observation led us to believe that aprotinin fails to preserve haemostatic function in patients undergoing deep hypothermic perfusion with or without circulatory arrest. A retrospective study was made of blood loss in 80 consecutive acute Type A dissection patients before and during the aprotinin era (1987-1992). After 1988 all patients were cooled below 20 degrees C pending circulatory arrest. Fourteen patients underwent aortic root replacement and 66 replacements of the ascending aorta. Age distribution (range 22-79 years) and type of operation were similar in the aprotinin and control groups. The impervious Hemashield (Meadox) graft was used for all but five patients. These underwent aortic root replacement with preclotted, valved conduits. Overall the mean blood loss for 27 patients operated without aprotinin was 837 ml per 24 h (standard error +/- 90) and for 53 patients with aprotinin 1,929 ml per 24 h (standard error +/- 90). There was a significant difference between the two groups when profoundly hypothermic perfusion was used, with greater bleeding in aprotinin-treated patients. There were six re-entries in the aprotinin group and none in the control patients. There were ten hospital deaths (11.1%). A greater incidence of bleeding and thrombosis-related deaths was recorded for the aprotinin-treated patients. In addition, four surviving aprotinin patients suffered severe coagulation defect with blood loss greater than 4,500 ml and platelets less than 50 x 10(6). We suggest that aprotinin inhibits the protease enzymes which maintain the fluid state of blood during hypothermic low flow and arrest states. Disseminated intravascular coagulation may consume platelets thereby predisposing to abnormal bleeding and potentially fatal thrombotic events. The use of aprotinin in profoundly hypothermic perfusion should be adopted cautiously.

Adult↗