PubMed Health⌕ Search

Biomedical subjects

P Macdonald

Publications and source records attributed to P Macdonald.

At least 19 recordsLinked to original sources
PubMed2004

Apoptosis as a mechanism for cell surface expression of the autoantigen pyruvate dehydrogenase complex.

A number of antigens implicated in the pathogenesis of autoimmune diseases including Sjogren's syndrome and systemic lupus erythematosus (SLE) are expressed aberrantly by apoptotic cells. It is also known that apoptogenic proteins are released from the mitochondrial intermembrane space at an early stage during the induction and development of apoptosis. Combination of this evidence led us to test the hypothesis that apoptotic mechanisms provide an explanation for the abnormal expression of the inner mitochondrial enzyme, pyruvate dehydrogenase complex (PDC), observed on the surface of some cells in patients with the autoimmune liver disease primary biliary cirrhosis (PBC). Using one murine and two human cell lines it was found that the induction of apoptosis led to early detection of PDC within the cytoplasm. However, cytochrome c oxidase subunit 4 (COX 4), which is also present on the inner surface of the inner mitochondrial membrane, remained within the mitochondria. Immunoreactive PDC was also detected on the outer surface of the intact plasma membrane of cells sampled after the induction of apoptosis. Serial release of PDC to the cytoplasm and then onto the external surface of the plasma membrane provides direct evidence that the antigen on the cell surface is of mitochondrial origin. Immunoreactivity specific for PDC is strongly implicated in the pathogenesis of PBC, but this autoantigen is normally concealed from the immune system by three membrane systems. Release of PDC onto the cell surface during apoptosis provides a possible route for recognition of this antigen by the immune system which could contribute to both afferent and efferent phases of the disease process.

Animals↗
PubMed2002

Bilateral vocal cord palsy following interscalene brachial plexus nerve block.

Acute respiratory complications of an interscalene brachial plexus block include ipsilateral phrenic nerve and recurrent laryngeal nerve palsies. A 71-year-old woman who had undergone a total thyroidectomy for papillary carcinoma 35 years ago was administered a right interscalene brachial plexus block for a shoulder hemi-arthroplasty. Subsequently she developed acute respiratory distress associated with marked stridor secondary to an acute right vocal cord palsy, which was superimposed on what was assumed to be a preexisting left-sided vocal cord palsy. On extubation the patient was noted to develop stridor again necessitating reintubation and tracheostomy was performed two weeks later. The vocal cord palsies failed to resolve over the subsequent 18-month follow-up. We describe this case to highlight the significant risk of this procedure in patients with preexisting or suspected contralateral vocal cord palsy.

Aged↗
PubMed2001

Diversity in translational regulation.

Translational control of individual mRNAs relies on cis-regulatory elements, which are often found in the 3' untranslated region. The best characterized of these regulate cytoplasmic polyadenylation, and much of this process can now be defined in terms of molecular interactions, protein modifications and their consequences. Biochemical and genetic approaches have advanced the understanding of the many instances of translational regulation that are crucial for body patterning in Drosophila. For example, in vitro translation systems have been used to study the regulatory mechanisms, and genetic interactions have been instrumental in establishing a link between a regulatory factor and a component of the translational apparatus. Although most examples of control are thought to affect the initiation of translation, two classes of regulatory factors, one a protein and one a short non-coding RNA now appear to inhibit protein synthesis during elongation. Diversity seems to be a central feature of translational control, both in the mechanisms themselves and in the situations where this form of regulation is used.

3' Untranslated Regions↗
PubMed2000

Efficacy and safety of pravastatin vs simvastatin after cardiac transplantation.

Prior studies of cardiac transplant recipients have shown that pravastatin reduces 12-month rejection and mortality after cardiac transplantation and simvastatin reduces 4-year mortality, low-density lipoprotein (LDL) cholesterol levels, and intimal thickening. In a 12-month observational study, cardiac transplant recipients received open-label pravastatin 40 mg (n = 42) or simvastatin 20 mg daily (n = 45) on an alternating basis from the time of transplantation. Lipid levels, safety, and post-transplant outcomes were compared. We found no significant differences in total LDL or high-density lipoprotein cholesterol, triglycerides, linearized infection or rejection rates, liver function tests, or immunosuppressant dosages between groups at 1, 3, 6, or 12 months. Rhabdomyolysis or myositis occurred only in patients on simvastatin (n = 6, 13.3%) with no episodes for patients on pravastatin (p = 0. 032). Survival at 12 months on an actual treatment basis was 97.6% for patients on pravastatin and 83.7% for those on simvastatin (p = 0.078). Immunosuppression-related deaths occurred in only 2.4% (1 patient) on pravastatin vs 15.6% (n = 7) on simvastatin (p = 0.06). Pravastatin and simvastatin resulted in comparable lipid profiles. Pravastatin use was however free from the high rates of rhabdomyolysis and myositis seen with simvastatin use. Pravastatin was additionally associated with a trend toward superior survival, attributable to fewer immunosuppression-related deaths. For safety and pharmacokinetic reasons, pravastatin should be considered the statin of choice after heart transplantation.

Cholesterol, HDL↗
PubMed2000

Pulmonary vascular resistance and reactivity in children with end-stage cardiomyopathy.

Pulmonary vascular resistance (PVR) and reactivity were compared in 63 children with end-stage cardiomyopathy (CM) referred for cardiac transplantation. Diagnostic category of CM was the sole determinant of PVR. Compared with other patients, children with restrictive CM were younger at diagnosis and had a significantly higher pulmonary vascular resistance index (PVRI). Children with a baseline PVRI of up to 11.8 units per meter squared (U.m(2)) who showed reactivity underwent successful orthotopic cardiac transplantation.

Adolescent↗
PubMed2000

Prevalence and epidemiology of onychomycosis in patients visiting physicians' offices: a multicenter canadian survey of 15,000 patients.

A prospective, multicenter study to determine the epidemiology of onychomycosis was performed in the offices of 3 dermatologists and 1 family physician in Ontario, Canada. In the sample of 15,000 patients, abnormal-appearing nails were observed in 2505 persons (16. 7%). There were 1199 patients (8%) with toenail or fingernail onychomycosis confirmed on mycologic examination, with 1137 patients (7.6%) who had only pedal onychomycosis, 40 patients with toenail and fingernail onychomycosis (0.27%), and 22 patients (0.15%) with only fingernail onychomycosis. The condition was more common in male patients (P <.0001) and older persons (P <.0001). The ratio of onychomycosis in toenails/fingernails was 19:1. When onychomycosis was present in toenails, the ratio of distal/lateral subungual onychomycosis (DLSO) to white superficial onychomycosis to proximal subungual onychomycosis was 360:59:1. The extent of DLSO in toenails was mild (< or =25% nail involvement), moderate (26%-74% disease), and severe (> or =75% nail involvement) in 27.6%, 39.9%, and 32.5% of patients, respectively. After adjusting for the age and sex distribution of the general population, the projected rate of onychomycosis in Canada is 6.5% (95% confidence interval [CI], 6. 1%-6.9%). The organisms causing toenail onychomycosis were 90.5% dermatophyte, 7.8% nondermatophyte molds, and 1.7% Candida spp. The corresponding organisms causing fingernail onychomycosis were 70.8%, 0%, and 29.2%, respectively. In a large sample of 15,000 patients, abnormal-appearing nails were present in 17% of the sample with mycologic evidence of toenail or fingernail onychomycosis in 8%. The projected prevalence of onychomycosis in Canada is 6.5% (95% CI, 6. 1%-6.9%).

Adolescent↗
PubMed2000

A clinical experience of malaria in east Timor.

BACKGROUND: The author spent February and March of this year as a doctor with Timor Aid, a local aid organisation based in Dili. That time was spent in the coastal region bordering west Timor at a place called Batugade and later in the central mountainous area known as Ainaro. The majority of cases of malaria were recorded and the morbidity patterns clinically documented, although no laboratory diagnosis was possible; indeed none was available. OBJECTIVE: A study of 107 cases of malaria seen in the remote areas of east Timor is reported and the implications for Australia are discussed. DISCUSSION: The disease is common in east Timor and is most prevalent in children. It is an extremely serious condition and deaths are occurring. The current treatment protocols are considered appropriate; the need for public health measures are stressed.

Adolescent↗
PubMed1998

The nitric oxide donor, diethylamine NONOate, enhances preservation of the donor rat heart.

BACKGROUND: Ischemia/reperfusion injury to transplanted organs may be associated with loss of endothelial release of nitric oxide. The aim of this study was to determine whether supplementation of an extracellular-based cardioplegic solution in routine clinical use at our institution with nitric oxide (as diethylamine NONOate) enhanced poststorage functionality of an isolated working heart model. METHODS: Excised hearts were ligated to an aortic cannula and immediately perfused retrogradely with oxygenated Krebs solution at a hydrostatic pressure of 100 cm H2O at 37 degrees C. This preparation was then converted to a working system by switching the supply of perfusate from the aorta to a left atrial cannula at a filling pressure of 15 cm H2O. After a 1-minute stabilization period, baseline measurements of heart rate, aortic flow, coronary artery flow, and cardiac output were performed. Oxygenated cardioplegic solution (0.1 micromol/L), with or without NONOate, was then infused into the coronary circulation. Hearts were then stored in the same solutions for 6 or 12 hours at 2 degrees to 3 degrees C. The hearts were then remounted on the perfusion apparatus and reperfused as before, and hemodynamic measurements were repeated. Water content of the hearts were then determined. RESULTS: Addition of the nitric oxide donor significantly improved all hemodynamic parameters measured after 12 hours storage and aortic flow at 6 hours storage compared with the untreated control groups. There was no significant difference between the water contents of the NONOate-treated and control groups. CONCLUSIONS: The presence of the nitric oxide donor diethylamine NONOate was associated with significantly better preservation of coronary artery flow and cardiac function in the isolated rat heart after a 12-hour period of hypothermic storage and suggests a novel use for this family of compounds in the transplantation context.

Animals↗
PubMed1996

The role of nitric oxide in heart failure. Potential for pharmacological intervention.

There is now considerable evidence that nitric oxide (NO) production and action are abnormal in patients with heart failure. Spontaneous NO release from the vascular endothelium is preserved or enhanced in patients with heart failure and this may help to maintain tissue perfusion by blunting the vasoconstriction induced by various neurohumoral factors. On the other hand, endothelial NO release in response to various stimuli including exercise appears to be diminished and this may contribute to the impaired exercise capacity of patients with heart failure. It is now apparent that NO produced within the heart plays an important role in the modulation of cardiac contractility under physiological conditions. In patients with heart failure, however, increased myocardial NO production in response to cytokines such as tumour necrosis factor-alpha may contribute to reduced contractility and myocyte injury. Our understanding of the role of NO in the control of vascular tone has provided an explanation for the efficacy of nitrovasodilators in heart failure and has stimulated novel approaches to augmenting endogenous vascular NO production. There is also evidence that ACE inhibitors act to restore normal endothelial function in patients with heart failure. Increased NO production within the heart, particularly that produced via the pro-inflammatory inducible NO synthase, may be detrimental. It remains to be determined whether selective inhibition of inducible NO synthase can favourably modify the course of this lethal condition.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Clinical heart transplantation. Total lymphoid irradiation for resistant rejection after heart transplantation: only moderate success medium-term.

Total lymphoid irradiation (640 cGy) was given to 19 heart and 1 heart-lung recipients on maintenance triple therapy at a mean of 4.9 +/- 4 months after transplantation (range 46 to 519 days). Mean number of treated rejection episodes before, during, and after total lymphoid irradiation was 6.4 +/- 1.7, 0.8 +/- 1.2, and 1.2 +/- 1.3 episodes per patient, respectively. During total lymphoid irradiation, 37% had at least one episode of rejection requiring treatment; after total lymphoid irradiation, 42% had no further rejection episodes, 21% had one further episode, and 37% had 2 or more episodes. Metastatic squamous cell carcinoma in one patient and coronary artery disease in three of five patients studied to date is of concern and requires longer follow-up.

Adult↗
PubMed1996

Ischemic preconditioning enhances donor lung preservation in the rat.

BACKGROUND: Ischemic preconditioning achieved by brief periods of ischemia and reperfusion before a prolonged period of ischemia can significantly reduce the extent of cardiac damage in many mammalian species and human beings. In this study we used a rat model of single lung transplantation to show that ischemic preconditioning also occurs in the lung. METHODS: Rats randomly selected for ischemic preconditioning had their left main bronchus and pulmonary artery occluded for 5 minutes, followed by 10 minutes of reperfusion and ventilation. Lungs of control rats were ventilated for 15 minutes. The lungs were perfused with University of Wisconsin solution, then heart and lungs were excised en bloc and stored in University of Wisconsin solution at 0 degree C for 6 or 12 hours. After left pneumonectomy, the left lung of the donor was then implanted into the recipient via left thoracotomy. After 1 hour of ventilation and reperfusion, a right pneumonectomy was performed making the animal completely dependent on the transplanted lung. Samples of arterial blood from the left ventricle were then taken for arterial oxygen tension and arterial carbon dioxide tension determination. Water contents of the donor lungs were measured before and after reperfusion. Thiobarbituric acid reactive substances were measured in the right donor lung after storage. RESULTS: Lungs transplanted after 12 hours of storage had profoundly impaired gas exchange (arterial oxygen tension = 34 +/- 5; arterial carbon dioxide tension = 69 +/- 7 mm Hg) compared with the normal levels in the 6-hour storage group (arterial oxygen tension = 308 +/- 22; arterial carbon dioxide tension = 17 +/- 1 mm Hg). Ischemic preconditioning significantly improved gas exchange in the 12-hour storage group (arterial oxygen tension = 83 +/- 11; arterial carbon dioxide tension = 40 +/- 4 mm Hg). Ischemic preconditioning also significantly decreased thiobarbituric acid reactive substances formation at both 6- and 12-hour storage. CONCLUSIONS: These results show that the phenomenon of ischemic preconditioning occurs in the lung and that it may reduce injury to the donor lung during prolonged cold ischemic storage.

Animals↗
PubMed1995

Failure of 29Si NMR to detect increased blood silicon levels in silicone gel breast implant recipients.

We have compared directly the results of atomic absorption (AA) spectroscopy and a 29Si magic angle spinning (MAS) nuclear magnetic resonance (NMR) technique reported in the literature by Garrido et al. (Garrido, L.; et al. Magn. Reson. Med. 1994, 31, 328-330) for analyzing blood silicon levels in control patients versus patients with silicone gel breast implants. AA spectroscopy yielded blood silicon levels in the nanogram per milliliter range for control patients, while somewhat higher values were found in patients with implants. The 29Si MAS NMR technique applied to the identical blood samples was unable to detect silicon in any of the samples. Sensitivity calculations demonstrate that 29Si MAS NMR should not be expected to detect silicon at the levels determined by AA spectroscopy under the spectroscopic conditions employed and that the concentration of silicon-containing compounds would need to 10(4) times the level detected by AA in order to be detected by this NMR method.

Breast Implants↗
PubMed1995

Ketoconazole to reduce the need for cyclosporine after cardiac transplantation.

BACKGROUND: Because ketoconazole can markedly reduce the need for cyclosporine and because it also has antimicrobial properties, it may offer benefits in the treatment of patients after cardiac transplantation. METHODS: We randomly assigned 43 patients at the time of cardiac transplantation to receive ketoconazole (200 mg per day) (23 patients) or no ketoconazole (20 patients). The main end points were the dose of cyclosporine required and the incidence of cardiac rejection and infection. RESULTS: Ketoconazole reduced the dose of cyclosporine needed to maintain target levels by 62 percent at one week and by 80 percent at one year. The cost savings per patient (in U.S. dollars, inclusive of the cost of ketoconazole) was about $5,200 in the first year and about $3,920 in each subsequent year. The mean (+/- SD) rate of rejection in the first month was lower in the ketoconazole group than in the controls (4.2 +/- 0.8 vs 5.7 +/- 1.0 episodes per 100 patient-days, P < 0.001), and the average number of days to the first rejection was higher (30 +/- 29 vs. 15 +/- 8, P = 0.03). In the first year, 22 percent of the ketoconazole group required cytolytic therapy, as compared with 35 percent of the controls, and 9 percent of the ketoconazole group required total lymphoid irradiation, as compared with 15 percent of the controls (P = 0.07). The incidence of infection was lower in ketoconazole-treated patients than in controls in the second month (1.4 +/- 0.5 vs. 2.8 +/- 0.7 episodes per 100 patient-days, P < 0.001) and in the third month (0.8 +/- 0.3 vs. 2.3 +/- 0.6 episodes per 100 patient days, P < 0.001). Transient, asymptomatic cholestasis was observed in the ketoconazole group. CONCLUSIONS: After cardiac transplantation, ketoconazole greatly reduced the need for cyclosporine, resulting in substantial cost savings. Ketoconazole also reduced the rates of rejection and infection, without persistent toxic effects. We now use ketoconazole routinely in cardiac-transplant recipients.

Actuarial Analysis↗