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Biomedical subjects

G McDonald

Publications and source records attributed to G McDonald.

At least 19 recordsLinked to original sources
PubMed1992

Recombinant human DNase inhalation in normal subjects and patients with cystic fibrosis. A phase 1 study.

OBJECTIVE: To evaluate the safety of recombinant human DNase (rhDNase) in normal subjects and in patients with cystic fibrosis. DESIGN: Nonrandomized trial in which individuals inhaled rhDNase three times a day Monday through Friday on two consecutive weeks. SETTING: The study was performed in the Clinical Research Center at the University of Washington, Seattle. Patients were recruited from the Cystic Fibrosis Center at the University of Washington. SUBJECTS AND PATIENTS: Twelve normal subjects and 14 patients with cystic fibrosis were studied (12 patients completed the protocol). The subjects and patients had to be aged 18 to 65 years and have a negative pregnancy test, if female. The normal subjects had to have a normal chest roentgenogram, be nonsmokers, and have normal pulmonary function testing. The patients with cystic fibrosis had to have a forced vital capacity greater than 40% predicted normal and have no recent exacerbation (within 2 weeks) of their lung infection or change in their medication. INTERVENTIONS: The study design was a repetitive dose escalation of aerosolized rhDNase. The subjects inhaled rhDNase three times a day, Monday through Friday, on 2 consecutive weeks and were rechallenged with a single dose 21 days after the last dose. Spirometry was measured before and 30 minutes after every rhDNase dose. MAIN OUTCOME MEASURES: Pulmonary function testing, serum DNase concentrations, and anti-DNase antibodies. Secondary outcome measures were dyspnea score and quantitative bacterial culture. MAIN RESULTS: Inhalation of rhDNase was well tolerated by all persons. There were no serious adverse reactions, and no allergic reactions were observed, even on rechallenge. No individual developed rhDNase antibodies. Improvement in both lung function and dyspnea score was observed in the adults with cystic fibrosis. Forced vital capacity was 3.2 +/- 0.3 L (mean +/- SE) on day 1 and was 3.5 +/- 0.3 L on day 12. Forced expiratory volume in 1 second was 2.1 +/- 0.2 L (mean +/- SE) on day 1 and was 2.3 +/- 0.3 L on day 12. CONCLUSIONS: Aerosolized rhDNase appears safe in normal subjects and in adults with cystic fibrosis and may improve lung function with short-term therapy.

Administration, Inhalation↗
PubMed1992

Heavy metal tolerance in the fission yeast requires an ATP-binding cassette-type vacuolar membrane transporter.

In response to heavy metal stress, plants and certain fungi, such as the fission yeast Schizosaccharomyces pombe, synthesize small metal-binding peptides known as phytochelatins. We have identified a cadmium sensitive S. pombe mutant deficient in the accumulation of a sulfide-containing phytochelatin-cadmium complex, and have isolated the gene, designated hmt1, that complements this mutant. The deduced protein sequence of the hmt1 gene product shares sequence identity with the family of ABC (ATP-binding cassette)-type transport proteins which includes the mammalian P-glycoproteins and CFTR, suggesting that the encoded product is an integral membrane protein. Analysis of fractionated fission yeast cell components indicates that the HMT1 polypeptide is associated with the vacuolar membrane. Additionally, fission yeast strains harboring an hmt1-expressing multicopy plasmid exhibit enhanced metal tolerance along with a higher intracellular level of cadmium, implying a relationship between HMT1 mediated transport and compartmentalization of heavy metals. This suggests that tissue-specific overproduction of a functional hmt1 product in transgenic plants might be a means to alter the tissue localization of these elements, such as for sequestering heavy metals away from consumable parts of crop plants.

ATP-Binding Cassette Transporters↗
PubMed1992

A pilot study of low-dose cyclosporin for graft-versus-host prophylaxis in marrow transplantation.

Nineteen patients with leukaemia, preleukaemia, and aplastic anaemia were treated by marrow transplantation from HLA-identical siblings. All were given postgrafting immunosuppression with a combination of methotrexate (days 1, 3, 6 and 11) and cyclosporin (days--1 to 180). In an attempt at reducing cyclosporin-associated toxicity, we explored whether the cyclosporin dose during the first 2 weeks could be decreased by 50% (from 3.0 to 1.5 mg/kg/d intravenously) without adversely affecting the incidence, onset, and severity of acute graft-versus-host disease (GVHD) and overall survival. Results from this pilot study were compared to those of a matched cohort of 38 patients given a standard dose of 3.0 mg cyclosporin/kg/d starting on day--1. The cumulative incidence of grade II and III acute GVHD in the 'low dose' cyclosporin group was 42% compared to 51% in the 'standard dose' group (P = 0.60). Three-year survival was 63% and 54% respectively (P = 0.59). Patients receiving the reduced cyclosporin dose during the first 14 d appeared to have less hepatotoxicity, and the methotrexate and cyclosporin doses administered were closer to the doses intended per protocol. We suggest that 'low dose' cyclosporin from day--1 to day 15 postgrafting might be as effective as 'standard dose' cyclosporin during that time period for the prevention of acute GVHD.

Acute Disease↗
PubMed1992

Purine biosynthetic genes are required for cadmium tolerance in Schizosaccharomyces pombe.

Phytochelatins (PCs) are metal-chelating peptides produced in plants and some fungi in response to heavy metal exposure. A Cd-sensitive mutant of the fission yeast Schizosaccharomyces pombe, defective in production of a PC-Cd-sulfide complex essential for metal tolerance, was found to harbor mutations in specific genes of the purine biosynthetic pathway. Genetic analysis of the link between metal complex accumulation and purine biosynthesis enzymes revealed that genetic lesions blocking two segments of the pathway, before and after the IMP branchpoint, are required to produce the Cd-sensitive phenotype. The biochemical functions of these two segments of the pathway are similar, and a model based on the alternate use of a sulfur analog substrate is presented. The novel participation of purine biosynthesis enzymes in the conversion of the PC-Cd complex to the PC-Cd-sulfide complex in the fission yeast raises an intriguing possibility that these same enzymes might have a role in sulfur metabolism in the fission yeast S. pombe, and perhaps in other biological systems.

Adenylosuccinate Synthase↗
PubMed1992

Cat-scratch disease.

Explore the source record for details and available documents.

Angiomatosis, Bacillary↗
PubMed1991

The prevalence of severe mental handicap in Northern Ireland.

There are four administrative areas (Health and Social Services Boards) in Northern Ireland. Two prevalence surveys, carried out several years apart, show that there is a significant geographical gradient in the rates of severe mental handicap (IQ less than 50). The rates in the 20-29-year-old groups in the Eastern and Northern Boards range between 4.07 and 4.82 per thousand; comparable rates in the Southern and Western Boards range between 5.17 and 6.37. A similar gradient was discernible in the distribution of Down's syndrome.

Adolescent↗
PubMed1990

Recurrent disseminated intravascular coagulation and fulminant intra hepatic thrombosis in a patient with the anti-phospholipid syndrome.

We describe a patient with the lupus anti-coagulant who had recurrent episodes, over a 2 year period, of a severe and disseminated intravascular coagulopathy. This patient also had positive serological assays for syphilis and anti-cardiolipin antibodies. Associated with the coagulopathy were co-expressed episodes of liver disease, ultimately terminating in fulminant liver failure. At autopsy the features were characteristic of the Budd-Chiari syndrome. This is the first report to document how consumptive coagulopathy may present as a dominant feature of the anti-phospholipid syndrome. It also clearly describes an immune mediated thrombotic mechanism as a cause of hepatic veno-occlusive disorders. Furthermore, this case highlights the varied clinical spectrum of the anti-phospholipid syndrome and suggests that a high index of suspicion is required to ensure its diagnosis.

Adult↗
PubMed1990

Heart and brain nucleotide pools during hemorrhage and resuscitation.

Sequential 31P nuclear magnetic resonance (NMR) spectra were measured in adult dogs to determine the relationship between cardiac function and myocardial intracellular pH (pHi) and phosphorylated energy metabolites during 2 h of hemorrhagic shock. Simultaneous measurements of coronary blood flow (radioactive microspheres), arterial and coronary sinus pH, blood gases, and oxygen content were performed. In addition, changes in brain NMR spectra were correlated with changes in cerebral blood flow during shock. Two hurs of hypovolemic shock resulted in significant decreases in phosphocreatine (PCr), PCr-to-ATP ratio, and pHi, whereas Pi rose significantly relative to baseline values. Return of shed blood and crystalloid fluid resuscitation improved cerebral and coronary perfusion and returned cardiac contractile function to near baseline values. We conclude that severe and sustained hemorrhagic shock produced significant alterations in brain and heart phosphorylated metabolites as well as significant intracellular acidosis; however, these changes in energy metabolites were reversible with adequate fluid resuscitation from shock.

Adenosine Triphosphate↗
PubMed1989

Probe directed at a segment of Rickettsia rickettsii rRNA amplified with polymerase chain reaction.

In an effort to explore a sensitive taxon-specific detection system for bacteria, we sequenced the 16S rRNA from two strains of Rickettsia rickettsii, five other rickettsiae, and Coxiella burnetti to find a probe site unique to R. rickettsii. We then synthesized a 16-mer that hybridized only to the rRNA of R. rickettsii. Using a primer complementary to a sequence found only in rickettsial rRNA, we then generated a cDNA. We amplified the probe site in a 180-base segment of the cDNA by using the cDNA primer and a second primer also unique to rickettsiae in a polymerase chain reaction. The segments of rRNA from each of the rickettsiae were amplified 10(6)- to 10(7)-fold, and the R. rickettsii probe hybridized only to the amplified segment from R. rickettsii. The rRNAs from Staphylococcus aureus, C. burnetii, and Neisseria meningitidis were not amplified and did not hybridize with the probe. The approach detailed below may prove clinically useful in the direct detection of pathogens that are difficult to cultivate.

Base Sequence↗
PubMed1988

Correlated in vivo 31P-NMR and NADH fluorometric studies on gerbil brain in graded hypoxia and hyperoxia.

Mitochondrial energy coupling in the gerbil brain was characterized by the relationship between intracellular phosphocreatine (PCr)/inorganic phosphate (Pi), phosphorylation ratio, and the mitochondrial redox state in graded hypoxia. Phosphorus-nuclear magnetic resonance (NMR) spectra of the brain and whole head were taken by surface and saddle coil, respectively. The NADH level of the brain cortex was monitored by in vivo fluororeflectometry. The PCr and Pi of the head and brain did not change between 100 and 10% O2 inhalation. PCr progressively decreased and Pi progressively increased with 6 and 4% 0% inhalation in the head. The PCr/Pi of the brain decreased by 44% at 6% fraction of inhaled oxygen (FIO2) and 57% at 4% FIO2. The ATP level did not change during hypoxia. The calculated phosphorylation ratio of the brain ([PCr] Kck[H+]/[Cr][Pi]) = ([ATP]/[ADP][Pi]) was 4.1 X 10(4) M-1 in normoxia. Hypoxia of increasing severity induced increasing NAD reduction of the brain cortex with 17% NAD reduction at 10% FIO2 when there was no change in phosphorylation ratio. The phosphorylation ratio decreased, i.e., the mitochondria failed to maintain the energy level of the brain when the magnitude of the change in NAD reduction to hypoxia was half of the total redox change between hyperoxia and anoxia. These studies demonstrated the feasibility of combined 31P-NMR and NADH fluorometry measurements on brain in vivo. The observations show similarities between the responses of mitochondrial oxidative phosphorylation to hypoxia in vivo and in vitro.

Algorithms↗
PubMed1987

Atrial natriuretic peptide, right atrial pressure, and sodium excretion rate in the rat.

This study examined the relationship between right atrial pressure (RAP), urine flow rate, sodium excretion rate, and plasma atrial natriuretic peptide (ANP) levels after an acute Ringer expansion. Two groups of rats had their RAP monitored and balloon catheters placed in their thoracic inferior venae cavae. In one group the balloon remained deflated, and in the second group the balloon was inflated during the volume expansion in an attempt to prevent the rise in RAP. The peak RAP was 7.3 +/- 0.8 mmHg when the balloon remained deflated and 3.5 +/- 0.6 mmHg in the group with the balloon catheter inflated (P less than 0.005). The corresponding peak ANP levels were 682 +/- 140 and 223 +/- 40 pg/ml. There was a significant correlation between the peak RAP and ANP levels (r = 0.754; P less than 0.05). The inflation of the balloon catheter significantly decreased the urine flow rate and the urine sodium excretion rate. A final group of animals had 200 microliters of rabbit serum containing antibody to ANP infused before the volume expansion. The antibody-treated animals had significantly lower urine flow and sodium excretion rates than nonantibody-treated control rats. We conclude that ANP is one of the factors which allows the rat to excrete an acute Ringer expansion.

Animals↗
PubMed1986

Applying posttraumatic stress disorder MMPI subscale to World War II POW veterans.

In order to determine whether the MMPI-PTSD subscale has application for assessing DSM-III diagnosed PTSD among populations other than Vietnam veterans, a group of WWII POWs (N = 69) were given the subscale. Results indicated that the use of the PTSD subscale can be generalized to older veterans; in a small sample of Pacific POWs, PTSD is more common among those from the Pacific theater than those from Europe. However, the subscale fails to distinguish between Pacific and European POW veterans. Difficulties in sampling and confounding stressors are discussed, as well as implications for treatment of WWII veterans.

Age Factors↗
PubMed1985

Recovery of left ventricular function after graded cardiac ischemia as predicted by myocardial P-31 nuclear magnetic resonance.

The purpose of this study was to determine noninvasively some critical level of high-energy phosphate stores that relates to the recovery of ventricular contractile function after graded cardiac ischemia. Rabbit hearts (n = 30) were equipped with an intraventricular balloon to monitor developed pressure and +/- dp/dt and placed in a nuclear magnetic resonance magnet (Bruker, 4.7 Tesla). Each heart underwent 10, 20, 40, or 60 minutes of global ischemia followed by 1 hour of reperfusion. The pH as determined by nuclear magnetic resonance dropped from 7.14 +/- 0.04 to 7.07 +/- 0.07 (p less than 0.02) at 1 minute and to 6.19 +/- 0.08 at 30 minutes of ischemia; pH ceased to fall thereafter. Phosphocreatine was depleted to 10% +/- 7% of its preischemic control in 10 minutes. Adenosine triphosphate (ATP) concentrations were 71% +/- 14% and 1% +/- 2% at 10 and 60 minutes. Regression analysis of recovered developed pressure on end-ischemic ATP (EIATP) revealed: developed pressure = 0.93 (EIATP) + 23 (r2 = 0.99). We conclude that: anaerobic metabolism as evidenced by a fall in pH appears to be active for 30 minutes after normothermic ischemia and then ceases; phosphocreatine buffers the fall in ATP during early ischemia; there is a tight correlation between EIATP and recovery of left ventricular contractile function with a threshold content of approximately 80% below which recovery of function will not be complete.

Adenosine Triphosphate↗