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Biomedical subjects

J Davidson

Publications and source records attributed to J Davidson.

At least 127 records · Page 7Linked to original sources
PubMed1993

A phase II study of weekly edatrexate (10-EDAM) in metastatic melanoma. A National Cancer Institute of Canada Clinical Trials Group study.

BACKGROUND: Phase I and II clinical trials have demonstrated acceptable toxicity and promising activity of Edatrexate (10-EDAM). The objective of this multicentre phase II study was to determine the efficacy and toxicity of this agent in patients with metastatic melanoma. PATIENTS AND METHODS: Sixteen previously untreated patients with metastatic melanoma received 10-EDAM, 80 mg/m2/week intravenously. Patients were evaluated for response and toxicity. RESULTS: There were no objective responses. The median dose intensity of 10-EDAM actually delivered was 56.25 mg/m2/week (70% of projected). Mucositis of any degree was encountered in 93.8% of patients. Grade 3 or 4 mucositis, skin rash, nausea, abdominal pain, neutropenia, thrombocytopenia, anemia and hyperbilirubinemia each were encountered in 1-2 patients. There was 1 toxic death due to 10-EDAM. CONCLUSION: 10-EDAM is an inactive agent in metastatic melanoma.

Adult↗
PubMed1993

Unusual DQA-DR haplotypes in rheumatoid vasculitis.

DQA and DQB variants and HLA haplotypes were defined in Caucasian subjects with rheumatoid arthritis (RA), in a rheumatoid subset characterized clinically by extra-articular features of major vasculitis, and in controls. DQ variants were defined using a panel of sequence specific oligonucleotide probes. In RA subjects without extra-articular features the frequency of DQB*0301 was significantly increased but this was secondary to the main association with DR4. In rheumatoid vasculitis by contrast, DQB*0302 rather than DQB*0301 was increased in frequency, in addition to an increase of C4A null alleles. Family studies showed that DR4 negative haplotypes had an increased frequency of unusual DR-DQA combinations as compared to other rheumatoid subsets. These findings are in keeping with the concept that genes within the MHC other than DR4 have a disease-modifying role in rheumatoid subsets. HLA haplotypes were defined in a family where the proband has RA and Felty's syndrome and an affected sister has rheumatoid vasculitis. These siblings share a DR4 bearing haplotype typing for DQB*0301, and the sister with rheumatoid vasculitis has a DR4 negative haplotype carrying a C4A null allele and an unusual DR-DQA combination.

Arthritis, Rheumatoid↗
PubMed1993

A unified perspective on copper deficiency and cardiomyopathy.

Dietary copper restriction in rats results in cardiomyopathy. In rats fed copper-restricted diets from weaning for 5 to 8 weeks, a concentric hypertrophy is apparent, whereas postweaning copper restriction does produce cardiomyopathy without apparent hypertrophy. Both sets of circumstances appear to affect the integrity of the basal laminae of cardiac myocytes and capillaries. In rats fed copper-restricted diets from weaning, decreases in cytochrome c oxidase are related not only to copper's role as a coenzyme, but also to a marked decrease in the nuclear encoded subunits of the enzyme complex. Decreased levels of the delta-subunit of ATP synthase have been observed. However, such aberrations in mitochondrial enzymes, as well as morphologic alterations, apparently do not affect cardiac levels of ATP. This review suggests mechanisms of cardiac adaptation and initiation factors leading to cardiac hypertrophy. We present a hypothetical working model explaining the events leading to cardiac failure in the copper-deficient rat heart based on the present body of knowledge, and compare the pathology with other models of cardiomyopathies.

Animals↗
PubMed1993

Post-traumatic stress disorder.

In the past few years, there has been a growing interest in the neurobiology of PTSD. A number of models have been proposed including possible structural changes. We have now seen the appearance in the literature of controlled and double-blind trials. Of interest are positive outcome studies associated with the use of drugs with serotonergic actions for a period of 8 weeks. Symptom relief provided by pharmacotherapy enables the patient to participate more thoroughly in individual, behavioral, or group therapy.

Arousal↗
PubMed1993

A re-evaluation of radical total glossectomy.

Total glossectomy, with or without accompanying total laryngectomy, in many respects represents the radical extreme of the treatment spectrum for oral cavity/oropharyngeal carcinoma. It necessarily impacts greatly upon the functions of speech and deglutition and thereby upon the patient's quality of life. The candidates for this surgical procedure are, however, already severely debilitated with respect to these functions due to the extent of their disease and tumor-induced pain. When considering the alternatives, radical surgery becomes more acceptable, for, at the very least, it offers substantial palliation. This article reviews the current literature regarding the procedure itself, potential outcomes and presents a small case series of reconstructive options.

Aged↗
PubMed1993

Technetium-99m-1,2-bis[bis(2-ethoxyethyl) phosphino]ethane: human biodistribution, dosimetry and safety of a new myocardial perfusion imaging agent.

A novel 99mTc complex (1,2-bis[bis(2-ethoxyethyl)phosphino] ethane, 99mTc-tetrofosmin) has been developed to replace 201Tl in myocardial perfusion imaging. Biodistribution, safety and dosimetry of 99mTc-tetrofosmin were studied in 12 male volunteers, each at rest and during exercise. Safety parameters measured to 48 hr postinjection revealed no clinically significant long-term drug-related changes. Biodistribution was studied by acquiring whole-body or serial static images up to 48 hr postinjection. Technetium-99m-tetrofosmin shows good heart uptake (1.2%) with retention. Clearance is excellent from blood (< 5% by 10 min), liver (< 4.5% by 60 min) and lung. Sequestration of activity by skeletal muscle is enhanced during exercise. Radiation dosimetry calculations indicate that the effective dose, assuming a 3.5 hr bladder voiding period, is 32.9 x 10(-3) rad/mCi (8.9 x 10(-3) mSv/MBq) at rest and 26.7 x 10(-3) rad/mCi (7.1 x 10(-3) mSv/MBq) after exercise. Technetium-99m-tetrofosmin can produce high quality myocardial images from 5 min to several hours postinjection.

Heart↗
PubMed1993

Are endoscopic measurements of colonic polyps reliable?

Many clinical studies of colorectal adenomatous polyps rely on endoscopic estimation of polyp size. To examine the reliability of such measurements, we conducted a study using artificial polyps in an endoscopy teaching model. Eight experienced endoscopists estimated the size of 13 polyps in two separate sessions 2 wk apart. Endoscopic estimates of polyp size tended to be significantly lower than the true polyp size for all polyps and all endoscopists at both sessions. We also found a statistically significant difference in the magnitude of the underestimation between the first and second session (p < 0.0001). At the first session, polyps tended to be estimated at 64% of their true size, and at the second session, the estimates tended to be at 77% of the actual polyp size. We estimate the magnitude of the variation in polyp measurements due to individual polyps, endoscopist, and examination session, and discuss the impact these sources of variation have in planning of clinical trials.

Colonic Neoplasms↗
PubMed1992

The bisphosphonate, alendronate, prevents bone loss in ovariectomized baboons.

We examined the effect of the amino bisphosphonate alendronate, administered IV every 2 weeks at 0.05 and 0.25 mg/kg for 1 year, on bone loss and parameters related to bone metabolism in ovariectomized baboons. Relative to non-OVX animals, the OVX baboons experienced increased bone turnover, reflected in biochemical and histomorphometric measurements, and bone loss assessed by dual-beam absorptiometry in the lumbar spine, which was similar to changes observed in ovariectomized women. Alendronate treatment maintained all parameters of bone turnover at control (nonovariectomized) levels and prevented the bone loss in a dose-dependent manner. We concluded that ovariectomized baboons offer a suitable model for the bone changes observed in ovariectomized women and that these changes can be prevented by sustained administration of an appropriate dose of this aminobisphosphonate.

Acid Phosphatase↗
PubMed1992

A single base change at a splice acceptor site leads to a truncated CAD protein in Urd-A mutant Chinese hamster ovary cells.

We have previously reported the isolation and characterization of mutant Chinese hamster ovary (CHO-K1) cells of the Urd-A complementation group, which require uridine for growth, are deficient in the activities of the first three enzymes of de novo UMP biosynthesis, and produce markedly reduced amounts of a truncated form of the multifunctional protein CAD, which contains these three enzyme activities. We report here that a single base change of G to A at a highly conserved RNA splice acceptor site is responsible for the phenotype of this mutant. In addition to a small amount of apparently normal CAD mRNA, this mutation causes production of two alternative forms of CAD mRNA in the mutant, one that includes the intron just prior to the mutation and one that excludes the exon just after the mutation. The affected splice site is located at the intron-exon boundary just preceding the exon that encodes the beginning of the aspartate transcarbamylase (ATCase) domain of the CAD protein. Both intron inclusion and exon exclusion during RNA processing introduce a translation stop codon upstream of the region encoding this domain, resulting in the production of the truncated CAD protein seen in the Urd-A mutant. This mutation also results in markedly decreased levels of CAD mRNA and protein in the mutant.

Amino Acid Sequence↗
PubMed1992

Cardiac ultrastructural and electrophysiological abnormalities in postweanling copper-restricted and copper-repleted rats in the absence of hypertrophy.

Cardiac ultrastructural and functional characteristics were determined in copper-depleted and copper-repleted rats. Male weanling rats were randomized into five groups that were fed either copper-adequate or copper-deficient diets. After 5 wk, one group fed each diet was studied to obtain baseline values. At this time, one copper-adequate postweanling group continued to receive the adequate diet as control, one deficient postweanling group was fed the adequate diet to evaluate the effect of copper repletion and one postweanling adequate group was fed the deficient diet to evaluate copper depletion in relatively older rats. These dietary treatments were continued for six additional weeks. Copper-depleted rats of both ages exhibited significant cardiac ultrastructural pathology and electrocardiogram abnormalities and the postweanling copper-depleted rats exhibited these abnormalities in the absence of hypertrophy and anemia. Increased mitochondrial volume density, disarranged cristae, and nonaligned myofibrils with disturbances at Z-bands were displayed. Additionally, all copper-depleted rats demonstrated fragmented basal laminae at capillary-myocyte interface. Increased QRS amplitude and notching and greater QT intervals were displayed. Copper-repleted rats exhibited some, but not total, reversal of these abnormalities. These results suggest that capillary-myocyte interface changes may play an important role in the developing pathology of copper depletion.

Animals↗
PubMed1992

The role of inositol lipids in the activation of monocytes by interleukin-1 and bacterial endotoxin.

The effect of interleukin-1 (IL-1) and bacterial endotoxin (lipopolysaccharide, LPS) on the activation of phosphoinositidase C (PIC) and on prostaglandin E2 release was studied in monocytes (M phi). Both IL-1 alpha and IL-1 beta increased the release of PGE2 in a concentration-dependent manner, with EC50s of 0.48 nM and 0.12 nM, respectively. Intact M phi were prelabelled with [3H]inositol and the formation of inositol phosphates (IPs) was estimated by ion exchange chromatography. PIC activity was estimated directly by measuring the conversion of [3H]phosphatidylinositol-4,5-bisphosphate to aqueous soluble radioactivity by M phi homogenates. IL-1 alpha (5.8 nM) increased the accumulation of IPs within 1-4 minutes and increases in IP3 and IP4 occurred before the increase in IP1+2 whereas LPS only increased the IPs level after at least 30 min. IL-1 alpha increased PIC activity in M phi homogenates within 15 min with an EC50 of 0.58 nM and IL-1 beta (0.1 nM) also increased activity. Neither IL-1 alpha nor IL-1 beta affected the PIC activity of membrane or cytosolic fractions. LPS decreased activity in all fractions. These data indicate that IL-1, but not LPS, can directly lead to an increased activity of PIC which may be involved in eicosanoid formation in M phi.

Animals↗
PubMed1992

Alpha-melanocyte-stimulating hormone suppresses fever and increases in plasma levels of prostaglandin E2 in the rabbit.

1. The effect of alpha-melanocyte-stimulating hormone (alpha-MSH) on changes in body temperature and plasma levels of prostaglandin E2 (PGE2) were measured in the rabbit following intravenous injection of bacterial lipopolysaccharide (LPS), rabbit endogenous pyrogen (EP), human recombinant tumour necrosis factor-alpha (TNF-alpha), human recombinant interleukin-1 beta (IL-1 beta) and intracerebroventricular injection of PGE2. 2. LPS (25 ng kg-1), EP (25 microliters kg-1), TNF-alpha (11 micrograms kg-1) and IL-1 beta (5 ng kg-1) produced increases in body temperature simultaneously with increases in plasma PGE2 levels. alpha-MSH (5 or 10 micrograms kg-1) attenuated both the increase in body temperature and increases in plasma levels of PGE2. 3. Intracerebroventricular injection of PGE2 (500 ng) produced a monophasic increase in body temperature. alpha-MSH (5 micrograms kg-1) administered 20 min after PGE2 had no effect on the hyperthermic response. 4. alpha-MSH (10 micrograms kg-1) had no effect on either body temperature or plasma levels of PGE2 in response to I.V. injection of sterile saline. 5. These data demonstrate that alpha-MSH inhibits both the pyrogenic actions of LPS, EP, TNF-alpha and IL-1 beta and their ability to increase PGE2 release without affecting the direct actions of PGE2, suggesting the possibility that alpha-MSH may prevent the synthesis of PGE2 either by preventing the actions or release of mediators such as TNF-alpha and IL-1 in response to LPS.

Animals↗
PubMed1992

Comparison of aspiration and scintigraphic techniques for the measurement of gastric emptying rates of liquids in humans.

A comparison was made of two techniques to measure the rate of gastric emptying. A noninvasive scintigraphic technique using a gammacamera and an invasive aspiration technique based on dye dilution were performed simultaneously. Seven healthy male volunteers each consumed two different liquid meals on two separate occasions. Scintigraphic measurements were performed continuously with aspiration every 10 minutes for a total of one hour. Gastric emptying rates were expressed as slope values after semilog linearisation of the emptying curves. Agreement between the two methods was assessed from the individual differences and mean of the two techniques, as well as from the geometric mean, including 95% limits of agreement. The scintigraphic technique gave a 70% slower emptying rate than the dye dilution technique. However, the 95% limits of agreement are large (1.56 to 0.30), reflecting the small sample size and the large coefficient of variation in the techniques used.

Adult↗
PubMed1992

Regional mapping of a liver alpha-subunit gene of phosphorylase kinase (PHKA) to the distal region of human chromosome Xp.

X-linked liver glycogenosis (XLG) is a glycogen storage disorder resulting from deficient activity of phosphorylase kinase (PHK). PHK consists of four different subunits: alpha, beta, gamma, and delta. Several genes encoding PHK subunits have been cloned and localized, but only the muscle alpha-subunit (PHKA) gene has been assigned to the X chromosome, in the region Xq12----q13. However, we have previously excluded the muscle PHKA gene as a candidate gene for the XLG mutation, as linkage analysis indicated that the mutation responsible for XLG is located in Xp22 and not in Xq12----q13. We report here the chromosomal localization by in situ hybridization of a liver PHKA gene to the distal region of chromosome Xp. Strong hybridization signals were observed on the distal part of the short arm of a chromosome identified as the X chromosome by cohybridization with an X chromosome-specific centromeric probe. The localization of this gene in the same chromosomal region as the disease gene responsible for XLG suggests that the liver PHKA gene is a highly likely candidate gene for the XLG mutation.

Chromosome Mapping↗