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Biomedical subjects

C MacDonald

Publications and source records attributed to C MacDonald.

At least 37 records · Page 2Linked to original sources
PubMed1998

NMR detection of slow conformational dynamics in an endonuclease toxin.

The cytotoxic activity of the secreted bacterial toxin colicin E9 is due to a non-specific DNase housed in the C-terminus of the protein. Double-resonance and triple-resonance NMR studies of the 134-amino acid 15N- and 13C/15N-labelled DNase domain are presented. Extensive conformational heterogeneity was evident from the presence of far more resonances than expected based on the amino acid sequence of the DNase, and from the appearance of chemical exchange cross-peaks in TOCSY and NOESY spectra. EXSY spectra were recorded to confirm that slow chemical exchange was occurring. Unambiguous sequence-specific resonance assignments are presented for one region of the protein, Pro65-Asn72, which exists in two slowly exchanging conformers based on the identification of chemical exchange cross-peaks in 3D 1H-1H-15N EXSY-HSQC, NOESY-HSQC and TOCSY-HSQC spectra, together with C alpha and C beta chemical shifts measured in triple-resonance spectra and sequential NH NOEs. The rates of conformational exchange for backbone amide resonances in this stretch of amino acids, and for the indole NH of either Trp22 or Trp58, were determined from the intensity variation of the appropriate diagonal and chemical exchange cross-peaks recorded in 3D 1H-1H-15N NOESY-HSQC spectra. The data fitted a model in which this region of the DNase has two conformers, NA and NB, which interchange at 15 degrees C with a forward rate constant of 1.61 +/- 0.5 s-1 and a backward rate constant of 1.05 +/- 0.5 s-1. Demonstration of this conformational equilibrium has led to a reappraisal of a previously proposed kinetic scheme describing the interaction of E9 DNase with immunity proteins [Wallis et al. (1995) Biochemistry, 34, 13743-13750 and 13751-13759]. The revised scheme is consistent with the specific inhibitor protein for the E9 DNase, Im9, associating with both the NA and NB conformers of the DNase and with binding only to the NB conformer detected because the rate of dissociation of the complex of Im9 and the NA conformer, NAI. is extremely rapid. In this model stoichiometric amounts of Im9 convert, the E9 DNase is converted wholly into the NBI form. The possibility that cis-trans isomerisation of peptide bonds preceding proline residues is the cause of the conformational heterogeneity is discussed. E9 DNase contains 10 prolines, with two bracketing the stretch of amino acids that have allowed the NA [symbol: see text] NB interconversion to be identified, Pro65 and Pro73. The model assumes that one or both of these can exist in either the cis or trans form with strong Im9 binding possible to only one form.

Amino Acid Sequence↗
PubMed1998

High-dose etoposide with granulocyte colony-stimulating factor for mobilization of peripheral blood progenitor cells: efficacy and toxicity at three dose levels.

High-dose etoposide (2.0-2.4 g m(-2)) with granulocyte colony-stimulating factor (G-CSF) is an effective strategy to mobilize peripheral blood progenitor cells (PBPCs), although in some patients this is associated with significant toxicity. Sixty-three patients with malignancy were enrolled into this non-randomized sequential study. The majority (55/63, 87%) had received at least two prior regimens of chemotherapy, and seven patients had previously failed to mobilize following high-dose cyclophosphamide with G-CSF. Consecutive patient groups received etoposide at three dose levels [2.0 g m(-2) (n = 22), 1.8 g m(-2) (n = 20) and 1.6 g m(-2) (n = 21)] followed by daily G-CSF. Subsequent leukaphereses were assayed for CD34+ cell content, with a target total collection of 2.0 x 10(6) CD34+ cells kg(-1). Toxicity was assessed by the development of significant mucositis, the requirement for parenteral antibiotics or blood component support and rehospitalization incidence. Ten patients (16%) had less than the minimum target yield collected. Median collections in the three groups were 4.7 (2 g m(-2)), 5.7 (1.8 g m(-2)) and 6.5 (1.6 g m(-2)) x 10(6) CD34+ cells kg(-1). Five of the seven patients who had previously failed cyclophosphamide mobilization achieved more than the target yield. Rehospitalization incidence was significantly lower in patients receiving 1.6 g m(-2) etoposide than in those receiving 2.0 g m(-2) (P = 0.03). These data suggest that high-dose etoposide with G-CSF is an efficient mobilization regimen in the majority of heavily pretreated patients, including those who have previously failed on high-dose cyclophosphamide with G-CSF. An etoposide dose of 1.6 g m(-2) appears to be as effective as higher doses but less toxic.

Acute Disease↗
PubMed1998

Effect of the beta-diketones diferuloylmethane (curcumin) and dibenzoylmethane on rat mammary DNA adducts and tumors induced by 7,12-dimethylbenz[a]anthracene.

Curcumin is a beta-diketone constituent of the spice turmeric that possesses anticarcinogenic properties in several animal models. The present studies were conducted in order to identify beta-diketones structurally-related to curcumin that would be effective dietary blocking agents toward the initiation stage of 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary carcinogenesis. Of the beta-diketone compounds initially screened for their capacity to induce quinone-reductase (QR) activity in wild-type Hepa1c1c7 cells and a mutant subclone, curcumin (diferuloylmethane) and dibenzoylmethane were most effective. However, when added to semipurified diets fed to female rats, dibenzoylmethane (1%), but not curcumin (1%), was effective in inhibiting in vivo mammary DMBA-DNA adduct formation. This inhibitory effect on mammary adduct formation was associated with a significant increase in liver activities of glutathione S-transferase, QR and 7-ethoxyresorufin-O-deethylase activities. Female rats provided diets supplemented with dibenzoylmethane at 0.1, 0.5 and 1.0% for 14 days prior to dosing with DMBA exhibited a significant decrease in mammary tumor development, compared with controls. However, tumor development for animals fed diets containing 1.0% curcumin was not different from that of controls. Therefore, dibenzoylmethane, and possibly other structurally-related beta-diketones, warrant examination as breast cancer chemopreventative blocking agents.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1998

Randomised controlled trial of advice on an egg exclusion diet in young children with atopic eczema and sensitivity to eggs.

BACKGROUND: The role of exclusion diets in the management of atopic eczema in young children is uncertain. This randomised controlled trial evaluates the effect of excluding egg from the diet in young children with atopic eczema and sensitivity to eggs. Fifty-five such children were randomised either to a 4-week regimen, in which mothers were given general advice on care of eczema and additional specific advice from a dietician about an egg exclusion diet (diet group), or to a control group in which general advice only was given. Both groups continued conventional topical treatment. Disease activity was assessed by estimates of the surface area affected by eczema and by an arbitrary severity score. Possible egg sensitivity was identified by RAST before randomisation and after the trial by double-blind placebo-controlled egg challenge. RESULTS: The mean reduction in surface area affected by eczema was significantly greater (p = 0.02) in the group receiving dietary advice (from 19.6% to 10.9% area affected) than in the control group (from 21.9% to 18.9%). A significant improvement also occurred in severity score (p = 0.04): from 33.9 to 24.0 units for the diet group compared with a decrease from 36.7 to 33.5 in the control group. The study suggests that advice on the dietary exclusion of eggs is useful as part of the overall management of young children with atopic eczema and sensitivity to eggs.

Dermatitis, Atopic↗
PubMed1998

Cytotoxicity of xenobiotics and expression of glutathione-S-transferases in immortalised rat hepatocyte cell lines.

1. Immortalised rat hepatocyte cell lines are more sensitive to the cytotoxicity of 1-chloro-2,4-dinitrobenzene and ethacrynic acid than primary cultures of hepatocytes. 2. Class alpha glutathione S-transferases are not expressed in immortalised hepatocyte cell lines. Class pi glutathione S-transferase expression is elevated in the immortalised cell lines compared with freshly isolated hepatocytes, but it is not as high as in the HTC rat hepatoma cell line. 3. Immortalised hepatocyte cell lines may provide a sensitive model system for detecting cytotoxicity associated with xenobiotics which are detoxified by glutathione S-transferases.

Animals↗
PubMed1998

Mental health, physical health, and stressors reported by New Zealand Defence Force peacekeepers: a longitudinal study.

The psychological effect of peacekeeping duties on 277 New Zealand Defence Force personnel was investigated using a longitudinal, cross-sectional study. Self-report data were collected in five stages from before deployment to approximately 6 months after return. Multiple measures of mental health, physical health, and stressors were used. Results revealed that the most stressful periods of the deployment, and those with the greatest effect on overall health and well-being, appear to be the predeployment and follow-up stages. These findings demonstrate the need for effective predeployment training and postdeployment debriefing and support.

Adult↗
PubMed1997

Race, combat, and PTSD in a community sample of New Zealand Vietnam War veterans.

The association between posttraumatic stress disorder (PTSD), combat exposure, and race was examined in a New Zealand community sample of 756 Vietnam War veterans. Maori veterans reported higher levels of PTSD than their non-Maori counterparts. However, the race effect was shown to be mediated by combat exposure level, rank, and combat role. These findings support differential experience explanations for the relationship between postwar adjustment and race, suggesting that higher levels of psychological symptoms reported by minority group veterans can be accounted for by their experience of higher levels of combat stressors.

Adaptation, Psychological↗
PubMed1997

The plasticizer benzyl butyl phthalate (BBP) inhibits 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary DNA adduct formation and tumorigenesis.

Although the risk for cancer is multifactorial, a substantial portion of cancer incidence rates is related to environmental factors, including diet and environmental chemicals. The magnitude of the contribution to cancer of the breast from exposure to environmental chemicals remains unclear. The phthalate ester plasticizers are abundantly-produced industrial chemicals that have become widely-dispersed environmental pollutants. The present studies were conducted to determine the effect of the phthalate ester, benzyl butyl phthalate (BBP) on mammary gland carcinogenesis induced in the female rat by the polycyclic aromatic hydrocarbon (PAH) 7,12-dimethylbenz[a]anthracene (DMBA). Exposure to BBP (i.p. injection) at 100 and 500 mg/kg doses for 5 days resulted in a significant 72 and 92% inhibition, respectively, in the in vivo formation of mammary DMBA-DNA adducts, compared to controls. Treatment with BBP (i.g. intubation) for 7 days resulted in a significant (48%) inhibition in mammary DMBA-DNA adduct formation only for those animals receiving the 500 mg/kg dose, compared to controls. Administration of BBP (i.g.) at 500 mg/kg for 7 days also was associated with a significant 8.5-fold increase in the liver activity of 7-ethoxyresorufin-O-deethylase. No change in liver glutathione-S-transferase activity was observed for animals treated with both BBP (i.g.) doses. Treatment with BBP (i.g.) at 250 and 500 mg/kg doses for 7 days prior to DMBA administration resulted in a significant 37% decrease in mammary tumor incidence for both doses, compared to controls. The number of mammary adenocarcinomas per rat was significantly inhibited by 60 and 70% for rats exposed to BBP at the 250 and 500 mg/kg doses, respectively, compared to controls. Therefore, the present studies indicate that BBP acts as a blocking agent toward DMBA-induced rat mammary DNA adduct formation and mammary carcinogenesis. This effect partly may be due to increased metabolism of BBP in the liver. These results underscore the need to further examine the effect of BBP and other phthalates on the various stages of mammary carcinogenesis, as well as on the metabolism of mammary carcinogens.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1997

Paediatric echocardiography by telemedicine--nine years' experience.

In 1987 we established a realtime echocardiography service by telemedicine from the paediatric cardiology department of a tertiary-care hospital in Halifax. The service was initially provided to single regional hospital but was expanded to six regional hospitals in the three Canadian Maritime Provinces. The system used a dial-up broadband video-transmission service provided by the telephone companies. Records of all transmissions were kept prospectively and reviewed to January 1997. A total of 324 transmissions were made. During 1995-96 there were 135 studies: 69 (51%) were urgent examinations of newborn children and 30 (22%) were urgent examinations of older children; repeat studies and postoperative checks (usually for pericardial effusion) accounted for the other 36 studies (27%). The images were of broadcast quality except in five cases where problems with transmission or poor sedation occurred. A comparison of 26 transmitted studies with repeat, 'in person' studies showed no important discrepancies in diagnosis. During the two-year study period, the cost of the network (equipment leasing costs and telecommunications costs) was C$90,000. Use of the telemedicine network saved unnecessary patient transfer in 31 cases. The cost of the transportation avoided was C$100,000-C$118,000. This review confirms our preliminary findings that broadband echocardiography transmission provides a service comparable in availability and accuracy to that provided in our paediatric cardiology division.

Canada↗
PubMed1997

An evaluation of the specificity, validity and reliability of jumping tests.

BACKGROUND: There were three objectives of this study: 1. To describe the influence of using a single and double leg take-off as a function of run-up length in jumping for height. 2. To determine if various types of jumps are specific in nature. 3. To evaluate two methods of assessing jumping height (a modified Vertec or Yardstick and a Board) for validity and inter-day reliability. METHODS: Seventeen male subjects were tested on jumps for height from a standing position and using a 1, 3, 5 and 7 stride run-up. These jumps were performed using a single and double leg take-off measured by the Yardstick. Selected jumps were also tested using a Board method and repeated for assessment of reliability. RESULTS: The single leg take-off produced significantly higher jumps when the run-up was three or more strides. The inter-relationships among jump conditions were generally high, however jump types could be considered as specific when the run-up length and number of legs used in the take-off were different. The Yardstick produced significantly greater jump heights than the Board method, which questions the validity of using a board for assessment of maximum jump performance. The reliability of both methods was generally high however the jumps performed from a run-up produced less reliable results than the standing jumps for the Yardstick. CONCLUSIONS: It was suggested that the design of tests to assess jumping ability should consider the specific jump type used in the sport of interest and that the Yardstick is the preferred mode of testing, provided that attempts are made to maximise reliability.

Adolescent↗
PubMed1996

Inhibition by rosemary and carnosol of 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary tumorigenesis and in vivo DMBA-DNA adduct formation.

Extracts of the spice Rosemary officinalis L. have been reported to inhibit experimental carcinogenesis. Two rosemary components, carnosol and ursolic acid, appear to be partly responsible for the antitumorigenic activity of rosemary. The present studies were conducted in order to evaluate the activity of rosemary extract, carnosol and ursolic acid in inhibiting the in vivo formation of mammary 7,12-dimethylbenz[a]anthracene (DMBA)-DNA adducts and the initiation of DMBA-induced mammary tumorigenesis in female rats. Supplementation of diets for 2 weeks with rosemary extract (0.5% by wt) but not carnosol (1.0%) or ursolic acid (0.5%) resulted in a significant decrease in the in vivo formation of rat mammary DMBA-DNA adducts, compared to controls. When injected intraperitoneally (i.p.) for 5 days at 200 mg/kg body wt, rosemary and carnosol, but not ursolic acid, significantly inhibited mammary adduct formation by 44% and 40%, respectively, compared to controls. Injection of this dose of rosemary and carnosol was associated with a significant 74% and 65% decrease, respectively, in the number of DMBA-induced mammary adenocarcinomas per rat, compared to controls. Ursolic acid injection had no effect on mammary tumorigenesis. Therefore, carnosol is one rosemary constituent that can prevent DMBA-induced DNA damage and tumor formation in the rat mammary gland, and, thus, has potential for use as a breast cancer chemopreventative agent.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1996

Inhibition of 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumorigenesis and DMBA-DNA adduct formation by curcumin.

Curcumin, a constituent of the traditional Indian spice and medicine turmeric, was evaluated for its capacity to inhibit the mammary tumor initiating activity of 7,12-dimethylbenz[a]anthracene (DMBA) and the in vivo formation of mammary DMBA-DNA adducts in the female rat. Administration (i.p.) of curcumin at 100 mg/kg and 200 mg/kg doses was associated with a significant decrease in the number of palpable mammary tumors and mammary adenocarcinomas. The in vivo formation of mammary DMBA-DNA adducts also was depressed for animals administered curcumin doses from 50 mg/kg to 200 mg/kg. There was, however, no significant enhancement of liver glutathione-S-transferase activity following curcumin administration. Therefore, curcumin when administered i.p. can act as an effective chemopreventative agent towards DMBA-induced rat mammary tumorigenesis and mammary adduct formation.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1996

Detection of human viruses using primary cells immortalised by oncogene transfection, in comparison with primary cells and established cell lines.

No single established cell line was found capable of substituting for primary baboon kidney (PBK) or primary rhesus macacque kidney (PRK) cells for detection of human viruses. Although a panel of cell lines could detect influenza, parainfluenza, and enteroviruses, which are among the most important viruses encountered in routine diagnostic laboratories, the sensitivity of this panel was not as high as that of PBK or PRK cells. However, in a promising complementary approach, PBK and PRK cells have been immortalised successfully by oncogene transfection, and some of the resulting cell lines have retained susceptibility to human viruses, and may be suitable for routine diagnostic use.

Animals↗
PubMed1996

Prevalence of posttraumatic stress disorder, depression and anxiety in a community sample of New Zealand Vietnam War veterans.

OBJECTIVE: The aim of the paper is to investigate the prevalence of posttraumatic stress disorder (PTSD), depression and anxiety in a community sample of New Zealand Vietnam War veterans. METHOD: Data were collected as part of a national survey on the health and mental health of New Zealand Vietnam veterans. Five hundred and seventy-three randomly selected male Vietnam veterans participated in a postal survey. The questionnaire contained a number of demographic, biographical and psychological measures. RESULTS: The results revealed that 10% of the veterans could be classified as PTSD cases and that these veterans exhibited high levels of depression and anxiety. In PTSD cases, 15% were also classified with anxiety, 6% with depression, and 73% were classified with both anxiety and depression. In PTSD cases 94% were classified with more than one additional disorder. In non-PTSD cases 27% were classified with anxiety, and 1% with depression, while 12% experienced both anxiety and depression. CONCLUSIONS: The consequences of comorbidity for research and treatment are discussed and it is suggested that health professionals should be attentive to military experience as a predictor of these disorders.

Adult↗
PubMed1996

Interactions of orthopaedic metals with an immortalized rat osteoblast cell line.

The toxicity of nickel, chromium (III) and (VI), vanadium and aluminium was compared in an immortalized neonatal rat osteoblast cell line using the MTT assay and a novel index of cytotoxicity, alkaline phosphatase (ALP) activity. Where toxicity was observed, ALP was a consistently more sensitive detection method than the MTT assay. The toxicity of the metals increased in the order aluminium < chromium (III) < vanadium < nickel < chromium (VI). alpha-Tocopherol partially prevented nickel-induced toxicity (as assessed by ALP activity), whereas ascorbic acid had no protective effect. Chromium (VI) was more toxic than (III), with significant toxicity observed at 0.5 microM. It is thought that Cr (III) cannot readily penetrate the cell membrane and this may account for the lower toxicity. Aluminium had a stimulatory effect on cell growth at low concentrations (0.5 microM). The combination of immortalized rat osteoblasts and the ALP activity test provides a powerful tool for in vitro testing of orthopaedic materials.

Alkaline Phosphatase↗
PubMed1995

In vitro biocompatibility testing of polymers for orthopaedic implants using cultured fibroblasts and osteoblasts.

The biocompatibility of two polymers for potential use as orthopaedic implant materials in an isoelastic hip prosthesis was investigated. The interactions of polyetheretherketone (PEEK) and epoxy resin polymers (with and without carbon fibre reinforcement) with both fibroblasts and osteoblasts were tested using cell protein, intracellular reduced glutathione (GSH), leakage of lactate dehydrogenase and the MTT assay as indices of cellular cytotoxicity. The epoxy resin polymer was slightly cytotoxic to and inhibited the growth rate of fibroblasts (as assessed by total cell protein), and depleted GSH in both cell types. In contrast, the PEEK material did not display overt signs of cytotoxicity and, in fact, increased osteoblast cell protein content. This suggests that, of these two materials, PEEK would be the one of choice for development of an isoelastic implant and, in view of its stimulatory effect on osteoblast protein content, it may encourage ingrowth of bone around the prosthesis and thus minimize joint loosening.

3T3 Cells↗