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Biomedical subjects

C MacDonald

Publications and source records attributed to C MacDonald.

At least 19 recordsLinked to original sources
PubMed2001

Inhibition by dietary dibenzoylmethane of mammary gland proliferation, formation of DMBA-DNA adducts in mammary glands, and mammary tumorigenesis in Sencar mice.

Dibenzoylmethane (DBM) is a minor constituent of licorice and a beta-diketone analogue of curcumin. Feeding 1% DBM in the diet to Sencar mice during both the initiation and the post-initiation periods strongly inhibited 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumor multiplicity and mammary tumor incidence by 97%. In further in vivo studies to elucidate the possible mechanisms of the inhibitory action of DBM, feeding the 1% DBM in the AIN-76A diet to immature Sencar mice for 4-5 weeks decreased the uterine wet weight by 43%, inhibited the proliferation rate of mammary gland epithelial cells by 53%, uterine epithelium by 23%, and uterine stroma by 77%, when mice were killed during the first estrus phase of estrous cycle. In addition, feeding 1% DBM in the diet to Sencar mice at 2 weeks before, during and 1 week after DMBA treatment (intubation of 1 mg DMBA per mouse once a week for 5 weeks) inhibited formation of total DMBA-DNA adducts in mammary glands by 72% using a post-32P-labeling assay. Thus, feeding 1% DBM diet to Sencar mice inhibited formation of DMBA-DNA adducts in mammary glands and lowered the proliferation rate of the mammary gland in vivo. These results may explain the strong inhibitory actions of dietary DBM on mammary carcinogenesis in mice.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2001

Immortalisation of primary cells.

Knowledge of the target cells is fundamental to maximise efficiency in attempts at immortalisation of specific cell types. It is also important to optimise the primary cell culture system to promote the survival of the target cell population. Other important factors that may influence the success in obtaining immortalised cells include the toxicity and efficiency of the immortalisation procedure. These can be assessed experimentally and if necessary appropriate techniques can be employed to purify the target cells. When cell lines have been established it is vital to assess them at an early stage for desired scientific and practical features as well as determining their stability and life-span. Furthermore, early characterisation of cell line authenticity (e.g. genetic characters, species of origin) and quality control testing will avoid wasted time and resources should contamination with micro-organisms or another cell line occur. Establishing a programme of immortalisation is a serious undertaking that should only be considered when there are no candidate continuous cell lines available. However, new approaches to modify the biology of cells to give extended life-span, whilst retaining the characteristics of differentiated cells in vivo, will hopefully provide valuable new substrates for in vitro toxicology.

Animal Testing Alternatives↗
PubMed2001

Validity of double- and single-leg vertical jumps as tests of leg extensor muscle function.

The purpose of this research was to determine if 5 weeks of resistance training for the shoulder and hip flexor muscles produces improvements in vertical jumping (VJ) performance. Twenty-eight men were assessed on tests of shoulder power, leg extensor muscle function, and VJ performance using jumps performed from a standing position, a 3-stride run-up, and double- and single-leg takeoffs. A shoulder and hip flexor training group (n = 14) improved significantly more than a nontraining control group (n = 12) in shoulder power and 2 VJ performance tests, but not in the tests of leg extensor muscle function. It was concluded that the arm swing and free-leg drive significantly influence VJ performance and, therefore, VJ tests are not valid for assessment of leg extensor muscle function.

Adolescent↗
PubMed2000

Inhibition of benzo[a]pyrene- and 1,6-dinitropyrene-DNA adduct formation in human mammary epithelial cells bydibenzoylmethane and sulforaphane.

Numerous phytochemicals have been examined for their capacity to act as cancer chemopreventive agents. Dibenzoylmethane, a minor constituent of licorice and a compound structurally-related to curcumin, recently was identified as an effective inhibitor of chemically-induced rat mammary DNA-adduct formation and tumorigenesis (Carcinogenesis 19(1998)1039-1043). The present studies were conducted to examine the capacity of dibenzoylmethane to inhibit the formation of DNA adducts following exposure to benzo[a]pyrene (BP) and 1,6-dinitropyrene (1,6-DNP), and to stimulate the expression of glutathione-S-transferase (GST) and NAD(P)H-quinone reductase (QR) proteins in the human mammary epithelial cell line MCF-10F. In addition, the efficacy of dibenzoylmethane as an enzyme inducer and adduct inhibitor was compared with that of sulforaphane, a potent inducer of phase II detoxification enzymes and inhibitor of chemically-induced rat mammary tumorigenesis. Dibenzoylmethane at concentrations from 0.1 M to 2.0 microM inhibited BP-DNA adduct formation by 63 to 81%. Likewise, sulforaphane inhibited BP-DNA adduct formation by 68 to 80% over the same concentration range. DNA adduct formation following exposure to 1,6-DNP was significantly inhibited by 46 to 61% due to dibenzoylmethane treatment (0.1 to 2.0 microM) and 30 to 56% due to sulforaphane treatment at the same concentrations. The expression of QR and GSTP1-1 proteins were increased by 3 to 4-fold and 3 to 5-fold, respectively, for MCF-10F cells treated with sulforaphane (0.5-2.0 microM). Dibenzoylmethane treatment at the same concentrations did not induce GSTP1-1 expression and significantly stimulated QR expression only at the 2.0 microM concentration. These data indicate that human mammary epithelial MCF-10F cells can convert BP and 1,6-DNP to DNA-binding forms, and that DNA adduct formation can be inhibited by the phytochemicals dibenzoylmethane and sulforaphane. The inhibition of BP-DNA and 1, 6-DNP adduct formation by sulforaphane was associated with increases in QR and GST protein expression. The mechanisms underlying the capacity of dibenzoylmethane to inhibit BP-DNA and 1,6-DNP-DNA adduct formation could not be explained by changes in QR or GST expression and remain to be determined. Together these data suggest that dibenzoylmethane and sulforaphane warrant continued evaluation as breast cancer chemopreventive agents.

Anticarcinogenic Agents↗
PubMed2000

Balloon angioplasty of native coarctation: clinical outcomes and predictors of success.

OBJECTIVES: We sought to investigate the clinical impact of balloon angioplasty for native coarctation of the aorta (CoA) and determine predictors of outcome. BACKGROUND: Balloon dilation of native CoA remains controversial and more information on its long-term impact is required. METHODS: Hemodynamic, angiographic and follow-up data on 69 children who underwent balloon angioplasty of native CoA between 1988 and 1996 were reviewed. Stretch, recoil and gain of CoA circumference and area were calculated and related to outcomes. RESULTS: Initial systolic gradients (mean +/- SD, 31+/-12 mm Hg) fell by -74+/-27% (p < 0.001), with an increase in mean CoA diameters of 128+/-128% in the left anterior oblique and 124+/-87% in the lateral views (p < 0.001). Two deaths occurred, one at the time of the procedure and one 23 months later, both as a result of an associated cardiomyopathy. Seven patients had residual gradients of >20 mm Hg. One patient developed an aneurysm, stable in follow-up, and four patients had mild dilation at the site of the angioplasty. Freedom from reintervention was 90% at one year and 87% at five years with follow-up ranging to 8.5 years. Factors significantly associated with decreased time to reintervention included: a higher gradient before dilation, a smaller percentage change in gradient after dilation, a small transverse arch and a greater stretch and gain, but not recoil. CONCLUSION: Balloon dilation is a safe and efficient treatment of native CoA in children. Greater stretch and gain are factors significantly associated with reintervention, possibly related to altered elastic properties and vessel scarring.

Angioplasty, Balloon↗
PubMed2000

De novo 46,XX,t(6;7)(q27;q11;23) associated with severe cardiovascular manifestations characteristic of supravalvular aortic stenosis and Williams syndrome.

Supravalvular aortic stenosis may present as an isolated finding or as part of Williams syndrome. Williams syndrome is a contiguous gene syndrome associated with neurodevelopmental and multisystemic manifestations caused by hemizygous deletion at 7q11.23. We report on the prenatal and histopathological findings in a patient with a chromosome translocation involving the Williams syndrome critical region. The initial abnormality on fetal ultrasound was hydrops fetalis detected at 30 weeks and echocardiography showed narrowing of the aorta and the pulmonary arteries. The baby died shortly after delivery and an autopsy revealed diffuse tubular thickening with luminal narrowing of the aorta, aortic branches, and the pulmonary arteries. Histopathology showed dysplasia of the media with reduced elastic content and "cartwheel" arrangement of collagen, elastic, and muscle fascicles. The karyotype was 46,XX,t(6;7)(q27;q11.23). Three signals were detected using the Oncor fluorescent in situ hybridization probe for elastin-Williams syndrome (WSCR) suggesting that the break in chromosome 7 is within the elastin-Williams gene. This patient is of special interest because of the prenatal presentation and the chromosomal translocation involving the elastin-Williams syndrome locus.

Aortic Valve Stenosis↗
PubMed2000

Manipulation of the phenotype of immortalised rat hepatocytes by different culture configurations and by dimethyl sulphoxide.

The liver-specific phenotype of immortalised rat hepatocytes is not irretrievably lost as they age in culture but can be manipulated by modifying the culture environment. Testosterone metabolism was used to investigate the profile of cytochrome P450 isoenzymes present in two immortalised cell lines, P9 and LQC, and in primary cultures of rat hepatocytes, cultured on collagen films, gels and double gel cultures (sandwich configuration). The extent of testosterone metabolism, and the range of metabolites produced, was increased in immortalised cells by the presence of collagen as a substratum film or gel but survival was poorer and the range of metabolites was reduced in sandwich culture. In contrast, testosterone metabolism was retained in primary hepatocytes in sandwich cultures at a higher level than in collagen film or gel cultures. Expression of alpha class glutathione-S-transferases (GSTs) increased and that of GSTP1 decreased (changes which indicate a recovery of normal liver GST phenotype) when the medium of immortalised cell cultures was supplemented with dimethyl sulphoxide (DMSO). DMSO also improved ethoxyresorufin O-deethylation (EROD) and testosterone metabolism in immortalised cells. It also markedly inhibited proliferation, DNA, RNA and protein synthesis. Maximal testosterone metabolism was observed in immortalised cells cultured on collagen gels in the presence of 1% (v/v) DMSO. Development of a protocol for treating immortalised liver cells cultured on collagen gels with DMSO to switch between proliferation and differentiation may provide a convenient system expressing the xenobiotic metabolising enzymes required for in vitro toxicity testing.

Animals↗
PubMed2000

Umbilical cord endothelial cells expressing large T antigen: comparison with primary cultures and effect of cell age.

A number of human endothelial cell lines from umbilical cord cells (HUVECs) have been generated by transfection with SV40 large T and small t antigen sequences. Comparison of these lines with primary cultures of HUVECs has been carried out by monitoring the expression of a number of endothelial cell markers with specific regard to cell age. The secreted levels of the protein plasminogen activator inhibitor (PAI) was found to be significantly reduced in SV40-transfected cells when compared to untransfected controls. Tissue plasminogen activator (tPA) and urokinase (uPA) levels were unchanged. As cells entered crisis, there was a rapid and significant increase in the levels of tPA, uPA, and PAl and this was observed for all clones screened. The endothelial cell marker von Willebrand Factor (vWF) was found intracellularly and was also secreted into the medium. The levels were not altered between transfected and untransfected cells. Angiotensin converting enzyme (ACE) activity was maintained in cell lines at levels found in nonimmortalized HUVECs. Both isoforms (alpha and beta) of IL-1 (interleukin-1) increased as cells approached crisis, and the presence of these cytokines may be responsible for the increased levels of tPA, PAI, and uPA. With one exception, the ability of the transfected cells to produce prostacyclin (PGI2) was lost by all clones.

Antigens, Polyomavirus Transforming↗
PubMed2000

Angiographic findings of persistent primitive hepatic venous plexus with underdevelopment of the infrahepatic inferior vena cava in pediatric patients.

OBJECTIVE: We describe the angiographic diagnosis and significance of persistence of the primitive hepatic venous plexus with underdevelopment of the infrahepatic inferior vena cava. CONCLUSION: We recommend that inferior venacavography be performed in routine assessment before surgery of patients with azygos or hemiazygos continuation of the inferior vena cava, in whom redirection of systemic venous blood to the pulmonary artery is contemplated.

Adolescent↗
PubMed1999

Determination of domperidone in human serum and human breast milk by high-performance liquid chromatography-electrospray mass spectrometry.

A sensitive and selective method for the determination of domperidone in human breast milk and serum has been developed. The same method may be successfully applied to both matrices to a lower limit of quantitation of 0.5 ng/ml. Samples are processed by a liquid-liquid extraction, and analyzed by LC-ESI-MS in positive ion mode. There was no interference, on the domperidone quantitation, from over 30 drugs. Samples from patients, at various times post-dose, were analyzed and a large number showed significant levels of domperidone in the breast milk as well as in the serum.

Antiemetics↗
PubMed1999

Posttraumatic stress disorder and interpersonal functioning in Vietnam War veterans: a mediational model.

This study examines the association between posttraumatic stress disorder (PTSD) and interpersonal functioning in a New Zealand community sample of 756 Vietnam War veterans. The results support previous research findings showing that PTSD adversely affects veterans' interpersonal relationships, family functioning, and marital/dyadic adjustment and show that the effects of PTSD on family functioning and dyadic adjustment are mediated by severity of interpersonal problems. It is suggested that higher levels of PTSD affect the ability of veterans to initiate and maintain interpersonal relationships and that these interpersonal problems are evident in poorer levels of family functioning and poorer dyadic adjustment.

Combat Disorders↗
PubMed1999

Modified continuous femoral three-in-one block for postoperative pain after total knee arthroplasty.

UNLABELLED: We prospectively studied the continuous "modified" femoral three-in-one block for postoperative pain after total knee arthroplasty. Sixty-two patients undergoing elective knee arthroplasty under spinal anesthesia with bupivacaine (B) and fentanyl were randomized to receive 0.2% B, 0.1% B, or placebo at 10 mL/h for 48 h after an initial bolus of 30 mL of the same solution via the femoral block catheter. The catheters were inserted under the fascia iliaca using a "double pop" technique and a peripheral nerve stimulator and were advanced 15-20 cm cranially. Venous plasma levels of B, desbutylbupivacaine, and 4-hydroxy B were measured daily for 3 days. All patients received patient-controlled analgesia with morphine and indomethacin suppositories for 48 h. Using computed tomography, we evaluated the catheter location for 20 patients. The catheter tips, located superior to the upper third of the sacroiliac joint in the psoas sheath, were labeled as ideally located. The group receiving 0.2% B had a larger block success rate, smaller morphine consumption in the immediate postoperative period (15 vs 22 mg) and during the first postoperative day (9 vs 18 mg), and achieved a greater range of motion in the immediate postoperative period (91 degrees +/- 10 degrees vs 80 degrees + 13 degrees ). Visual analog scores for pain during both rest and activity were low but similar between the groups. Forty percent of the catheters evaluated were ideally located. Ideal location and use of 0.2% B resulted in 100% success of blockade of all three nerves. The S1 root was blocked in up to 76% of patients. The plasma levels of B, 4-hydroxy B, and desbutylbupivacaine were below the toxic range during the infusion. We conclude that continuous fascia iliaca block with 0.2% B results in opioid-sparing and improved range of motion during the immediate postoperative period. Larger doses of bupivacaine may safely be used in the immediate postoperative period if needed. IMPLICATIONS: Continuous fascia iliaca block with 0.2% bupivacaine reduces opioid requirements and improves range of motion in the immediate postoperative period compared with a placebo and 0.1% bupivacaine. Plasma levels are below the toxic range with this dose. Only 40% of the catheters are positioned in the ideal location. With the smaller dose of bupivacaine, the success rate with this block is small.

Aged↗
PubMed1998

Myocardial bridging in children with hypertrophic cardiomyopathy--a risk factor for sudden death.

BACKGROUND: Myocardial bridging may cause compression of a coronary artery, and it has been suggested that myocardial ischemia may result. The clinical significance and prognostic value of myocardial bridging of the left anterior descending coronary artery in children with hypertrophic cardiomyopathy are unknown. We sought to determine the prevalence and clinical effects of myocardial bridging in children with hypertrophic cardiomyopathy who underwent cardiac catheterization. METHODS: Angiograms from 36 children with hypertrophic cardiomyopathy were reviewed to determine whether myocardial bridging was present and, if so, to assess the characteristics of systolic narrowing of the left anterior descending coronary artery caused by myocardial bridging and the duration of residual diastolic compression. We also reviewed clinical data on these patients. RESULTS: Myocardial bridging was present in 10 (28 percent) of the patients. Compression of the left anterior descending coronary artery persisted for a mean (+/-SD) of 50+/-17 percent of diastole. As compared with patients without bridging, patients with bridging had a greater incidence of chest pain (60 percent vs. 19 percent, P=0.04), cardiac arrest with subsequent resuscitation (50 percent vs. 4 percent, P=0.004), and ventricular tachycardia (80 percent vs. 8 percent, P<0.001). On average, the patients with bridging had a reduction in systolic blood pressure with exercise of 17+/-27 mm Hg, as compared with an elevation of 43+/-31 mm Hg in those without bridging (P<0.001). The patients with bridging also had greater ST-segment depression with exercise (median, 5 vs. 0 mm, P=0.004) and a shorter duration of exercise (mean, 6.6+/-2.4 vs. 9.1+/-1.4 minutes, P=0.008). The degree of dispersion of the QT interval corrected for heart rate on the electrocardiogram was greater in patients with bridging than in those without bridging (104+/-46 vs. 48+/-31 msec, P=0.002). Kaplan-Meier estimates of the proportions of patients who had not died or had cardiac arrest with subsequent resuscitation five years after the diagnosis of hypertrophic cardiomyopathy were 67 percent among patients with bridging and 94 percent among those without bridging (P=0.004). CONCLUSIONS: Myocardial bridging is associated with a poor outcome in children with hypertrophic cardiomyopathy. Our observations suggest that bridging is associated with myocardial ischemia

Adolescent↗
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↗