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Biomedical subjects

R J Parker

Publications and source records attributed to R J Parker.

At least 19 recordsLinked to original sources
PubMed2005

Hypothyroidism--an unexpected diagnosis following emergency treatment for heatstroke.

Heat illness is a common presentation to emergency departments during periods of high ambient temperatures. The thyroid axis is involved in thermoregulation, and its dysfunction dysfunction leads to loss of thermal homeostasis. Hyperthyroidism predisposes an individual to heat illness and hypothyroidism to hypothermia. For heat illness to be the presenting feature of hypothyroidism is very rare. In this report, a case is presented and a discussion of the thyroid axis, thermoregulation, its failure and possible mechanisms follows on.

Emergencies↗
PubMed2005

Pneumothorax following central venous catheterisation?

A chest radiograph performed to check the position of a central venous catheter in a patient appeared to show a pneumothorax. Intercostal drain insertion was prepared. Reassessment of the patient and a further radiograph confirmed that the "pneumothorax" was an artefact from a prominent skin fold due to the patient's body habitus.

Aged↗
PubMed2002

The role of the New Zealand forest industry injury surveillance system in a strategic ergonomics, safety and health research programme.

Forestry is among the most hazardous of all industry sectors internationally. In New Zealand, highest work-related morbidity and mortality incidence rates are found in the logging sector. The New Zealand Forest Industry Accident Reporting Scheme (ARS) is a forestry injury surveillance system maintained by the Centre for Human Factors and Ergonomics (COHFE). The paper highlights the pivotal role of an industry-wide injury surveillance system in an industry-specific strategic research programme, giving examples of the use of ARS data in identification of priority areas for ergonomics, safety and health research attention, for safety awareness feedback to the industry, and in the evaluation of injury countermeasures. An analysis of injury patterns and trends for one high-risk forestry operation (skid work) is presented to illustrate both the capabilities and limitations of the ARS in its present stage of development.

Accidents, Occupational↗
PubMed2002

Genetic diversity among Canadienne, Brown Swiss, Holstein, and Jersey cattle of Canada based on 15 bovine microsatellite markers.

The genetic diversity among Canadienne, Brown Swiss, Holstein, and Jersey cattle was estimated from relationships determined by genotyping 20 distantly related animals in each breed for 15 microsatellites located on separate chromosomes. The Canadienne, Holstein, and Jersey cattle had an average of six alleles per loci compared with five alleles for Brown Swiss. Furthermore, a number of potentially breed-specific alleles were identified. The allele size variance among breeds was similar, but varied considerably among loci. All of the loci studied were equally heterozygous, as were Brown Swiss, Canadienne, and Holstein cattle (0.68-0.69) whereas Jersey cattle showed lower heterozygosity (0.59). The within-breed estimates of genetic distance were greater than zero and significant. The genetic distance between Canadienne and Holstein (0.156), Brown Swiss (0.243), and Jersey (0.235) was negligible, suggesting close relationship. Concurrently, Brown Swiss and Holstein (0.211) cattle also demonstrated close relationship. In contrast, the Jersey breed was genetically distant from the Brown Swiss and Holstein cattle (0.427 and 0.320, respectively). The characterization of Canadienne cattle, as part of the genetic resource conservation effort currently underway in Canada, underscores the difficulty in scientifically establishing unique breeds. Therefore, the need to consider all relevant morphological characteristics and production performance in combination with available cultural, historical, pedigree, and molecular information becomes relevant when identifying breeds for conservation.

Alleles↗
PubMed2001

The encapsulation of ferrocyanide by copper(II) complexes of tripodal tetradentate ligands. Novel H-bonding networks incorporating heptanuclear and pentanuclear heterometallic assemblies.

Substitution of the weakly binding aqua ligand in [Cu(tren)OH2](2+) and [Cu(tpa)OH2](2+) (tren = tris(2-aminoethyl)amine; tpa = tris(2-pyridylmethyl)amine) by a cyano ligand on ferricyanide results in the assembly of heteropolynuclear cations around the cyanometalate core. In water, the reduction of the Fe(III) core to Fe(II) generates complexes that feature heteropolycations in which ferrocyanide is encapsulated by the Cu(II) moieties: [(Cu(tpa)CN)6Fe][ClO4]8-3H2O 1, [(Cu(tren)CN)6Fe][ClO4]8-10H2O 2, [(Cu(tren)CN)6Fe][Fe(CN)6]2[ClO4]2-15.8H2O 3, and [(Cu(tren)CN)6Fe][(Cu(tren)CN)4Fe(CN)2][Fe(CN)6)]4-6DMSO-21H2O 4. The formation of discrete molecules, in preference to extended networks or polymeric structures, has been encouraged through the use of branched tetradentate ligands in conjunction with copper(II), a metal center with the propensity to form five-coordinate complexes. Complex 3 crystallizes in the monoclinic space group P2(1)/c (#14) with a = 14.8674(10), b = 25.9587(10), c = 27.5617(10) A, beta = 100.8300(10) degrees, and Z = 4, and it is comprised of almost spherical heptanuclear cations, [(Cu(tren)CN)6Fe](8+), whose charge is balanced by two ferricyanide and two perchlorate counteranions. Complex 4 crystallizes in the triclinic space group P1 (# 1) with a = 14.8094(8), b = 17.3901(7), c = 21.1565(11) A, alpha = 110.750(3), beta = 90.206(2), gamma = 112.754(3) degrees, and Z = 1, and it is comprised of the heptanuclear [(Cu(tren)CN)6Fe](8+) cation and pentanuclear [(Cu(tren)CN)4Fe(CN)2](4+) cation, whose terminal cyano ligands are oriented trans to each other. The charge is balanced exclusively by ferricyanide counteranions. In both complexes, H-bonding interactions between hydrogens on primary amines of the tren ligand, terminal cyano groups of the ferricyanide counterions, and the solvent of crystallization generate intricate 3D H-bonding networks.

Journal Article↗
PubMed2001

Breast cancer survival and in vitro tumor response in the extreme drug resistance assay.

PURPOSE: To determine whether in vitro extreme drug resistance (EDR) assay results for patients with breast carcinoma were associated with clinical outcome after chemotherapy. PATIENTS AND METHODS: EDR assays were performed on tumor tissue obtained from 103 newly diagnosed breast cancer cases. EDR scores of 2 for low, 1 for intermediate, or 0 for extreme drug resistance were determined for each agent tested. In vitro EDR scores for 4-hydroxycyclophosphamide (4HC) and doxorubicin were summed for patients treated with AC, or for 4HC and 5-FU for patients treated with CMF. Treatment selection was blinded to assay results. RESULTS: Median time to progression was significantly shorter for patients with extreme or intermediate in vitro resistance (n = 55, 48 months), compared to patients with low in vitro resistance, (n = 41, 100 months, p = 0.022). Patients demonstrating extreme to intermediate drug resistance also showed poorer survival than the low resistance group (49.5 months vs. not reached, median follow-up 48 months, p =0.011). Summed EDR scores, stage, and number of lymph nodes were significantly associated with survival in univariate and multivariate analysis. Compared to EDR scores of 4, summed EDR scores of 0-1 and summed EDR scores of 2-3 were associated with a relative risk of death of 3.09 (95%, CI 1.05-9.06, Cox proportional hazards model, p = 0.040) and 2.35 (95%, CI 1.07-5.15, Cox proportional hazards model, p = 0.033), respectively. CONCLUSION: Extreme drug resistance testing identified patients with individual patterns of drug resistance prior to therapy. In this cohort of breast cancer patients treated with chemotherapy, summed EDR scores were significantly associated with time to tumor progression and overall survival. EDR results may offer a method for optimizing treatment selection.

Adult↗
PubMed2001

The prognostic value of tumor markers in patients with glioblastoma multiforme: analysis of 32 patients and review of the literature.

Although several studies have examined brain tumor markers for prognostic value, few investigations have stratified analysis based on specific histologic grade. The objective of this study was to evaluate a single histologic grade of glioma, the grade IV glioma or glioblastoma (World Health Organization Classification), with a comprehensive panel of tumor markers in an attempt to identify those with prognostic significance. Tumor samples from a cohort of patients with glioblastoma multiforme (n = 32) were examined for tumor markers, DNA analysis, and clinical variables in an attempt to determine a 'profile' for this tumor. We used univariate and multivariate statistical analysis to determine the prognostic value of tumor cell ploidy, percent S-phase, DNA index, p53, and Ki-67 labeling index, as well as the variables of gender, race, age, location of tumor, history of chemotherapy, and primary versus recurrent tumor. Two additional tumor markers, multidrug resistance gene 1 and glutathione-S-transferase subtype pi, were included in the sample testing, but were not analyzed statistically. Univariate analysis indicated that increasing age had a strong association with decreased survival. Female gender, increasing Ki-67, no chemotherapy before sample collection, and primary glioblastoma showed some association with decreased survival in the univariate model. The univariate results indicated that race, side of tumor, ploidy, S-phase, DNA index, and p53 had no prognostic value. Multivariate modeling demonstrated that age, gender, and Ki-67 were the strongest factors associated with survival. The relevant literature is reviewed.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Cardiovascular effects of buccal exposure to dermal nicotine patches in the dog: a comparative evaluation.

OBJECTIVE: Safety concerns have been raised over the possible effects of inappropriate exposure to transdermal nicotine patches. This study was initiated to determine whether placement of these products into the mouth could affect cardiovascular function. METHODS: In a series of 10 anesthetized beagle dogs, Nicoderm, Habitrol, ProStep I (Intact), ProStep D (Damaged) transdermal nicotine products or the Skoal Bandit smokeless tobacco plug were placed in the buccal cavity for 5 minutes. Systemic arterial blood pressure and the electrocardiogram were monitored for up to 90 minutes after exposure with blood samples at intervals during the first 10 minutes for plasma nicotine concentration. RESULTS: The systolic and diastolic arterial blood pressures and heart rate increased within 2 minutes of buccal exposure to either the intact or the damaged ProStep nicotine product. Ventricular arrhythmias were observed in 6 of 10 dogs exposed to the intact patch and 7 of 10 dogs exposed to the damaged patch during the period of maximal cardiovascular response. Modest increases in systemic blood pressure and heart rate were seen with the Nicoderm and Habitrol products but not with the Skoal Bandit. The increases in systemic arterial pressure and heart rate occurring after exposure to ProStep were significantly more severe than those observed after Nicoderm and Habitrol. Mean peak nicotine levels of 9.8 microg/mL (ProStep 1), 5.4 microg/mL (ProStep D), 3.4 microg/mL (Habitrol), 2.5 microg/mL (Nicoderm), and 0.12 microg/mL (Skoal Bandit) were detected within 2 to 10 minutes after buccal placement of the product. CONCLUSIONS: Certain transdermal nicotine patches, when applied to a nondermal site such as the buccal cavity for a short period (5 minutes) can rapidly provoke significant cardiovascular alterations (hypertension, tachycardia, and ventricular arrhythmias). The magnitude of the cardiovascular responses occurring after buccal exposure to a product such as ProStep could pose a risk to susceptible individuals.

Administration, Oral↗
PubMed1998

Melanin content and downregulation of glutathione S-transferase contribute to the action of L-buthionine-S-sulfoximine on human melanoma.

L-buthionine-S,R-sulfoximine (L-S,R-BSO) was enriched for the active L-buthionine-S-sulfoximine (L-S-BSO) diastereomer. Comparative analysis was performed to determine if this enriched form possessed an increased capacity to deplete glutathione (GSH), and to inhibit the proliferation of tumor cell lines and fresh human tumor samples. Increased activity was observed for the enriched preparation of L-S-BSO in direct proportion to its increased L-S-diastereomeric percentage. Significant antitumor activity towards melanoma, breast and ovarian carcinoma specimens was noted, with the greatest activity directed against malignant melanoma. The activity of BSO on melanoma specimens was found to be correlated with their melanin content, suggesting that free radicals generated during melanin synthesis may become cytotoxic after GSH-dependent scavenging has been eliminated by BSO treatment. The antimelanoma activity of melphalan and BCNU were found to be significantly enhanced in combination with L-S-BSO. With respect to the mechanism of L-S-BSO synergy with alkylators, L-S-BSO treatment of M14 and ZAZ human melanoma cell lines resulted in decreased GSH levels and glutathione S-transferase (GST) activity. Western and Northern blot analyses indicated that GST-mu was the predominant isozyme downregulated after L-S-BSO treatment. Both M14 and ZAZ cell lines selected for resistance to L-S-BSO also showed decreased levels of GST-mu expression. However, in drug free media GST enzyme activity returned to pre-treatment levels without altering the BSO-resistance status of the cell lines. We conclude that L-S-BSO may be an active agent in the treatment of melanoma, and that it may enhance alkylator activity on melanoma through depletion of GSH and down-regulation of GST expression. Purified L-S-BSO should be explored clinically as an active agent for the treatment of melanoma.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

Directions of orthodontic tooth movements associated with external apical root resorption of the maxillary central incisor.

External apical root resorption is a multifactorial problem encountered in all disciplines of dentistry, but it is most commonly seen in cases treated orthodontically. Specific tooth movements that are most likely to exacerbate external apical root resorption are poorly understood. Purpose of the present investigation was twofold: (1) to quantify apical and incisal movements of the maxillary central incisor in the sagittal and vertical planes from cephalograms and (2) to use stepwise multivariate linear regression analyses to see which tooth movements and skeletodental relationships are most predictive of external apical root resorption. The sample consisted of 110 adolescents with similar pretreatment malocclusions (Class I crowded or bimaxillary protrusive) and treatment planned similarly (extraction of four first premolars) by experienced private practitioners. Each of three practitioners used a different orthodontic appliance; the sample was divided proportionately into cases treated with Tweed standard edgewise technique, Begg lightwire technique, and Roth-prescription straightwire technique. Lateral cephalograms were analyzed at the start, middle, and end of treatment. There was no statistical difference in average external apical root resorption between sexes or among techniques. Measures of tooth movement were highly predictive, explaining up to 90% of the variation in root resorption. Apical and incisal vertical movements and increase in incisor proclination were the strong predictors of external apical root resorption for each regression model. Incisor intrusion with increase in lingual root torque together were the strongest predictors of external apical root resorption. In contrast, distal bodily retraction, extrusion, or lingual crown tipping had no discernible effect.

Adolescent↗
PubMed1998

Levels of multidrug resistance (MDR1) P-glycoprotein expression by human breast cancer correlate with in vitro resistance to taxol and doxorubicin.

To determine whether multidrug resistance (MDR1) P-glycoprotein (Pgp) expression correlated with clinical MDR1-related drug resistance, we established a protocol for quantitative measurement of Pgp expression and in vitro drug resistance in doxorubicin resistant MCF7 breast cancer cell lines and 359 freshly resected specimens of breast carcinoma. Pgp expression was detected with 4E3, UIC2, and JSB-1 monoclonal antibodies using flow cytometry and immunohistochemistry (IHC). Pgp function was determined using PSC833 in a drug resistance-reversal assay and with a three-dimensional agarose-based extreme drug resistance assay. MCF7 calibrator cell lines expressed Pgp, which was functional and in proportion to the degree of drug resistance. Flow cytometry, UIC2 shift assays, IHC scores, and determination of absorbance products by image analysis were all highly correlated (r > 0.9). Overall Pgp expression increased from 11% in untreated patients to 30% in patients who had previously received chemotherapy. Compared with Pgp-negative tumors, a significant increase in doxorubicin and Taxol resistance was seen for breast cancers that expressed Pgp, regardless of prior treatment. A strong correlation between the degree of Pgp expression and in vitro resistance to Taxol and doxorubicin (but not to 5-fluorouracil) was found when either IHC scores or image analysis-based methods were used to quantify Pgp expression (n = 185, P < 0.0001). The degree of Pgp expression strongly correlated with the degree of drug resistance in the clinical specimens studied. These data suggest that (a) Pgp contributes to clinical MDR1-related drug resistance, and (b) both intrinsic and acquired expression of Pgp in breast cancer may contribute in part to therapeutic failure and relapse.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Synergistic effect and possible mechanisms of tumor necrosis factor and cisplatin cytotoxicity under moderate hyperthermia against gastric cancer cells.

BACKGROUND: Peritoneal carcinomatosis is a difficult management problem, and intraperitoneal treatment approaches may provide an opportunity to intensify dose and minimize toxicity. The current experiments were conducted to characterize the cytotoxic effects of cisplatin (cDDP), tumor necrosis factor (TNF), and hyperthermia (HT) on a gastric cancer cell line in vitro under conditions achievable with intraperitoneal treatment. METHODS: Seoul National University gastric cancer cell line (SNU-5), a poorly differentiated gastric cancer cell line, was tested for sensitivity to various doses of cDDP, TNF, or combinations of the two at normothermia (37 degrees C) or HT (42.5 degrees C). The effect of TNF on cellular rates of cDDP accumulation, efflux, and cDDP-DNA adduct formation were evaluated using atomic absorbance spectrometry with Zeemen background correction. RESULTS: During a 2-h exposure to various doses of cDDP HT, we observed a supraadditive cytotoxicity of SNU-5 with 1 to 50 micrograms/ml of TNF (p2 = 0.0001). In the presence of the three-agent combination (HT, TNF, and cDDP) we observed statistically significant increases in total cellular accumulation of cisplatin (p2 = 0.016); a nonsignificant decrease in cellular efflux of drug (p2 = 0.098); and a 40% increase in persistent cisplatin DNA damage as measured by atomic absorption spectrophotometry (p2 = 0.06). These patterns were specifically not seen with the combinations of cDDP and HT, or cDDP and TNF. CONCLUSIONS: These data provide the experimental basis for the use of TNF and cDDP with HT in the treatment of gastric cancer and support the investigation of these agents in vivo in the regional treatment of peritoneal carcinomatosis.

Antineoplastic Agents↗
PubMed1997

Selective and synergistic activity of L-S,R-buthionine sulfoximine on malignant melanoma is accompanied by decreased expression of glutathione-S-transferase.

L-buthionine-S,R-sulfoximine (BSO) selectivley inhibits glutathione (GSH) synthesis. Malignant melanoma may be uniquely dependent on GSH and its linked enzymes, glutathione S-transferase (GST) and GSH-peroxidase, for metabolism of reactive orthoquinones and peroxides produced during melanin synthesis. We compared the in vitro effects of BSO on melanoma cell lines and fresh melanoma specimens (n = 118) with breast and ovarian cell lines and solid tumors (n = 244). IC50 values (microM) for BSO on melanoma, breast and ovarian tumor specimens were 1.9, 8.6, and 29, respectively. The IC90 for melanoma was 25.5 microM, a level 20-fold lower than steady state levels achieved clinically. The sensitivity of individual specimens of melanoma correlated with their melanin content (r = 0.63). BSO synergistically enhanced BCNU activity against melanoma cell lines and human tumors. We followed GSH levels, GST enzyme activity, GST isoenzyme profiles and mRNA levels after BSO. BSO (50 microM) treatment for 48 hr resulted in a 95% decrease in ZAZ and M14 melanoma cell line GSH levels, and a 60% decrease in GST enzyme activity. GST-mu protein and mRNA levels were significantly reduced in both cell lines. GST-pi expression was unaffected. These data suggest that BSO action on melanoma may be related to GSH depletion, diminishing the capacity to scavenge toxic metabolites produced during melanin synthesis. We report here for the first time that BSO enhancement of alkylator action may be related in part to down regulation of GST. BSO may be a clinically useful adjunct in the treatment of malignant melanoma.

Antimetabolites, Antineoplastic↗
PubMed1997

Determination of cerebral glucose transport and metabolic kinetics by dynamic MR spectroscopy.

A new in vivo nuclear magnetic resonance (NMR) spectroscopy method is introduced that dynamically measures cerebral utilization of magnetically labeled [1-13C]glucose from the change in total brain glucose signals on infusion. Kinetic equations are derived using a four-compartment model incorporating glucose transport and phosphorylation. Brain extract data show that the glucose 6-phosphate concentration is negligible relative to glucose, simplifying the kinetics to three compartments and allowing direct determination of the glucose-utilization half-life time [t1/2 = ln2/(k2 + k3)] from the time dependence of the NMR signal. Results on isofluorane (n = 5)- and halothane (n = 7)-anesthetized cats give a hyperglycemic t1/2 = 5.10 +/- 0.11 min-1 (SE). Using Michaelis-Menten kinetics and an assumed half-saturation constant Kt = 5 +/- 1 mM, we determined a maximal transport rate Tmax = 0.83 +/- 0.19 mumol.g-1.min-1, a cerebral metabolic rate of glucose CMRGlc = 0.22 +/- 0.03 mumol.g-1.min-1, and a normoglycemic cerebral influx rate CIRGlc = 0.37 +/- 0.05 mumol.g-1.min-1. Possible extension of this approach to positron emission tomography and proton NMR is discussed.

Animals↗
PubMed1997

The involvement of cytochrome P450 3A4 in the N-demethylation of L-alpha-acetylmethadol (LAAM), norLAAM, and methadone.

The N-demethylation of LAAM, norLAAM, and methadone has been investigated in human liver microsomes and microsomes containing cDNA-expressed human P450s. Gas chromatography/mass spectrometry methods allowed detection of norLAAM and dinorLAAM formation from LAAM, dinorLAAM formation from norLAAM, and EDDP and EMDP formation from methadone. The rates of N-demethylation varied 4- to 7-fold in microsomes from four different donors with activities for LAAM and norLAAM consistently greater (5- to 14-fold) than for methadone. The N-demethylation of LAAM, norLAAM, and methadone were significantly inhibited by ketoconazole. IC50s could be determined for ketoconazole inhibition of LAAM and norLAAM N-demethylation of 1.6 and 1.1 microM, respectively. The ability of ketoconazole to reduce methadone N-demethylation below 40% varied in regard to liver donor. No other P450-selective inhibitors reduced the average activities more than 43%. cDNA-expressed P450 3A4 N-demethylated LAAM, norLAAM, and methadone at greater rates than the other cDNA-expressed P450s studied (1A2, 2C9, 2D6, or 2E1). P450 3A N-demethylation of LAAM, norLAAM, and methadone exceeded the next most active P450, respectively, by at least 2.5, 9.6, and 13.4 times when expressed per milligram protein and by 18.2, 6.0, and 6.1 times when expressed per nanomole P450. These results suggest that P450 3A4 is the primary site of N-demethylation of LAAM, norLAAM, and methadone in human liver. Although other enzymes may also be capable of N-demethylating these compounds, identification of specific enzymes, except P450 3A4, has yet to be established. Knowledge of these enzymatic pathways is essential for assessment of the impact of metabolic drug-drug interactions on therapeutic success and/or adverse events.

Cytochrome P-450 CYP3A↗