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Biomedical subjects

T Hurst

Publications and source records attributed to T Hurst.

At least 55 records · Page 3Linked to original sources
PubMed1992

Insufflated halothane increases venous admixture less than nitroprusside in canine atelectasis.

Although it generally is agreed that halothane is a pulmonary vasodilator, its effect on venous admixture and hypoxic pulmonary vasoconstriction are more controversial. The effects of 2.4% halothane on pulmonary vascular resistance and venous admixture were investigated in an isolated canine lobe made atelectatic. Halothane was administered by three different methods: insufflation, addition to the pulmonary artery blood through a bubble deoxygenator, or a combination of both techniques. Pulmonary vascular resistance was divided into arterial, venous, and middle segmental resistance by a vascular occlusion technique. Middle resistance increased with 3% O2 ventilation (0.0238 +/- 0.0092 cmH2O.ml-1.min-1) or after production of atelectasis (0.0225 +/- 0.0074 cmH2O.ml-1.min-1), compared to control ventilation in the nonatelectatic lung 0.01 +/- 0.0067 cmH2O.ml-1.min-1). Halothane by any delivery method variably decreased middle resistance, with increasing potency from addition of halothane through the bubble deoxygenator (0.0118 +/- 0.0047 cmH2O.ml-1.min-1) to halothane insufflation (0.0072 +/- 0.0058 cmH2O.ml-1.min-1), and finally to a combination of both techniques (0.0026 +/- 0.0041 cmH2O.ml-1.min-1). In contrast to vascular resistance, venous admixture in the atelectatic (8 +/- 5%) and nonatelectatic lobes (7 +/- 4%) was increased with halothane insufflation (11 +/- 4%), addition of halothane through the bubble deoxygenator (26 +/- 16%), and a combination of both techniques (22 +/- 13%). Compared to intravenous nitroprusside (26 +/- 12%), halothane insufflation was less potent in increasing venous admixture when total pulmonary vascular resistances were of similar magnitude (0.0526 +/- 0.0112 and 0.0484 +/- 0.0088 cmH2O.ml-1.min-1, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Interactions of endotoxin, prostaglandins, and circulating cells upon pulmonary vascular resistance.

We studied the effects of endotoxin on total pulmonary vascular resistance (PVR) and hypoxic pulmonary vasoconstriction (HPV) in 24 isolated canine lung lobes. Group 1 lobes were perfused with whole blood; group 2 lobes with granulocyte/platelet depleted blood; group 3 lobes with whole blood and ibuprofen (12.5 mg/kg); group 4 lobes with granulocyte/platelet depleted blood and ibuprofen (12.5 mg/kg). All groups were otherwise treated in a similar manner and all received endotoxin (1 mg/kg) after baseline periods of normoxic and hypoxic ventilation. We found endotoxin increased PVR by 18% in group 1 and by 41% in group 2. Endotoxin administration inhibited HPV in group 1 but did not inhibit HPV in group 2. Ibuprofen administration prevented the increase in PVR and the loss of HPV caused by endotoxin. We conclude that endotoxin administration causes release of a lung-derived vasoconstrictor, but this is obscured by concomitant release of a granulocyte/platelet associated vasodilator. Our data also suggest that granulocytes or platelets may modulate baseline PVR by producing a nonprostaglandin vasodilator.

Animals↗
PubMed1992

Frequent loss of heterozygosity on chromosome 18 in ovarian adenocarcinoma which does not always include the DCC locus.

Inactivation of the DCC gene on chromosome 18 owing to loss of heterozygosity is a common finding in colorectal cancer. Because both ovarian and colon cancer are features of Lynch syndrome II, which has been provisionally mapped to chromosome 18, we hypothesized that loss of heterozygosity at the DCC locus may also occur in ovarian neoplasia. Fifty-two sporadic ovarian adenocarcinoma tumours were analysed by Southern blotting for loss of heterozygosity (LOH) at six chromosome 18 loci. Overall, tumours from 31 patients (60%) showed allelic loss at one or more of these loci. A similarly high level of LOH, 66%, was found at D17S5 (17p13.3). In contrast, moderate levels of LOH, of 31%, 39% and 33%, were found at MYCL1 (1p32), D1S57 (1p) and D14S20 (14q32.33) respectively. However, analysis of partial chromosome deletions in 11 patients indicates that the smallest region of overlap appears to exclude the DCC gene but to be between the D18S5 and D18S11 loci. This suggests that another locus, as well as or apart from DCC, may be involved.

Adenocarcinoma↗
PubMed1991

Detection of somatic DNA alterations in ovarian cancer by DNA fingerprint analysis.

The M13 phage single-strand DNA probe which recognizes highly polymorphic loci was applied to HinfI-digested DNA isolated from tumor tissue and peripheral leukocytes from 20 patients with ovarian cancer. An average of 22 minisatellite-containing DNA fragments were observed per individual. DNA fingerprint analysis revealed a change in restriction-fragment-length patterns in the DNA from 12 of 20 (60%) tumors compared with the patient's constitutional DNA. Deletion of one or more bands from the tumor was recognized by the probe in seven cases, new bands were identified in two, and intensity shift was demonstrated in eight. The authors conclude that the unmapped M13 minisatellite probe is a useful method for identifying cancer-related somatic DNA alterations.

Adult↗
PubMed1991

Cardiopulmonary effects of an anterior mediastinal mass in dogs anesthetized with halothane.

The authors evaluated the cardiac effects of an anterior mediastinal mass to better understand the acute cardiovascular collapse that has been associated with anesthesia and positive-pressure ventilation. An 800-ml-capacity intravenous bag was placed within the anterior mediastinum of 12 dogs to simulate a mediastinal mass. After mediastinal mass inflation, the authors measured cardiac index (CI) during periods of spontaneous ventilation (SV), SV with added continuous positive airway pressure (CPAP), intermittent positive-pressure ventilation (IPPV), and continuous positive-pressure ventilation (CPPV). Similar mediastinal mass volumes resulted in similar decreases in CI during SV (169 +/- 51 to 105 +/- 10 ml.kg-1.min-1); CPAP (175 +/- 48 to 122 +/- 34 ml.kg-1.min-1); IPPV (151 +/- 15 to 93 +/- 24 ml.kg-1.min-1); and CPPV (183 +/- 56 to 117 +/- 46 ml.kg-1.min-1). The authors also found, by linear regression, that the relationship between CI and mass volume was similar during both SV and IPPV. In six dogs, transesophageal echocardiography (TEE) was used to measure ventricular short axis dimensions. The authors found that mass inflation caused left ventricular end-diastolic dimension to decrease significantly by 6 +/- 2 mm and 4 +/- 1 mm during SV or IPPV, respectively, and right ventricle dimensions to increase by 2 +/- 1 mm and 3 +/- 1 mm during SV or IPPV, respectively. The changes in chamber dimensions were similar with either SV or IPPV. These results suggest that the decrease in CI associated with a mediastinal mass results from an increase in right ventricular afterload, causing right ventricular enlargement. Subsequently, there is impingement on the left ventricle volume because of interventricular interdependence.

Anesthesia, Inhalation↗
PubMed1991

Interactions of tumor necrosis factor and granulocytes with pulmonary vascular resistance.

We studied the effects of endotoxin and tumor necrosis factor (TNF-alpha) on hypoxic pulmonary vasoconstriction (HPV) in 12 isolated perfused canine lung lobes. Group 1 lobes were perfused with whole blood, and group 2 lobes were perfused with granulocyte-depleted blood. All lobes were sequentially ventilated with control (35% O2) and hypoxic (3% O2) gas mixtures before and after receiving TNF-alpha. After TNF-alpha, group 2 lost HPV but group 1 retained HPV. After TNF-alpha, total pulmonary vascular resistance decreased in group 2 from 0.085 +/- 0.013 to 0.049 +/- 0.016 cmH2O.ml-1.min (P less than 0.05). We conclude that TNF-alpha acts as a pulmonary vascular vasodilator. In lobes perfused with whole blood, HPV is paradoxically preserved. We speculate that in the presence of cells rich in TNF-alpha receptors, i.e., granulocytes, the circulating levels of TNF-alpha are depressed and full expression of its vascular effects is blunted.

Animals↗
PubMed1990

Relationships between resistance to cross-linking agents and glutathione metabolism, aldehyde dehydrogenase isozymes and adenovirus replication in human tumour cell lines.

In a panel of 10 human tumour cell lines with no prior exposure to drugs in vitro, resistance to cisplatin correlated with resistance to the nitrogen mustard derivatives Asta Z-7557 (mafosfamide, an activated form of cyclophosphamide), melphalan and chlorambucil. Simultaneous treatment with DL-buthionine-S,R-sulfoximine did not enhance the toxicity of cisplatin or Asta Z-7557, and no correlation was found between drug resistance and cellular levels of metallothioneins (as judged by sensitivity to cadmium chloride), glutathione (GSH), GSH reductase, GSH transferase, or gamma-glutamyltranspeptidase. The two cell lines most resistant to Asta Z-7557 expressed aldehyde dehydrogenase cytosolic isozyme 1, found also in normal ovary, but not isozyme 3. Treatment of resistant cells with cisplatin or Asta Z-7557 inhibited cellular DNA synthesis and replication of adenovirus 5 to a lesser extent than in sensitive cells. The virus could be directly inactivated by both drugs prior to infection, subsequent replication being inhibited to the same extent in sensitive and resistant cells. In contrast to Asta Z-7557 and other DNA damaging agents, cisplatin was much more toxic to adenovirus (D37 0.022-0.048 microM) than to cells (D37 0.25-2.5 microM). The adenovirus 5 mutant Ad5ts125 having a G----A substitution was even more sensitive to cisplatin (D37 7-8 nM) than wild type virus and another mutant. Cisplatin was detoxified less by sonicated resistant resistant cells than sensitive cells, as judged by inactivation of Ad5ts125 added to the reaction mixture. It can be inferred that (i) the major differences in cellular resistance to cisplatin and Asta Z-7557 in the present material did not involve enhanced DNA repair or protection by metallothioneins or GSH, but were associated with the ability to continue cellular and viral DNA synthesis during treatment, (ii) resistance was not associated with less template damage, and (iii) the adenovirus genome may be a suitable probe for predicting tumour resistance to cisplatin and for elucidating the DNA sequence dependence of cisplatin toxicity.

Adenoviruses, Human↗
PubMed1990

Halothane inhibits hypoxic pulmonary vasoconstriction in the presence of cyclooxygenase blockade.

Using an isolated lung the effects of halothane on hypoxic pulmonary vasoconstriction (HPV) were studied in the presence of cyclooxygenase blockade. The pulmonary vasculature can be divided into arterial, middle and venous segment resistances. Analysis of the vascular pressure-flow relationship further separates resistance into a flow dependent resistance (1/slope) and a zero-flow pressure intercept (PCRIT). We ventilated six lobes with control (35 per cent O2) and hypoxic (three per cent O2) gas mixtures with the addition of either 0, 0.5, 1.0, or 2.0 per cent halothane. We found that after addition of indomethacin (5 mg.kg-1), ventilation with three per cent O2 increased total resistance by 87 per cent over baseline with the increase primarily in the middle vascular segment. During normoxic ventilation PCRIT was 7.9 cm H2O and this increased significantly with hypoxia to 11.5 cm H2O). Only 2.0 per cent halothane blocked the increases in middle segment resistance and in PCRIT. We conclude that following cyclooxygenase blockade, halothane inhibits HPV by acting on middle segment vessels.

Animals↗
PubMed1990

Prognostic significance of tumor ploidy in patients with advanced ovarian carcinoma.

Fresh tumor specimens obtained from 53 consecutive patients with FIGO Stage III ovarian carcinoma were analyzed by flow cytometry. All patients were treated by a standard protocol: maximal tumor excision and cisplatin/cyclophosphamide/adriamycin chemotherapy, and followed-up for at least 24 months. Thirty-two percent of tumors were diploid (DNA index = 1.00) and 68% aneuploid (DNA index greater than 1.00), with more aneuploid tumors being associated with larger residual tumor and poor cellular differentiation. Patients with diploid tumors were found to survive significantly better than those with aneuploid tumors, in terms of survival rate (65% versus 31%), median survival time (33 months versus 13 months), and mean disease-free interval (17.8 months versus 8.2 months). The influence of the amount of residual tumor after primary surgery on survival was only significant in patients with diploid tumors. Our results support previous findings that tumor ploidy is an important prognostic indicator in ovarian cancer. We found aneuploidy to be associated with a poorer clinical outcome in Stage III disease, regardless of the amount of residual tumor after primary surgery and the degree of cellular differentiation.

Adenocarcinoma↗
PubMed1990

Evaluation of two new assays for tumor-associated antigens, CASA and OSA, found in the serum of patients with epithelial ovarian carcinoma--comparison with CA125.

Two new assays have been developed to measure tumor-associated antigens designated ovarian serum antigen (OSA) and cancer-associated serum antigen (CASA). Both assays are dual epitope ELISAs using the same capture monoclonal antibody (BC2); the second antibodies in the OSA and CASA assays are OM-1 and BC3, respectively. Using arbitrary cutoffs of 2.5 and 3.0 units/ml, 82 and 76% of 80 serum samples from ovarian cancer patients were positive for OSA and CASA, respectively, compared with 5 and 2.5% of samples from a control population of 40 women. A strong correlation was found between the two assays (r = 0.80, P less than 0.001). CA125 levels were obtained from 49 of the 80 samples; 82% of these samples were positive for CA125 (greater than 35 U/ml), 82% for OSA and 73% for CASA. Of the 9 samples negative for CA125, 3 were positive for OSA and 3 were positive for CASA. Serum OSA, CASA, and CA125 levels were determined in serial samples from 20 ovarian carcinoma patients throughout the course of their treatment. Clinical course was accurately reflected by CA125 levels in 85% of patients, by CASA in 65%, and by OSA in 75%. In 4 patients, a rise in CASA levels and, in 2 patients, a rise in OSA levels significantly predated rising CA125 levels to predict recurrence. Six of 7 serum samples obtained prior to positive second-look laparotomy were negative for CA125, while 4 were positive for OSA and 6 were positive for CASA. These results indicate that the OSA and CASA assays could be superior to CA125 for detection of small volume occult ovarian carcinoma.

Antigens, Neoplasm↗
PubMed1989

Clinical value of in vitro drug sensitivity testing based on short-term effects on DNA and RNA metabolism in ovarian cancer.

The hypothesis that in vitro chemosensitivity testing could predict clinical outcome was tested in women with ovarian cancer. Short-term drug effects on DNA and RNA metabolism (by inhibition of 3H-thymidine and 3H-uridine incorporation) were measured in primary cultures of tumor cells. In vitro inhibitory effects were found with the four drugs tested: cisplatin, adriamycin, melphalan, and methotrexate. From data based on impaired RNA and/or DNA metabolism (greater than or equal to 20% inhibition), correct prediction of "sensitivity" was 79% and that of "resistance" was 84%. An analysis of the predictive value of both assays, used singly or together, revealed a high specificity but moderate sensitivity; the best positive predictive value (94%) was obtained when both RNA and DNA metabolisms were impaired. Our results support the idea that two subsets of patients who are being considered for cytotoxic chemotherapy can be selected; those who may benefit from treatment and those who may not, regardless of the drugs tested in vitro or used in vivo.

Antineoplastic Agents↗
PubMed1989

In vitro sensitivity of ovarian cancer as determined by a short-term biochemical assay: comparison between primary and metastatic sites in the same patient.

Tumor sensitivity of ovarian cancer to cytotoxic drugs in vitro was examined between paired samples taken from the primary tumor and its metastases in the same patient. A 3-hour assay of primary cultures of the tumor was used to determine cellular response to the drugs by measurement of the incorporation of [3H]thymidine. Although there was variability, a reasonable correlation was found between the primary tumor and its different metastases, between the different metastases, and between the different tumor sites and cells from the peritoneal fluid. However, there was discordance between some of the pairings; the rate varied between 12 and 42% when the criterion was greater than 20% inhibition. Consistent drug sensitivity for all sites tested was present in only 8 of the 18 patients. Because of the discordance in some pairings, attempts should be made to sample all metastatic tumors, particularly those which cannot be removed completely by surgery. The discordant subgroup may be a source of false-negative and false-positive results of the assay.

Cisplatin↗
PubMed1988

Measurement of tumor cell activity in short-term primary culture. Clinical significance in women with ovarian cancer.

In vitro activity was determined by primary culture of tumor samples obtained at surgery from 63 patients with Stage III ovarian cancer. These patients had completed at least 24 months of follow-up. Proliferative activity was measured after 3-hour culture by 3H-thymidine incorporation and metabolic activity by 3H-uridine incorporation. A large range of individual tumor activity was found; no correlation was present between proliferative and metabolic activity in the same tumor, the distribution of tumors with high and low activity was similar between histologic types, and the activity was not higher in undifferentiated tumors. There was a strong association between in vitro activity of the tumor and patient outcome (both clinical status and survival). On the basis of in vitro activity, a subset of patients was identified within subgroups with known amount of residual tumor; proliferative activity was a better predictor of good outcome in patients with no residual disease, whereas metabolic activity was better in those with more extensive disease. In these patients, a tumor showing high proliferative and/or metabolic activity (greater than 5000 cpm) was associated with poor survival.

Cell Division↗
PubMed1988

Cisplatin chemotherapy of ovarian cancer: is short-term in vitro chemosensitivity predictive of long-term patient survival?

The in vitro response to cis-diamminodichloroplatinum (cisplatin) in primary culture of tumour samples obtained at surgery was studied in 61 patients with Stage III ovarian cancer who were also treated with cisplatin. The drug-induced inhibitory effect on cell proliferation (measured by 3H-thymidine incorporation) and metabolism (by 3H-uridine incorporation) was assessed over a 3-hour incubation. At greater than or equal to 20% level of inhibition, the true prediction rate of survival by the proliferative assay was 72% among those with 'sensitive' tumours and of mortality was 66% among those with 'resistant' tumours; at greater than or equal to 50% level of inhibition, the prediction rate of survival by the proliferative assay increased to 88% but that of mortality decreased to 58%. The results with the metabolic assay were comparatively lower at all levels. When the amount of residual disease was taken into the determination of mortality rate, significant differences were found between 'sensitive' and 'resistant' tumours as defined by the proliferative assay in patients with no/minimal disease. The pattern of survival differed significantly between 3 subgroups of tumours, as defined by their responses to cisplatin in the proliferative and metabolic assays -- the best survival was obtained in patients whose tumours were 'sensitive' in both assays.

Cisplatin↗
PubMed1987

Predictive value of serial CA 125 antigen levels in ovarian cancer evaluated by second-look laparotomy.

Serial serum CA 125 levels were measured before definitive surgery and during chemotherapy for 12 months or more in 64 patients with ovarian cancer. In the 42 patients who had a complete clinical remission and thus were subjected to a second-look laparotomy, an absence of disease was not predicted by patterns of CA 125 levels. Whilst rising or persistently high levels indicated the presence of tumour in 92% of patients, declining levels to negative predicted the absence of tumour in only 50%. Although the majority of these patients showed microscopic foci or a tumour mass less than 1 cm, 3 patients had a larger amount of disease. In the follow-up of 49 patients, the accuracy of prediction of a good outcome was better than that of a poor outcome on the basis of CA 125 patterns, with rates of 92% and 79%, respectively. Our findings indicate that CA 125 lacks sensitivity in detecting small tumour masses (less than 1 cm dia.) but rising or persistently high levels suggest a strong likelihood of a residual tumour to be found at a second-look laparotomy.

Antigens, Neoplasm↗
PubMed1986

Short-term in vitro chemosensitivity testing of tumours of the ovary, cervix and uterus. Measurement of DNA metabolism by 3H thymidine incorporation.

A 3-hour biochemical assay was chosen in the present prospective study to determine the in vitro chemosensitivity of tumours of the ovary, cervix and uterus. The basis of the assay was to determine the ability of a panel of cytotoxic drugs to inhibit the proliferative activity of tumour cells in culture, using 3H thymidine as a precursor of DNA synthesis. We found variability in the in vitro responses of individual tumours to the 4 drugs (cisplatin, adriamycin, melphalan, methotrexate). In ovarian cancer, cisplatin and adriamycin produced the best inhibitory effects; serous cystadenocarcinomas were most frequently inhibited by cisplatin, whilst undifferentiated carcinomas were more affected by adriamycin. Only 14% of tumours were sensitive to all 4 drugs. We found a good correlation between in vitro results and in vivo response in the medium term. For cisplatin, the predictive accuracy was 85% for 'sensitive' tumours and 72% for 'resistant' tumours. These findings should increase our confidence in the test as a new aid to planning of chemotherapeutic strategies.

Antineoplastic Agents↗