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Biomedical subjects

R Brown

Publications and source records attributed to R Brown.

At least 523 records · Page 29Linked to original sources
PubMed1990

Response of mouse skin tumors to doxorubicin is dependent on carcinogen exposure.

To investigate the role of carcinogenesis in determining the response of tumors to anticancer drugs, we have used the in vivo model of multistage carcinogenesis of the mouse skin. Mice were initiated with Harvey murine sarcoma virus or single and repeated applications of dimethylbenzanthracene (DMBA). The papillomas which developed as a result of these initiation protocols were monitored quantitatively for their response to the anticancer drug doxorubicin. A single dose of 10 mg/kg doxorubicin is relatively inefficient at reducing the frequency of papillomas arising as a result of either single or repeated applications of the chemical DMBA. However, virally initiated papillomas are sensitive to the single 10-mg/kg dose of doxorubicin and are reduced in frequency by greater than 80%. Repeat treatment with four doses of 5 mg/kg doxorubicin over a 4-week period also reveals differences in the responses of the papillomas to doxorubicin. As with the single dose of doxorubicin, papillomas initiated with multiple applications of DMBA showed only a limited response to four 5-mg/kg doses of doxorubicin. In comparison both the virally initiated and the single DMBA initiated papillomas responded to the four doses of doxorubicin and are reduced in frequency by about 80%. These data show that the response of papillomas to doxorubicin is related to the initiating event. Papillomas derived by viral initiation are most sensitive to doxorubicin while increasing the level of exposure to the chemical carcinogen DMBA increases the proportion of papillomas which do not respond to treatment with doxorubicin. There was no obvious relationship between the method of initiation or the treatment of the mice with doxorubicin and the levels of P-glycoprotein expression observed in the papillomas. All the papillomas expressed detectable levels of P-glycoprotein approaching that of the multidrug resistant cell line, CHRC5.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1990

Hepatocellular carcinoma with cardiac cirrhosis.

Hepatocellular carcinoma is a recognized complication of hepatic cirrhosis, most commonly associated with alcohol excess, haemochromatosis and chronic hepatitis B infection. Long-standing hepatic venous congestion may cause cirrhosis. A search of the literature has not revealed a case of hepatocellular carcinoma complicating cardiac cirrhosis. A case is described and the association is discussed.

Carcinoma, Hepatocellular↗
PubMed1990

Construction and hormone regulation of a novel retroviral vector.

We report the analysis of a self-inactivating retroviral vector, constructed to allow inducible gene expression of inserted sequences from the mouse mammary tumour virus hormonal response element. The cloning strategy has been designed to allow for ease of insertion of the genes of interest. The vector contains the aph gene, allowing geneticin-resistance selection in mammalian cells. We have characterised dexamethasone (Dex)-induced increase in gene expression using the reporter gene encoding chloramphenicol acetyltransferase (CAT) inserted into the retroviral vector. We observe low basal levels of CAT activity in infected cells which is increased up to 50-fold by induction with Dex. The induction of pooled clones is 13.3-fold. Variation in Dex-induced CAT activity is observed in independently infected clones, which is not explained by proviral copy number.

Animals↗
PubMed1990

Bone marrow transplantation for childhood acute lymphoblastic leukaemia after marrow relapse.

Children with acute lymphoblastic leukaemia in whom relapse in bone marrow occurs have a poor outlook when treated with chemotherapy alone. Twenty-seven patients with childhood acute lymphoblastic leukaemia were treated for marrow relapse with high-dose chemotherapy with or without total body irradiation followed by bone marrow transplantation (BMT). Twenty patients received allogeneic marrow from partially or completely matched histocompatible donors. In this group, nine patients (45%) were free of disease with a median follow-up of 57 months (range, 22 to 126 months) after transplantation, four (20%) died from interstitial pneumonitis and seven (35%) died after a further relapse. Seven patients received autologous marrow collected while they were in remission. In this group, one patient died from infection and six died after a further relapse. We conclude that allogeneic BMT is more effective than autologous transplantation and results in long-term disease-free survival in a significant number of patients. New methods are needed to eradicate residual disease in the patient and to purge marrow ex vivo.

Actuarial Analysis↗
PubMed1990

Familial adult T-cell leukemia/lymphoma.

Clinical and laboratory data are described for two siblings who both developed adult T-cell leukemia/lymphoma resulting from infection by human T lymphotropic virus type I (HTLV-I). These findings suggest that genetic factors or virus-specific factors may determine which HTLV-I-infected individuals will develop leukemia.

Adult↗
PubMed1990

Decreased L system amino acid transport and decreased gamma-glutamyl transpeptidase are independent processes in human chronic lymphocytic leukemia B-lymphocytes.

The L system of amino acid transport is markedly diminished in chronic lymphocytic leukemia (CLL) B-lymphocytes, with a maximal velocity less than 15% that of normal B-lymphocytes. Another membrane-associated function, the activity of the ectoenzyme, gamma-glutamyl transpeptidase (GGT), is diminished in CLL B-cells to 30% that of normal B-cells. In addition to its transpeptidase activity, a role for GGT has been postulated in the transport of amino acids. In the present report, the possible relationship of these two physiologic functions CLL B-cells was studied. The L system transport defect in CLL is restored by phorbol ester-induced cell maturation; following incubation with 0.15 microM tetradecanoyl phorbol acetate (TPA) for 17 hours, the L system initial velocity showed a 20-fold increase. In contrast, there was no significant effect on GGT activity with cell maturation. Furthermore, an antibody which diminished GGT activity by 50% in lymphoid cells did not inhibit L system transport. Thus, the impaired L system amino acid transport and GGT activity appear to be independent processes in CLL B-cells.

Amino Acids↗
PubMed1990

Heterotopic gastrointestinal cyst of the tongue.

A 6.5-month-old white male presented with a cyst involving the left posterior half of his tongue which partially compromised his airway. A computed tomography scan revealed that the mass also involved the left floor of the mouth. Surgical excision of the mass was performed, and the mass was demonstrated to be a gastrointestinal heterotopic cyst. The clinical and pathological features of this rare lesion are presented and the pathogenesis is discussed.

Choristoma↗
PubMed1990

Investigations into the route of uptake and pharmacokinetics of intraperitoneally-administered monoclonal antibodies: I. Transdiaphragmatic blockade of the terminal lymphatics in the rat.

Recent studies on the intraperitoneal administration of radiolabeled monoclonal antibodies indicate that the diaphragm and, in particular, the lymphatics associated with the diaphragm are more involved in the transport of such high-molecular-mass moieties than was earlier suspected. The current study examines the role of the diaphragm in the i.p. transport of an IgG2a murine monoclonal antibody, 5G6.4, by observing the effect on the absorption of the antibody produced when the diaphragm has been scarred. Normal, sham-operated, and diaphragmatically scarred (abrasions made with 600-grade sandpaper) female Sprague Dawley rats (150-250 g) were administered intraperitoneal injections of 125labeled 5G6.4 in a volume of 2.0 cm3. Approximately 5 micrograms antibody protein was administered in the individual 19-microCi injections per rat. Scarring was effective in partially blocking the amount of labeled antibody that crossed the diaphragm. Mean diaphragm levels (% injected dose/g) of 125I-labeled 5G6.4 from the scarred group were 16.8% lower than values from the sham-operated rats and 37.2% lower than those from the control rats. The blockade was effective in slowing the appearance of the labeled antibody in the systemic circulation. The half-time to absorption was significantly prolonged in the scarred group; mean t1/2 absorption values of 2.5 h for the control group, 5.3 h for the sham-operated group, and 9.6 h for the diaphragmatically blocked group were recorded. Scarring the diaphragm reduced the mean maximum blood concentration by 27.6% over the control group and 23.9% over the sham-operated group. The mean time to maximum blood concentration was lengthened by 93..0% over the control group and 35.3% over the sham-operated group due as a result of scarification. Presumably this impedence to absorption would increase the time that the radiolabeled antibody bathed the peritoneal space. The scarred group also had the largest "system mean residence time" (162.5 h) compared to the sham-operated (147.9 h) and control (118.7 h) groups. These values further verify the effect of surgery on the kinetics of the i.p. administered radiolabeled monoclonals. This work demonstrates that scarifying the diaphragm does alter the kinetics of the i.p. administered monoclonal antibodies and supports the concept that transdiaphragmatic lymphatic absorption is an important route of antibody clearance from the peritoneal cavity.

Absorption↗
PubMed1990

Are antibiotic effects on sleep behavior in the rat due to modulation of gut bacteria?

The sleep-inducing substance Factor S (FS) is unique among candidate sleep molecules because of its bacterial origin. FS is derived from the bacterial cell wall and accumulates in the brain and body fluids of sleep-deprived animals including man. Exogenous administration of FS and related muramyl peptides results in an increase in slow-wave sleep (SWS). To test the possibility that gastrointestinal bacteria are a source of FS, rats were placed on an antibiotic regimen (neomycin and metronidazole in drinking water) and sleep measures taken after one week. There was a significant reduction in SWS in the first three hours of the lights-on period as well as an increase in sleep latency. No other sleep parameters, including Rapid Eye Movement (REM) sleep measures, were affected, suggesting that there was a specific SWS effect due to bacterial reduction. Possible toxic effects of the antibiotic treatment were unlikely factors in SWS reduction due to the stability of other sleep measures such as number of episodes of SWS and REM, total sleep time and REM latency. Oral administration of live E. coli to rats did not affect any sleep measures. It appears that FS may be specifically involved in the early sleep period where it promotes sleep onset and SWS generation.

Animals↗
PubMed1990

'Air hunger' from increased PCO2 persists after complete neuromuscular block in humans.

The tolerance of totally curarized subjects for prolonged breath hold is viewed by many as evidence that respiratory muscle contraction is essential to generate the sensation of breathlessness. Although conflicting evidence exists, none of it was obtained during total neuromuscular block. We completely paralyzed four normal, unsedated subjects with vecuronium (a non-depolarizing neuromuscular blocker). Subjects were mechanically ventilated with hyperoxic gas mixtures at fixed rate and tidal volume. End-expiratory PCO2 (PETCO2) was varied surreptitiously by changing inspired PCO2. Subjects rated their respiratory discomfort or 'air hunger' every 45 sec. At low PETCO2 (median 35 Torr) they felt little or no air hunger. When PETCO2 was raised (median 44 Torr) all subjects reported severe air hunger. They had reported the same degree of air hunger at essentially the same PETCO2 before paralysis. When questioned afterwards all subjects said the sensation could be described by the terms 'air hunger', 'urge to breathe', and 'shortness of breath', and that is was like breath holding. They reported no fundamental difference in the sensation before and after paralysis. We conclude that respiratory muscle contraction is not important in the genesis of air hunger evoked by hypercapnia.

Adult↗
PubMed1990

Large scale optimization of beam weights under dose-volume restrictions.

The problem of choosing weights for beams in a multifield plan which maximizes tumor dose under conditions that recognize the volume dependence of organ tolerance to radiation is considered, and its solution described. Structures are modelled as collections of discrete points, and the weighting problem described as a combinatorial linear program (LP). The combinatorial LP is solved as a mixed 0/1 integer program with appropriate restrictions on normal tissue dose. The method is illustrated through the assignment of weights to a set of 10 beams incident on a pelvic target. Dose-volume restrictions are placed on surrounding bowel, bladder, and rectum, and a limit placed on tumor dose inhomogeneity. Different tolerance restrictions are examined, so that the sensitivity of the target dose to changes in the normal tissue constraints may be explored. It is shown that the distributions obtained satisfy the posed constraints. The technique permits formal solution of the optimization problem, in a time short enough to meet the needs of treatment planners.

Humans↗
PubMed1990

Microsurgical revascularization of ischemic rat femoral heads.

To demonstrate whether revascularization could be surgically induced in avascular bone the femoral heads of female albino rats were excised and drilled through and through. The femoral heads were then placed in the opposite thigh and by use of microvascular techniques the femoral artery was divided and lengthened with a 1 cm artery or vein graft, and reanastomosed after passing one end through the drilled hole in the transplanted femoral head. Arterial blood flowed through the graft within the drilled femoral head on its way to its normal distribution down the leg. Technetium 99m MDP methylene diphosphate, tetracycline labeling, latex injection, and histologic review were used to demonstrate new vessel growth. All grafts patent at the end of the experiment were associated with tetracycline labeling, positive technetium 99m methylene diphosphate counts and latex-filled vessels in the matrix of the femoral heads. Histologically the vascularized femoral heads showed evidence of neovascularization and new bone formation.

Anastomosis, Surgical↗
PubMed1990

Expression of mdr1 and gst-pi in human breast tumours: comparison to in vitro chemosensitivity.

Increased expression of the mdr1 gene, encoding the 175 kDa P-glycoprotein, and the gst-pi gene, encoding the anionic isozyme of glutathione S-transferase (GST), have previously been detected in continuous human breast cancer cell lines selected in vitro for resistance to doxorubicin. In this present study we have measured RNA levels of mdr1 and gst-pi in primary human breast tumour biopsies prior to chemotherapy and from tumours which have different inherent responses to doxorubicin treatment, including colon, head and neck squamous cell carcinomas and myeloid leukaemias. Detectable levels of mdr1 mRNA was observed in 25 out of 49 breast tumours, with up to a 100-fold range in expression. A narrower range of gst-pi expression has also been observed in these tumours. Chemosensitivity of cells grown in short-term culture from some of the breast tumours has been measured by an in vitro colony forming assay in the presence of doxorubicin. Comparison of the dose of doxorubicin causing 50% inhibition of growth (ID50) with RNA levels showed that the tumours with high mdr1 expression had high ID50, while the more sensitive explants had low mdr1 expression. These results support a role for mdr1 gene expression in determining the response of human breast cancer cells to chemotherapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1990

Retrovirus mediated transfer and expression of GM-CSF in haematopoietic cells.

Two retrovirus vectors were compared for their ability to express granulocyte-macrophage colony stimulating factor (GM-CSF) in a haematopoietic cell line, FDCP1, which is dependent on GM-CSF for survival. Both a MoMLV-based vector pVneoGM, and a MPSV-based vector, M3neoGM, were found to be capable of transmitting and expressing both GM-CSF and neomycin sequences in the myeloid FDCP1 cell line. Our results also demonstrate that pVneoGM is more efficient at generating GM-CSF independent colonies than M3neoGM. Analysis of cell lines derived after infection confirmed pVneoGM expressed higher levels of GM-CSF. Cell lines generated by infection with pVneoGM responded to levels of exogenous recombinant GM-CSF which did not stimulate growth of the parental cell line, suggesting autocrine stimulation may convey a proliferative advantage under sub-optimal growth conditions. Finally the parental vectors pVneo and M3neo were shown to be capable of expressing the neomycin gene in both murine haematopoietic progenitor and stem cells.

Animals↗
PubMed1990

Speech breathing in individuals with cervical spinal cord injury.

Ten men with cervical spinal cord injury were studied using magnetometers to record surface motions of the chest wall during speech breathing. Individual speech breathing patterns reflected inspiratory and expiratory muscular sparing. Subjects compensated for expiratory muscle impairment by speaking at large lung volumes, presumably to take advantage of the higher recoil pressures available at those volumes. Similarly, subjects used larger lung volumes to increase loudness. Abnormal chest wall behavior was attributed in large part to loss of abdominal muscle function. Because of this, speech breathing in individuals with cervical spinal cord injury may be improved by the use of abdominal binders.

Adult↗