An extrapolation of radionuclide retention data from mouse to man.
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Biomedical subjects
Publications and source records attributed to J M Thomas.
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Dimethylamine was formed in municipal sewage that was amended with creatinine, and trimethylamine was formed from choline or phosphatidylcholine. The maximum level of product that accumulated was equivalent to 0.13, 0.096, and 6.7% by weight, respectively, of the added chemicals. No dimethylamine or trimethylamine was detected in sewage amended with betaine, and no dimethylamine was found in sewage that was amended with methylamine and methionine.
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Mice immunologically deprived by thymectomy, cytosine arabinoside treatment and whole-body irradiation were used to study the growth of human tumours as xenografts. 10/16 melanoma biopsies, 4/13 ovarian carcinoma biopsies and 3/6 uterine cancer biopsies grew as serially transpllantable xenograft lines. The tumour lines were studied through serial passages by histology, histochemistry, electron microscopy, chromosome analysis, immune fluorescence, growth rate measurement and mitotic counts. They retained the characteristics of the tumours of origin, with the exception of loss of pigmentation in two melanomas, histological dedifferentiation in the uterine carcinomas, and increased mitotic frequency and growth rate in some melanomas. It was concluded that this type of animal preparation is as useful as alternative methods of immunological deprivation, or as athymic nude mice, for the growth of human tumour xenografts, at least for some experimental purposes.
Assessment of living related donor (LRD) survival statistics offers the opportunity to gauge the effects of recipient characteristics without the perturbations of viability, function, and antigen sharing that are inherent in cadaveric organ grafting. From January 1, 1969 to January 1, 1979, 167 LRD grafts were performed. Crude patient survival at one year is 92% and 84% at five years. Graft function at one year is 79%, and at five years it is 64%. One year patient survival has steadily improved: 1969-73: 83%, 1973-75: 91%, 1975-79: 98%. Graft survival improved during the first two periods and has since remained unchanged. HLA identical grafts showed the expected advantage compared with single haplotype grafts (93 vs 74%). Recipient age was without effect until 50 years, all younger subgroups having one-year patient survival of 92-95%, while those older than 50 had a one-year survival of 60%. Juvenile diabetes was associated with a one-year patient survival of 85% and graft survival of 74%. Glomerulonephritis did not affect early graft survival statistics, but there was a greater frequency of graft loss after 2.5 years, with function at five years of 51 versus 68% for recipients with all other diagnoses. Cadaveric graft statistics vary with recipient race when adjusted to exclude older patients and diabetics, white recipient one-year graft survival 74%, black 38%. No meaningful difference exists among LRD recipients as to graft function, but there is a trend toward improved black patient survival. This suggests that there is not an inherent difference in immune response to genetically similar grafts, but that the disparate results with racially mixed donor-recipient combinations rests with other factors.
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Two patients with acute osteomyelitis of the foot caused by mixed aerobic organisms are described; sources of infection and predisposing factors are discussed. Serratia marcescens was isolated in each instance. Antimicrobial therapy which did cover this organism failed; a change to treatment directed against it succeeded.
Studies using 2 different cloning assays to grow colonies and measure cell survival after treatment of human melanoma xenografts are reported and reviewed. Clonogenic cell survival curves were constructed for 5 melanoma xenografts with a clinically relevant range of drugs, using a soft agar diffusion chamber assay. Cells in colonies were similar to human melanoma cells in morphology, histochemistry, ultrastructure and antigenicity and xenograft tumours could be grown from the colonies. The survival curves were compatible with the known clinical patterns of response of malignant melanoma. The sensitivities of the xenografts correlated with the response of the same tumour in the patient when assessable. In 2 xenograft lines, it proved possible to grow colonies in the lungs of immune deprived mice. Studies of drug sensitivity using this lung colony assay agreed closely with the soft agar assay. It is concluded that the measurement of clonogenic cell survival can be a valuable endpoint in the assessment of the response of some xenograft tumours to therapy. The agreement between the 2 assays in which colonies were grown under widely different conditions decreases the likelihood that cells cloned represent an atypical subpopulation.
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A lung colony assay for clonogenic cells of human tumours in immune-suppressed mice is presented. The assay was used to determine the chemosensitivity of two malignant melanomas. One tumour reproduced the spectrum of chemosensitivity associated clinically with three cytotoxic agents. The other melanoma reproduced the chemosensitivity demonstrated in the patient from whom the tumour was biopsied. The importance of tumour size as a determinant of response to melphalan was investigated and the clonogenic cell survival in smaller tumours was found to be slightly but significantly lower than in larger tumours. An invesitgation of the importance of size as a determinant of response to radiotherapy demonstrated that 0.5-mm diameter tumour nodules were significantly more sensitive to irradiation than 2-cm diameter nodules. The hypoxic fraction of the larger tumours was 65 per cent, which is higher than that reported for experimental animal tumours or a human pancreatic tumour. This could be a factor in the clinical radioresistance of malignant melanoma.
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Immunological monitoring assays are of current value in the management of transplant recipients. These assays allow the pre-transplant quantitation of both donor-recipient histocompatibility and recipient "responder status." In addition, these assays allow the individualization of immunosuppression, permitting a more uniform and effective immunosuppression in the difficult early post-transplant period. Individualized modulation of recipient immune reactivity avoids the documented pitfalls of conventional stereotyped suppression and permits better abrogation of acute rejection responses and lesser rates of serious infections consequent to excessive immune suppression. Immunological monitoring of long-surviving recipients permits early detection of immune reactivity which often culminates in clinical chronic rejection, as well as permits the quantitation of immune facilitory mechanisms (reduced capability to generate anti-donor cytotoxic T cells and/or cellular suppressor mechanisms) that indicate an immune milieu conductive to long-term graft survival. The primary limitations to the more widespread use of immunological monitoring assays at present are the need for more consensual validations of the utility of these assays in different laboratories, more standardization and better controls of techniques, and improvement in the technology of the assays to permit rapid, reproducible, and accurate results with a lesser expenditure of laboratory time and money and greater economy in demands for recipient blood and donor tissue. Finally, immunological monitoring assays are notable for the great promise they offer in terms of immunobiological probes to dissect mechanisms of rejection, mechanisms of graft facilitation, mechanisms of action of immunosuppressive agents, and mechanisms by which empirical technology of recipient pre-treatment may condition the host to better acceptance of an incompatible graft.
Detailed necropsies were performed on 26 individuals who had died of disseminated breast carcinoma, to assess the frequency of spread to the lungs, pleura and pericardium, and to determine the likely routes of spread to these sites. Tumour was present in the lung parenchyma in 67% of the lungs examined, in the visceral pleura in 75% and the parietal pleura in 50%. Although even small deposits of pleural tumour were invariably visible to naked-eye examination, lung parenchymal involvement was almost invariably microscopic, despite its frequently extensive distribution. This finding draws attention to the difficulties of clinical staging with respect to lung metastases. Tumour in lymphatics predominated over that in blood vessels in both lung and pleura and this, together with the widespread mediastinal lymphnode infiltration found, suggests that the lymphatic system forms the dominant route of spread of breast carcinoma to the thorax. The possible role of mediastinal lymphatics in the dissemination of breast cancer to bone and liver is also discussed. Our findings suggests that the fields of adjuvant irradiation after primary surgery should include the mediastinal lymphatic network.
The survival time of skin allografts from RhLA-nonidentical, unrelated donors was increased from a mean of 7.69 days in controls (n = 20) to a mean of 32.53 days in rhesus monkeys (n = 21) receiving a total dose of 250 mg of rabbit anti-human thymocyte globulin (RATG) per kg. Immunological monitoring studies were performed on the peripheral blood of mononuclear cells in control and treated monkeys. After administration of RATG, the percentage of E rosette-forming cells (E-RFC) was greater than 90% depressed, and the percentage of EAC rosette-forming cells was increased 5-fold in the circulation. Significant numbers of RATG-coated cells were detected only during the first week after RATG treatment. The percentage of E-RFC recovered to pretreatment levels within 3 to 4 weeks after RATG treatment, although the absolute E-RFC count remained depressed for 2 to 3 months. In addition, the in vitro proliferative responsiveness to polyclonal mitogens and to allogeneic lymphocytes remained greater than 80% depressed for 2 to 3 months after RATG treatment. The incidence of post-transplant-specific antidonor lymphocyte-mediated cytotoxicity (LMC) was similar in controls (85%) and RATG-treated monkeys (81%), and the appearance of LMC was correlated (r = 0.711) with partial recovery of absolute ERFC counts in the treated group. The appearance and peak of LMC were delayed (P less than 0.001) in RATG-treated monkeys, but preceded and correlated with rejection. Prior to rejection, the serum of RATG-treated monkeys inhibited LMC. Antibody-dependent cellular cytotoxicity appeared after rejection in the majority of recipients in both groups. The appearance and peak of antibody-dependent cell-mediated cytotoxicity (ADCC) were delayed (P less than than 0.001) in RATG-treated monkeys, but did not exhibit a significant correlation with the time of rejection.
Spermine and spermidine in vitro are potent inhibitors of proliferation of phytohaemagglutinin-stimulated rat thymic lymphocytes, lymphoma cells and human lymphoblastic leukaemia cells, but only in media supplemented by foetal calf serum. This inhibition is shown to be due to a bovine plasma polyamine oxidase, with a high specificity for these polyamines. Spontaneously dividing lymphocytes are not subject to this inhibition. This, plus direct evidence from synchronous cultures of EB2 cells demonstrates that the inhibition is expressed in the late G1 or G1/S interface of the cell cycle. Putrescine was not an inhibitor in the presence of foetal calf serum but became so in the presence of human pregnancy serum, possibly due to the action of diamine oxidase.
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