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T D Anderson

Publications and source records attributed to T D Anderson.

At least 19 recordsLinked to original sources
PubMed1992

Effect of chronic interleukin-2 treatment on RES phagocytic activity in the rat.

The effect of chronic interleukin-2 (IL-2) injection upon reticuloendothelial system (RES) function in the rat has been determined. Seven-day treatments with two doses of human recombinant IL-2 resulted in a dramatic reduction in the phagocytic uptake of the liver and spleen, while increasing the weight of both organs. There were dramatic histological changes in the intestine, liver and spleen as well. These results suggest that the chronic use of IL-2 can result in hepatic dysfunction, which is associated with altered RES phagocytic function.

Animals↗
PubMed1992

Hematological effects of 2',3'-dideoxycytidine in rabbits.

The antiviral nucleoside analogue 2',3'-dideoxycytidine (ddC) is a DNA chain terminator and/or inhibitor of human immunodeficiency virus (HIV) reverse transcriptase. We evaluated the effects of ddC in 36 New Zealand white rabbits. Three/sex were assigned to a control group and 5 treatment groups (10-250 mg/kg/day) for 13 or 18 weeks. Blood samples were taken 1 week prior to treatment and weekly thereafter to termination with the exception of the 2 highest dose groups, where blood sample collection was terminated at week 13. Selected hematological analytes were measured weekly with the exception of prothrombin time (PT) and activated partial thromboplastin time (APTT). PT and APTT and selected biochemical analytes were measured prior to treatment, at 7 weeks, and after 13 weeks of treatment. All rabbits were necropsied. Giemsa and hematoxylin and eosin sections were prepared from methacrylate-embedded marrow. Hematological effects included decreases in red blood cell count, hemoglobin, hematocrit, and white blood cell count and increases in mean corpuscular volume and red cell distribution width. Platelets, platelet volume, PT, APTT, and mean corpuscular hemoglobin concentration values were variable or unchanged. Effects were dose-related, most were seen at 1 week, and they persisted to term. Bone marrow histopathologic changes included megalocytosis, erythroid hypoplasia, bizarre erythroid nuclear morphology, nuclear-cytoplasmic asynchrony, and increased mitotic figures. Lymphopenia caused by ddC plateaued at 2 weeks and persisted until termination. Heteropenia (neutropenia) was sporadic. Biochemical values for serum analytes were unchanged by treatment. The principal hematological effect of ddC upon the erythron was characterized as a nonregenerative macrocytic anemia with erythroid hypoplasia and megaloblastic erythropoiesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Peripheral neuropathy induced by 2',3'-dideoxycytidine. A rabbit model of 2',3'-dideoxycytidine neurotoxicity.

The nucleoside analog 2',3'-dideoxycytidine (ddC) is a potent inhibitor of the reverse transcriptase of human immunodeficiency virus and a DNA chain terminator. In clinical trials in patients with acquired immunodeficiency syndrome, ddC treatment has been associated with a dose-limiting and dose-dependent, painful, sensorimotor peripheral neuropathy. In search of an animal model for ddC-induced neurotoxicity we studied 36 New Zealand White rabbits (3 males/3 females/group) given 0, 10, 50, 100, 150, or 250 mg/kg/day of ddC, by oral intubation, for 13 or 18 weeks. Rabbits in the 150 and 250 mg/kg/day groups were sacrificed at 13 weeks because of hematopoietic toxicity. After 16 weeks, rabbits in the 50 and 100 mg/kg/day groups showed hindlimb paresis and/or gait abnormalities. Nerve conduction velocities and amplitudes in the 100 mg/kg/day rabbits were reduced by 30 to 50%. The most prominent pathologic changes in peripheral nerve and ventral roots of ddC-treated rabbits were (a) myelin splitting and intramyelinic edema, (b) demyelination and remyelination of axons, and (c) axonal loss. Treatment-related histologic lesions were not observed in spinal cord, brain, or retina. The pathology in these ddC-treated rabbits is consistent with a peripheral myelinopathy and axonopathy. This represents the first clinical, electrophysiologic, and pathologic description of an animal model of a peripheral neuropathy induced by a nucleoside analog.

Administration, Oral↗
PubMed1992

Ultrastructure of peripheral neuropathy induced in rabbits by 2',3'-dideoxycytidine.

The nucleoside analogue, 2',3'-dideoxycytidine (ddC), an inhibitor of human immunodeficiency virus reverse transcriptase, mediates virologic and immunologic improvements in acquired immunodeficiency syndrome patients. However, in clinical studies ddC treatment is associated with a dose-limiting peripheral neuropathy. The purpose of this study was to characterize the ultrastructural features of the peripheral neuropathy induced in rabbits. Rabbits received 0, 10, 50, or 100 mg/kg/day of ddC for 18 weeks. A prominent ultrastructural change induced by ddC in sciatic nerve and ventral root was separation of myelin lamellae at the intraperiod line and vacuolation and fragmentation of myelin sheaths. Many demyelinated and remyelinated axons were observed. Although pathologic alterations in Schwann cells were evident by the presence of lipid droplets and myelin figures, their formation was not considered a primary event. Axons containing abnormal cytoplasmic components were occasionally observed. Other changes included redundance of Schwann cell basal lamina and the presence of lipid droplets and/or myelin figures within endoneurial fibroblasts and macrophages. The results of this study indicate that ddC induces a myelinopathy in rabbits characterized by myelin splitting and intramyelinic edema and an axonopathy that may be secondary to the myelin changes.

Animals↗
PubMed1991

Differential release of active proteinase inhibitors by two rat mammary adenocarcinoma variants possessing different metastatic potentials.

The ability of tumor cells to express elevated levels of proteinases capable of degrading tissue matrix and basement membrane components in vitro has been correlated to their invasive and metastatic potential. Many in vitro invasion assays have been performed either in the presence of serum or with tumor cells that had been previously grown in serum. Since serum contains large amounts of active proteinase inhibitors, their presence could complicate interpretations. We have, therefore, attempted to measure the amounts of serine proteinase inhibitors released into culture medium by two rat mammary adenocarcinoma metastatic variants selected in vitro for serum-independent growth and differing in their in vivo metastatic behavior. Concentrated spent media (CSM) derived from cultures of poorly metastatic MTLn2(T42D) and highly metastatic MTLn3(T17D) tumor cells, grown in the presence and absence of fetal bovine serum (FBS) for 20-24 h, were compared for the presence of serine proteinase inhibitors capable of inactivating alpha-chymotrypsin. Our results show that when MTLn2(T42D) and MTLn3(T17D) tumor cells were exposed to FBS, the CSM of MTLn2(T42D) exhibited nearly 5-fold greater amounts of active proteinase inhibitors than that of MTLn3(T17D). The amount of proteinase inhibitory activity detected in the CSM of tumor cells not exposed to FBS was not eliminated but declined by 82% and 37% for MTLn2(T42D) and MTLn3(T17D), respectively. Analysis for enzyme-inhibitor (E-I) complex formation by nonreducing sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by autoradiography confirmed the kinetic results and revealed that the major inhibitor present in CSM/FBS of both variants forms a heat- and sodium dodecyl sulfate-stable E-I complex with an apparent molecular weight of approximately 79,000, identical to that formed when FBS or purified alpha 1-proteinase inhibitor is incubated with [alpha-125I]chymotrypsin. E-I complexes with apparent molecular weights of 44,000 and 50,000 were formed from CSM/bovine serum albumin of MTLn3(T17D) and MTLn2(T42D), respectively, that were not detected when [alpha-125I]chymotrypsin was incubated with bovine serum albumin. We infer from these observations that, in culture, poorly metastatic MTLn2(T42D) tumor cells, as compared to their highly metastatic MTLn3(T17D) counterparts, exhibit an increased capacity to retain and subsequently release significantly greater amounts of serum-derived active proteinase inhibitors. Moreover, the detection of proteinase activity by kinetic analysis and E-I complexes by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography in CSM prepared from cultures not exposed to FBS indicates that both variants have the capacity to produce their own inhibitors.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenocarcinoma↗
PubMed1991

Comparison between effects of interleukin-1 alpha administration and sublethal endotoxemia in primates.

Interleukin (IL)-1 is an early mediator of host response to inflammation, although its contribution to individual components of the acute phase reaction is still unclear. To evaluate how the hemodynamic, metabolic, and hormonal responses to sublethal endotoxemia compare with IL-1 administration, baboons received intravenously either lipopolysaccharide (LPS) or 0.1, 10, or 100 micrograms/kg IL-1 alpha. LPS induced an early tachycardia and a fall in mean arterial pressure, as well as lacticacidemia and hypoaminoacidemia. Similar hemodynamic and metabolic changes were seen with 10 or 100 micrograms/kg of IL-1 alpha. An increase in adrenocorticotropic hormone and fall in serum iron were induced by IL-1 alpha but not by LPS. Plasma tumor necrosis factor-alpha (TNF-alpha) was not measurable after IL-1 alpha administration, whereas LPS induced a monophasic TNF-alpha response. IL-6 levels were significantly greater after LPS than IL-1 alpha administration. Histopathological lesions, similar in LPS- and 100 micrograms/kg IL-1 alpha-treated groups, were present only in the adrenal cortex. We conclude that many, but not all, of the effects of sublethal endotoxemia can be replicated by IL-1 alpha administration, and these responses are dose dependent.

Amino Acids↗
PubMed1990

Peroxidase-antiperoxidase and immunogold labeling of Salmonella typhimurium and Salmonella choleraesuis var kunzendorf in tissues of experimentally infected swine.

Peroxidase-antiperoxidase immunoenzymatic labeling and immunogold labeling techniques were evaluated for microscopic detection and location of Salmonella organisms in tissues of experimentally infected swine. Salmonella typhimurium and Salmonella choleraesuis var kunzendorf were labeled specifically by the peroxidase-antiperoxidase technique in paraffin-embedded tissues of infected swine for conventional light microscopy and by postembedding immunogold labeling on ultrathin sections for electron microscopy. Salmonella typhimurium had a low tendency to invade the enteric mucosa and did not reveal any predilection for a specific intestinal location. Salmonella choleraesuis var kunzendorf, however, was located preferentially in colon and on the luminal surface of ileal M cells of Peyer patches and had a tendency to invade the enteric mucosa there.

Animals↗
PubMed1989

Regulation of hemopoiesis in myelosuppressed mice by human recombinant IL-1 alpha.

Human rIL-1 alpha was shown to be a potent stimulus of granulopoiesis in mice that have been myelosuppressed with cyclophosphamide. Stimulation of granulopoiesis was demonstrated in IL-1-treated mice by an accelerated recovery of granulocyte-macrophage colony-forming cells, bone marrow and splenic granulocytic hyperplasia, and a profound granulocytosis. Granulopoiesis was stimulated by IL-1 in a dose-dependent manner at doses ranging from 0.5 to 50 micrograms/kg. Maximal increases in granulocytes were observed after 4 days of IL-1 treatment. Mice treated with IL-1 also exhibited increased splenic megakaryopoiesis with a resultant increase in the number of peripheral blood platelets. In contrast to these positive effects on hemopoiesis, bone marrow, but not splenic, erythropoiesis was depressed in IL-1-treated mice. IL-1 effects were observed in mice treated with a wide dose range (50 to 300 mg/kg) of cyclophosphamide, with optimal effects occurring at a dose of 200 mg/kg. The doses of IL-1 leading to enhanced granulopoiesis caused only minor and transient changes in selected clinical chemistry parameters and caused no toxicities that were evident by histologic examination of tissues. The stimulation of granulopoiesis in the absence of overt toxicity suggests that IL-1 may be useful clinically to enhance the recovery of granulocytes in myelosuppressed patients.

Animals↗
PubMed1989

The therapeutic activity in cancer of IL-2 in combination with other cytokines.

Animal studies have been carried out to assess the antitumour efficacy of recombinant interleukin-2 (rIL-2) in combination with other cytokines. In several murine tumour models, rIL-2 in combination with recombinant alpha interferon (rIFN-alpha) elicits a potent antitumour response which is often greater than that which can be reached with the individual agents at non-toxic doses. By contrast, recombinant gamma interferon (rIFN-gamma) usually fails to potentiate the antitumour response to rIL-2. Recombinant alpha tumour necrosis factor (rTNF) can synergize with rIL-2 in some circumstances, but, as with the rIL-2/rIFN-alpha combination, the correct regimen is critical for generating a potent response without overt toxicity. Although appropriate cytokine combinations can lead to markedly enhanced tumour infiltration by lymphocytes, it is not clear that only a single type of lymphocyte is invariably involved in the antitumour response or, for that matter, the toxic side effects; nor has the mechanism of action of any of the cytokines in the therapeutic action been unequivocally elucidated. Finally, results of early clinical studies appear to be consistent with results in preclinical models: promising clinical responses to the combination of rIL-2 and rIFN-alpha have already been observed and further study is merited.

Animals↗
PubMed1989

Toxicity of human recombinant interleukin-2 in rats. Pathologic changes are characterized by marked lymphocytic and eosinophilic proliferation and multisystem involvement.

To characterize the subacute toxicologic and pathologic effects of human recombinant interleukin-2 (rIL-2) in rats, rIL-2 was administered to rats at doses ranging from 3.0 to 150 X 10(6) units/kg/day for 14 to 16 days, in once or twice daily dosing regimens by intravenous or intraperitoneal dosing routes. The hematologic, clinical chemical, gross pathologic and histopathologic findings were determined. Rats given rIL-2 had dose- and regimen-related incidences of hemolytic anemia, lymphocytosis, neutrophilia, eosinophilia, thrombocytopenia, increased hepatic transaminases, hyperbilirubinemia, hypoalbuminemia, ascites and pleural effusions, and prerenal azotemia. Marked lymphoid infiltration of the liver and eye were associated with hepatocyte necrosis and retinal damage. Eosinophilic infiltration of the adrenal medulla was associated with medullary cell necrosis. Other histopathologic changes included infiltration of multiple tissues by eosinophils and/or lymphocytes, lymphoid hyperplasia and splenic extramedullary erythropoiesis and eosinopoiesis. Hematologic, clinical chemistry, and histopathologic changes were of markedly greater severity in rats receiving rIL-2 twice daily as compared with those receiving the same total dose of rIL-2 once daily. Mortality in severely affected rats was secondary to severe anemia and/or hepatic damage. The results of these studies demonstrate that the major pathologic changes associated with rIL-2 administration in rats are characterized by marked tissue infiltration with lymphocytes and eosinophils. Many of the adverse effects of rIL-2 administration to rats are similar to those reported in humans receiving rIL-2 immunotherapy and the results confirm that the rat is an appropriate species in which to study selected aspects of rIL-2 toxicity.

Adrenal Medulla↗
PubMed1988

Role of asialo-GM1-positive lymphoid cells in mediating the toxic effects of recombinant IL-2 in mice.

Studies were performed to characterize the toxic effects of human rIL-2 in mice and to examine the mechanism of toxicity. Intraperitoneal administration of rIL-2 at doses greater than or equal to 2 X 10(6) U/kg twice each day for greater than or equal to 4 days led to toxicity in several strains of mice. The toxic effects of rIL-2 included the vascular leak syndrome (manifested by pulmonary edema, pleural effusions, and ascites), elevated hepatic transaminases, hyperbilirubinemia, hypoalbuminemia, pre-renal azotemia, anemia, thrombocytopenia, mild eosinophilia, and death. Marked lymphoid cell infiltration of pulmonary and hepatic vasculature was present in mice suffering from rIL-2 toxicity, and the pleural and ascitic fluids also contained high numbers of mononuclear cells. Mononuclear cells isolated from the pleural fluids and livers of these mice were 74 to 98% Thy-1+, 55 to 83% asialo-GM1+, 29 to 45% Lyt-2+, and less than 10% L3T4+. These cells possessed potent lymphokine-activated killer (LAK)-like activity in that their ability to lyse cells of the NK-resistant P815 mastocytoma line was 10- to 100-fold higher on a per cell basis than splenocytes from the same animals. A correlation was found between the dose level, duration, and frequency of dosing with rIL-2 required to induce pleural effusions and hepatotoxicity and the dosage regimens required to produce the LAK-like cells in the pleural cavities and livers, respectively, of rIL-2-treated mice. Moreover, treatment of mice with anti-asialo-GM1 (anti-ASGM-1) antiserum in vivo at the same time they were receiving toxic doses of rIL-2 abolished or greatly reduced the severity of the vascular leak syndrome and hepatotoxicity and significantly prolonged the survival of the mice. Administration of anti-ASGM-1 to mice receiving toxic doses of rIL-2 resulted in a marked reduction in the LAK-like cytolytic activity of their pleural and liver lymphoid cells and a corresponding reduction in the percentage of ASGM-1+ cells in pulmonary and hepatic lymphoid infiltrates. Nevertheless, the overall extent of pulmonary and hepatic lymphoid infiltration, as well as other consequences of rIL-2 administration, including splenomegaly, hypoalbuminemia, eosinophilia, and thrombocytopenia, were not diminished as a result of anti-ASGM-1 treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

Toxicity of human recombinant interleukin-2 in the mouse is mediated by interleukin-activated lymphocytes. Separation of efficacy and toxicity by selective lymphocyte subset depletion.

Human recombinant interleukin-2 (rIL-2) was administered to normal and tumor-bearing BDF mice for 1 to 3 weeks, and the hematologic, clinical chemistry, gross and histopathologic findings were evaluated. Vascular leak syndrome (pulmonary edema, pleural effusion, ascites), hepatocyte necrosis, elevated hepatic serum transaminases, hypoalbuminemia, tissue and peripheral eosinophilia, thrombocytopenia, and prerenal azotemia were the detrimental effects of rIL-2 treatment. Vascular leak syndrome and hepatocyte necrosis were causally associated with vascular-oriented lymphocytic infiltration of pulmonary and hepatic parenchyma. Pleural effusions contained up to 99,000 cells/mm3, most of which were large granular lymphocytes. Antiserum to the glycolipid asialo GM1 (ganglio-n-tetrosylceramide), given simultaneously with rIL-2, prevented overt toxicity of rIL-2 (mortality, vascular leak syndrome, and hepatic damage) and substantially reduced infiltration of pulmonary and hepatic vasculature by asialo GM1+ lymphocytes. Asialo GM1 antiserum did not inhibit lymphoid hyperplasia, tissue infiltration by Lyt 2+ lymphocytes, tissue and peripheral eosinophilia, or thrombocytopenia in rIL-2 treated mice. Additionally, asialo GM1 antisera prevented toxicity, but not anti-tumor efficacy, of high dose rIL-2 therapy in BDF mice bearing the colon 38 adenocarcinoma. These results suggest that, in BDF mice and with this tumor model, vascular leak syndrome and hepatocyte necrosis are mediated by an endogenous subset of rIL-2-stimulated lymphocytes which are asialo GM positive, that mechanisms of toxicity and efficacy associated with high dose rIL-2 therapy are not necessarily the same, and that these mechanisms can be therapeutically separated.

Adenocarcinoma↗
PubMed1987

Rotational delivery with Kielland's forceps.

A retrospective study over 15 months showed that 10.7% of primigravid women and 1.6% of multigravid women were delivered by Kielland's forceps: a total of 145 babies. The successful vaginal delivery rate for attempted Kielland's forceps was 96.7%. The neonatal outcome was good and there were no perinatal deaths. Traumatic injuries were present in 7.6% of babies and were minor. The data show that even in the presence of fetal distress, Kielland's forceps can be safely employed for rotational delivery from the mid-pelvic cavity. This approach can avoid some caesarean sections without undue risk to the baby, the caesarean rate being 9.5%. As 10.7% of primigravid women required rotational delivery with Kielland's forceps, it is desirable that primigravid women should be cared for by obstetricians who are skilled in the use of the instrument, in order to maintain a low caesarean section rate in this group, with a good neonatal outcome.

Adult↗
PubMed1986

Pathogenesis of placentitis in the goat inoculated with Brucella abortus. I. Gross and histologic lesions.

Pregnant goats were given Brucella abortus intravenously or in uterine arteries, and tissues from the uterus and placentae were examined at various post-inoculation intervals to study mechanisms of placental infection. Placentitis was present by 5 days post-inoculation and abortions occurred within 11 days. B. abortus was identified in placentae by light microscopy and immunoperoxidase techniques. B. abortus was first seen in erythrophagocytic trophoblasts of the placentome. Subsequently, high numbers of B. abortus were seen in periplacentomal chorioallantoic trophoblasts. Trophoblast necrosis, chorioallantoic ulceration, and large numbers of B. abortus in chorionic villi were present in later stages of infection. These results suggest that entry and replication of B. abortus in trophoblasts precede placentome and fetal infection and that trophoblasts are the source of B. abortus for these tissues. Experimental caprine brucellosis closely resembles bovine and ovine brucellosis and it provides a model to study the intracellular development of B. abortus in trophoblasts.

Abortion, Veterinary↗
PubMed1986

Pathogenesis of placentitis in the goat inoculated with Brucella abortus. II. Ultrastructural studies.

Pregnant goats were inoculated intravenously or in uterine arteries with Brucella abortus, and tissues from the uterus and placenta were examined by electron microscopy. Identification of B. abortus in placentae was with antibody-coated colloidal gold. B. abortus was first seen in phagosomes of erythrophagocytic trophoblasts and in the rough endoplasmic reticulum of chorioallantoic trophoblasts. Subsequently, trophoblast necrosis and ulceration of chorioallantoic membranes were present. Coincidently, B. abortus was present in the lumen of placental capillaries. In late stages of infection, placental vasculitis was present, and placentomal trophoblasts were separated from maternal syncytial epithelium. In lesions with vasculitis, large numbers of B. abortus were in connective tissue of chorionic villi. Within the placentome, trophoblasts that lined chorionic villi contained no intracellular bacteria and were separated from B. abortus by intact basement membranes. These results suggest that bacteremic B. abortus is endocytosed by erythrophagocytic trophoblasts and that B. abortus replicates in the rough endoplasmic reticulum of chorioallantoic trophoblasts. Replication of brucellae in trophoblastic rough endoplasmic reticulum is unique; we believe that B. abortus may utilize endoplasmic reticulum for synthesis and glycosylation of bacterial membrane proteins or that B. abortus catabolizes trophoblast secretory proteins.

Abortion, Veterinary↗
PubMed1986

Ultrastructural morphometric analysis of Brucella abortus-infected trophoblasts in experimental placentitis. Bacterial replication occurs in rough endoplasmic reticulum.

Trophoblasts in normal and Brucella abortus-infected caprine placentas were examined by ultrastructural morphometric analysis to establish structural relationships of B abortus with cytoplasmic organelles; brucellae were identified with colloidal gold-labeled anti-B abortus bovine IgG. Cytotrophoblasts had large numbers of B abortus in cisternae of rough endoplasmic reticulum; binucleate trophoblasts did not contain bacteria. In infected trophoblasts there was a significant hypertrophy of B abortus-filled rough endoplasmic reticulum (RER) and a corresponding reduction in normal-appearing RER. Volume and surface density of RER in trophoblasts were: normal placentas (control), 2.8% and 0.30 sq mu; infected placentas, 27.9% (27.4% of which contained B abortus) and 0.56 sq mu (cells containing B abortus) and 3.3% and 0.34 sq mu (cells not containing B abortus). These data suggest that B abortus replicates within the RER of trophoblasts, possibly for synthesis and glycosylation of bacterial membrane proteins.

Animals↗