Alpha 2-antiplasmin, plasminogen activator inhibitor (PAI) and dilute blood clot lysis time in selected disease states.

This paper is an attempt to assess the relevance of the inhibitors of fibrinolysis for clot lysis in selected disease states and to discuss the mechanisms leading to acquired abnormal levels of such inhibitors. When compared to 20 control subjects the 30 hypertriglyceridemic patients (14 with type IIb and 16 with type IV) displayed significantly (p less than 0.001) increased plasma plasminogen activator inhibitor (PAI) activity (221 +/- 88% and 290 +/- 104% respectively; mean +/- SD), moderately (p less than 0.01) increased alpha 2 antiplasmin (alpha 2AP) level (112 +/- 11% and 115 +/- 16%) and accordingly an obviously prolonged dilute blood clot lysis time (DBCLT). Neither PAI activity and alpha 2AP level nor DBCLT were significantly different from controls in the 10 patients with hyperlipoproteinemia type IIa. The 18 patients with severe hepatic cirrhosis had low alpha 2AP level (59 +/- 19.7%) and accelerated clot lysis, while mean PAI activity (160 +/- 87%) was slightly (p less than 0.05) increased. In the 17 nephrotic patients alpha 2AP was increased (115 +/- 12%) while PAI activity was similar to controls and DBCLT rather shorter. Two liver secretion enzymes, namely serum cholinesterase and plasma protein C, were found to be decreased in cirrhotic patients, similar to control values in hyperlipoproteinemia type IIa and obviously increased in nephrotic patients as well as in hypertriglyceridemic subjects. The relevance of PAI and alpha 2AP for clot lysis was considered in relation to data in the literature concerning the behaviour of t-PA and factor XIII.(ABSTRACT TRUNCATED AT 250 WORDS)     

Carcinoembryonic antigen expression of resurgent human colon carcinoma after treatment with therapeutic doses of 90Y-alpha-carcinoembryonic antigen monoclonal antibody

We have previously shown that the colon carcinoma (LS174T) xenografts that emerged shortly after radioimmunotherapy with 90Y-labeled anti-CEA monoclonal antibody (MAb) ZCE025 lacked significant expression of CEA in comparison with the untreated tumors. The present study was designed to establish if the immunophenotype of the treated tumors was the result of CEA specific therapy and if the effect was permanent. Athymic mice bearing LS174T tumors were treated either with 120 mu Ci of 90Y-ZCE025, an equal dose of 90Y-96.5 (nonspecific MAb), or received no treatment. When the treated tumors grew to approximately 1.5 cm in diameter (6 weeks after therapy), they were resected and aliquoted to be transplanted to other mice, plated in tissue culture, fixed in formalin, and homogenized for CEA quantitation. The procedure was repeated 3 times (a total of 4 months after treatment). The CEA content was evaluated 2 and 6 weeks after therapy and when the tumors were transplanted. We confirmed a 4-fold decrease of CEA in the resurgent tumors 6 weeks after specific 90Y-ZCE025 therapy, which was twice the decrease experienced by the tumors treated with nonspecific 90Y-96.5, indicating substantial and specific killing of CEA-expressing cells. The CEA content slowly but progressively increased with each new pass of the tumor in the mice, reaching approximately one-half the value of the controls at the end of the study. The resurgent tumors were also studied by immunohistochemistry with MAbs detecting different epitopes of CEA, keratin, TAG-72, and epithelial membrane antigen to evaluate possible additional immunophenotypic changes induced by radioimmunotherapy. Only the expression of TAG-72 (recognized by MAb B72.3) increased immediately after therapy, but it returned to the original levels by the end of the study. These results suggest that: (a) specific radioimmunotherapy with 90Y-ZCE025 selectively kills cells that express higher levels of CEA; (b) the immunophenotype of the surviving fraction of the tumor appears to slowly revert to its original form; and (c) other tumor markers unrelated to CEA can also be affected. These observations have important implications for the design of radioimmunotherapy trials.     

Enhanced behavioral stereotypies elicited by intrastriatal injection D1 and D2 dopamine agonists in intact rats

Five components of behavior elicited by dopamine (DA) agonists (locomotor hyperactivity, sniffing, oral activity, grooming and paw nibbling) were evaluated after bilateral infusion of the selective D1 agonist fenoldopam (SKF 82526; 2.5-10 micrograms), the selective D2 agonist quinpirole (LY 171555; 5-40 micrograms) and the muscarinic cholinergic antagonist scopolamine (5-20 micrograms) into the ventral striatum of awake, unrestrained rats. Simultaneous bilateral infusion of various dose combinations of fenoldopam (2.5-10 micrograms) and quinpirole (5-20 micrograms) elicited dramatic increases in stereotyped behaviors relative to the effects produced by corresponding doses of each drug alone. Stereotyped sniffing and paw nibbling (self-directed oral activity) were markedly enhanced, whereas conventional oral behaviors (licking, chewing and/or biting) were either slightly or not at all increased. These potentiated responses were reduced or blocked by concomitant infusion of either the selective D1 antagonist SCH 23390 (1 and 5 micrograms) or the selective D2 antagonist sulpiride (0.15 microgram). Scopolamine (10 micrograms) only slightly increased the effects of quinpirole (5 micrograms) on both sniffing and oral behaviors, whereas it dramatically potentiated the effects of fenoldopam (2.5 micrograms) on oral activity; sniffing was only slightly increased. The effects of both drug combinations were almost completely antagonized by infusion of either SCH 23390 (1 microgram) or sulpiride (0.1 microgram). The results demonstrate that the synergistic effects of co-activation of D1 and D2 receptors observed after systemic administration are mediated at least in part by an interaction at the level of the striatum. Differences and similarities between the behaviors expressed after various treatments are discussed.     

Cerebrovascular and metabolic perturbations in delayed heavy charged particle radiation injury

Focal heavy charged particle irradiation of the rabbit brain created defined lesions which were observable by nuclear magnetic resonance (NMR) and positron emission tomography (PET) imaging techniques. The lesions appeared approximately 9-11 months after left partial hemibrain irradiation with 30 Gy (230 MeV/u helium ions), and were restricted to the white matter tracts and deep perithalamic and thalamic regions. 82Rubidium PET and Gadolinium DTPA enhanced NMR imaging were used to detect blood-brain barrier perturbations. 18Fluordeoxyglucose PET studies demonstrated widespread decreases in cerebral glucose uptake in the cortex and thalamus of the irradiated hemisphere. NMR and PET imaging results correlated well with histological findings. Rabbits irradiated with 15 Gy did not demonstrate any abnormalities in the brain with sequential NMR scans through 14 months post-irradiation.     

Enhanced take of spontaneous murine tumors in mice treated with inhibitors of macrophage and/or NK cell function

Both macrophages and NK cells have been suggested to play a role in recognizing and eliminating early, in situ neoplasms. Therefore we studied the effect of inhibitors of macrophage and/or NK cell function on the take of transplantable spontaneous murine tumors in syngeneic mice. The treatment of animals with trypan blue, a selective inhibitor of macrophage function, decreased considerably the period of latency of BSP3 adenocarcinoma; however, it did not increase the take of SP4, SP82 and SP84 adenocarcinomas. The treatment of recipients with neutral red, a selective inhibitor of NK cell function, enhanced the take of SP4 adenocarcinoma. The treatment of mice with agents depressing both macrophage and NK cell function (silica or carrageenan) decreased the both macrophage and NK cell function (silica or carrageenan) decreased the period of latency and/or increased the take of SP4, SP82 and SP84 adenocarcinomas. Carrageenan or a combined treatment with both trypan blue and neutral red also enhanced the take of BaF1, a benzo(a)pyrene-induced fibrosarcoma. We concluded that both macrophages and NK cells may function as effector cells of an antitumoral surveillance system.     

Morphological findings during retinal development and maturation in hereditary rod-cone degeneration in Abyssinian cats

The sequence of structural changes involved in postnatal photoreceptor differentiation, maturation and early degeneration was studied in young Abyssinian cats and kittens with hereditary rod-cone degeneration and compared to maturation in normal controls. In affected cats the earliest change seen was disorientation of outer segment discs in the majority of the rods, while other rods appeared to develop and mature normally. Such disorientation of discs (at oblique angles or parallel to the longitudinal axis of the outer segment, or whorls of discs) is considered as 'immaturity', since controls also showed a substantial number of disoriented rod outer segment discs at this young age. At postnatal day 35 the difference between affected animals and controls was marked with a high frequency of immature appearing rod outer segment discs in affected animals, while all rod outer segment discs were adult-like and arranged in an orderly manner in controls. Cones seemed unaffected at this age. More severe changes in affected rod outer segments in the form of disintegration of discs (vacuolization and clumping of disc material, or formation of debris), which we consider to represent degeneration, were first observed at the time when retinal maturation normally occurs in the cat, i.e. 150 days postnatally. Subsequently a drop-out of rods was seen, primarily of rods with disoriented and disintegrated outer segment discs, followed by a slow, progressive degeneration of rods that had developed and matured normally. Cones appeared normal during the time of retinal development and maturation and it was not until the age of 2-3 years (Narfstr?m and Nilsson, 1986, Incest. Ophthalmol, Vis. Sci. 27, 1569-76) that degenerative changes were seen also in cones.     

New antihepatotoxic naphtho-pyrone glycosides from the seeds of Cassia tora

Two new naphtho-pyrone glycosides, 9-[(beta-D-glucopyranosyl-(1----6)-O-beta-D-glucopyranosyl)oxy]-10- hydroxy-7-methoxy-3-methyl-1H-naphtho[2,3-c]pyran-1 -one (5) and 6-[(alpha-apiofuranosyl-(1----6)-O-beta-D-glucopyranosyl)oxy]- rubrofusarin (6), together with cassiaside (3) and rubrofusarin-6-beta-gentiobioside (4) were isolated from the seeds of Cassia tora L. Their structures were elucidated on the basis of chemical and spectral data. The naphtho-gamma-pyrone glycosides (3, 4, and 6) were found to have significant hepato-protective effects against galactosamine damage, which were higher than that of silybin from Silybum marianum.