Distribution of the [3H]-label from low doses of radioactive ochratoxin a ingested by rats,and evidence for DNA single-strand breaks caused in liver and kidneys

The distribution of a single low dose of [³H]ochratoxin A (OTA) in different tissues of male Wistar rats, after administration by intubation, was investigated after 5 h, 24 h and 48 h. This dose corresponds to concentrations encountered in naturally contaminated feed (4 ppm). The distribution of [³H]-label varied with the time elapsed after administration; at 5 h the highest specific label was found in the stomach contents and in decreasing order in: intestinal contents, lung, liver, kidney, heart, fat, intestine, testes, and the lowest in muscles, spleen and brain. With exception of brain, fat, stomach and lung, all tissues showed maximum levels at 24 h, after which time the label decreased steadily, whereas in fat it increased.After a 12-week feeding experiment, with doses of 288.8 g/kg corresponding to an intake of 4 ppm in feed each 48 h, the DNA in liver and kidneys was investigated for damage. By the alkaline elution method combined with micro-spectrofluorimetric determinations of DNA, evidence for DNA single-strand breaks was obtained. These findings support reports on the carcinogenic action of OTA.     

Disposition of the naturally occurring antimutagenic plant phenol, ellagic acid, and its synthetic derivatives, 3-O-decylellagic acid and 3, 3'-di-O-methylellagic acid in mice

The effect of ellagic acid and some of its more lipophilk derivativeson the mutagenicity of (? )-7ß, 8-di-hydroxy-9 10-epoxy-7,8, 910-etrahydrobenz[a]pyrene was examined in Salmonella typhimuriumTA100. Ellagic acid, 3, 3' -di-O-methylellagic add, 4, 4' -di-O-methylellagicacid and 3-O-decyiellagic acid were found to have approximatelyequal antimutagenic activity. The tissue distribution and eliminationof ellagic add, 3, 3' -di-O-methyleCagic add and 3-O-decylellagicacid were examined in CD-I mice. Little or no ellagic acid (<1 nmol/g) was found in blood, lung or liver after the oral administrationby gavage of 300 µunol of ellagic acid per kg body weightor after feeding 1% of ellagic acid in the diet for 1 week.Following the i.p. administration of 120 µmol/kg of ellagicacid, the blood and lung levels of ellagic acid were 15–20nmol/g at 30 min after the dose, and the concentrations of ellagicacid decreased to 1–3 nmol/g at 6–8 h after thedose. A portion of the administered i.p. dose precipitated inthe abdominal cavity. After i.v. administration, ellagic acidwas eliminated very rapidly from blood, lung and liver, and 70% of the administered dose was recovered in the urine andfeces as free ellagic acid and its conjugates. At 2 h afteran i.v. injection of 60 µ/kg of ellagic add, 46% of thedose was recovered in the urine as ellagic acid and its conjugates.Of this amount, about half was excreted as free ellagic acidand half was excreted as conjugates. An additional 25% of thedose was recovered in the feces (mostly as free ellagic acid)after 7 h. The disposition of 3, 3' -di-O-methylelIagic acidor 3–O-decyIellagic acid after i.v. administration (32µmol;sol;kg) was examined and compared to the dispositionof the same i.v. dose of ellagic acid. The concentrations ofellagic acid, 3,3' -di-O-methylellagic acid and 3-O-decytellagicadd decreased rapidly in the blood, liver and lung, but theconcentrations of 3-O-decylellagic add in the lung throughoutthe experimental period (2–360 min) was on average 20-to 40-fold higher than the corresponding average concentrationsof ellagic acid or 3, 3' -di-O-methylellagic acid.     

Surgical stabilization of pathological neoplastic fractures

The most important factor to consider in deciding between treatment options in the management of metastatic bone disease is the level of the patient's dysfunction and pain. Severe dysfunction or pain demands a treatment that predictably leads to a quick resumption of the painless activities of daily living. A treatment that predictably will restore function in months may seem reasonable in patients with a normal remaining life span, but is untenable if those months represent a high percentage of remaining life span, as they do in metastatic disease afflicted patients. The treating physician needs also to understand the basis for the patient's dysfunction. A destroyed joint will not return to painless function even if the metastasis responsible is totally eliminated. A bone that has lost its structural integrity, even though not grossly fractured, will not support weight bearing for months even if the metastasis is eliminated. Control of the metastatic tumor does not always equate with return to function. Treatment options in the management of metastatic bone disease are not mutually exclusive. In many patients treatment options are combined. Surgical stabilization may best return the patient's function while he is being treated postoperatively with radiotherapy or chemotherapy for good neoplasm control. Neoplasm control should not be such an overriding concern that function is not addressed. Function can almost always be returned to the patient, but neoplasm "cure" is rarely achieved in this group of patients. It is a reasonable goal to avoid allowing bone metastasis to progress to pathological fracture. Routine periodic examinations and bone scans should commonly alert the treating physician to the presence of metastatic bone disease well before fracture occurs. Pathological fracture narrows the range of treatment options, mitigates against full functional restoration, demands a rehabilitation hiatus, and acutely frightens the patient who does not have time to participate fully in treatment decisions. An impending pathological fracture can be treated with surgery, radiotherapy, chemotherapy, or hormonal manipulation. The options are basically operative or nonoperative. Lesions that predictably will fracture short term, involve joints, or will cause catastrophic consequences if fracture occurs should be strongly considered for surgical stabilization. Other factors to consider are the location of the metastasis, the primary tumor, and the expected response to nonoperative therapy. The patient becomes a surgical candidate for the above reasons and not because of any estimated life span.(ABSTRACT TRUNCATED AT 400 WORDS)     

Autocrine and paracrine growth regulation of human breast cancer

Summary We consider the hypothesis that estrogen control of hormone dependent breast cancer is mediated by autocrine and paracrine growth factors secreted by the breast cancer cells themselves. Though we show direct, unmediated effects of estrogen on specific cell functions, we also provide evidence that human breast cancer cells secrete a collection of growth factors (IGF-I, TGF, TGF, a PDGF-like competency factor, and at least one new epithelial colony stimulating factor). Some of these are estrogen-regulated in hormone dependent cells, and are constitutively increased in cells which acquire independence either spontaneously or byras transfection. Collectively, the secreted growth factors are capable of promoting tumor formation by MCF-7 cells in nude mice, though not to the same extent as estrogens. There would seem to be potential for clinical intervention in the autocrine and paracrine control of breast cancer cells, including some cells which are no longer dependent on estrogens.     

Ruthenium nitrosyl complexes: Toxicity toEscherichia coli and yeasts and uptake by marine bacteria

The toxicity and possible accumulation of ruthenium nitrosyl complexes by marine bacteria and test organisms have been studied, A range of these complexes show no toxic effects towardsEscherichia coli K12 at concentrations of mM and below. Yeasts are more sensitive, showing effects on growth at 10 M. The ruthenium nitrosyl complexes tested are unable to permeate the cytoplasmic membrane ofE. coli. This may account for their lack of toxicity. However, these compounds did not have significant inhibitory effects on Mg²⁺-ATPase activity in cell-extracts, I₅₀ values lying in the range 2 to 125 mol(mg protein)^–1. Marine bacteria are capable of taking up ruthenium complexes from simulated effluent, but this cannot be demonstrated in the presence of sediment which competes effectively for binding of complexes. There is minimal likelihood of concentration of ruthenium compounds from effluents by marine bacteria.     

Anastomotic false aneurysms with aortic Dacron graft after twenty-five years

One of the early diamond crimped knitted polyester (Dacron) grafts was surgically excised after implantation for 25 years in the aorto-billiac position because of false aneurysm formation at the three anastomotic sites. The sutures were no longer visible. While the areas around the false aneurysm were poorly incorporated, the graft limbs were well encapsulated with some endothelial-like cells on the luminal surface. The integrity of the graft was well preserved despite mild fraying and the disruption of one stitch.     

Effects of ethanol on murine aggression assessed by biting of an inanimate target

The effects of acutely administered ethanol (0, 0.5, 1.0 and 2.0 g/kg, IP) were studied in a tube-restraint/target biting model of aggressive responding using naive group-and individually-housed male Swiss mice. Behavioural measures were the latency to the first bite and the biting frequency. In saline-injected control animals, the levels of responding were significantly higher in group-housed than isolated mice. Animals given alcohol exhibited a dose-dependent suppression of biting frequency, and an increase in biting latency. Mice experienced in the tube-testing situation showed reduced baseline levels of biting, but alcohol produced similar effects to those in naive mice. There was no evidence of a biphasic action of alcohol.     

Studies on the biochemical mechanism of the novel antitumor agent,CI-920

Summary Biochemical studies on a new antitumor antibiotic, CI-920, have been directed toward understanding its mode of action. The most striking effect brought on by CI-920 was a marked inhibition of macromolecular synthesis. L1210 leukemia cells exposed to 10 M CI-920 exhibited a decreased rate of DNA, RNA, and protein synthesis within 45 min, and maximal inhibition occurred within 60 min. The reduction in nucleic acid synthesis was not due to precursor depletion, since ribonucleoside and deoxyribonucleoside triphosphate levels in cells exposed to 10 M CI-920 for 2 h either remained unchanged relative to control cells or were elevated, suggesting a block more directly at the level of nucleotide incorporation. Nevertheless, CI-920 (50 M) had no effect on DNA or RNA polymerase activity as assessed in permeabilized L1210 cells. However, if viable cells were exposed to 20 M CI-920 for 1 h prior to permeabilization and then the polymerases assayed in the absence of drug, there was a 60% depression in enzyme activity. The inhibition of RNA polymerase appears to result from an effect on the enzyme rather than the template, since inhibition of RNA polymerase activity in cell-free systems from drug-treated cells could not be restored by addition of excess DNA template. DNA polymerase, however, was at least partially restored by addition of template and therefore was inconclusive in this respect. The data, then, suggest that CI-920 inhibits nucleic acid synthesis directly at the level of nucleotide incorporation, either by direct inhibition of DNA or RNA polymerase or by inactivation of an essential component of these enzyme systems. Since the drug in its parent form did not inhibit nucleic acid synthesis in cell-free systems the effects may possibly be mediated through conversion of this agent to another chemical form within viable cells.     

Unilateral striatal dopamine denervation: Reduced motor inhibitory effects of dopamine antagonists revealed in models of asymmetric and circling behaviour

Summary Circling and asymmetric behaviours to apomorphine (dopamine agonist/antagonist) challenge were studied in rats with unilateral striatal electrolesions or 6-hydroxydopamine (6-OHDA) lesions, each induced by combined lesions at 3 striatal locations, to allow an assessment of drug action on normal receptors in the intact striatum or supersensitive receptors in the lesioned striatum respectively. The minimally effective dose of 6-OHDA (given in the presence of DMI and tranylcypromine) to cause functional change was 3×8 g, with 3×32 g providing maximal change. Electrolesions were shown histologically to be confined to striatal tissue, and dopamine depletions caused by 6-OHDA were selective for the striatum.Temporal differences were recorded for onset of asymmetry and circling behaviour, both between behaviours and between lesions. Thus, asymmetry developed during the 2nd–4th days after 6-OHDA lesion but circling developed more abruptly on postoperative days 10–12. In contrast, both asymmetry and circling behaviours were apparent from the first day following electrolesion. The dose-dependent effects of apomorphine were apparent at much lower doses in 6-OHDA lesioned than electrolesioned rats. This potency difference was also demonstrated for two further dopamine agonists, 2-di-n-propylamino-5,6-dihydroxytetralin and SK & F 38393. In contrast, the agonist-induced asymmetric and circling behaviours of electrolesioned rats were some 9–44 times more sensitive than those of 6-OHDA lesioned rats to antagonism by the neuroleptic agents haloperidol, -flupenthixol and oxiperomide, although tiapride antagonism was very similar in both the electrolesioned and 6-OHDA-lesioned rats. Thus, selective striatal denervation techniques are used to show that asymmetric and circling behaviours can be differentially induced and manipulated, and that the increased sensitivity (over electrolesions) of 6-OHDA lesioned rats to dopamine agonist action to induce these behavioural effects is associated with a reduced sensitivity to neuroleptic activity to reduce the asymmetric and circling responses.     

Employment Consequences of COVID-19 for People with Disabilities and Employers

Journal of Occupational Rehabilitation - Purpose The COVID-19 pandemic has disproportionately affected the lives of people with disabilities (PWD). How the pandemic affects the employment of PWD...