Interaction of DNA and liposomes as a model for membrane-mediated DNA damage.
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Biomedical subjects
Publications and source records attributed to G Jones.
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The effects on the lung of some synthetic compounds related to monocrotaline pyrrole have been studied and compared with those previously found with that compound. When injected into a systemic vein doses of pyrrole mono- and dicarbamate produced acute pulmonary oedema. Pyrrole alcohol and ethyl carbamate had no such effect and although furyl carbamate did not cause pleural effusion in rats it did so in mice. Like monocrotaline pyrrole, when injected into other vessels the pyrrole carbamates produced oedema in the region of the first capillary bed encountered. When colloidal carbon was injected intravenously after the pyrrole carbamates, carbon "labelling" was seen in both the post-capillary venules and the capillaries of the lungs. On the whole, venular "labelling" occurred before capillary "labelling" which was best seen when the carbon was injected more than 4 hr after the pyrrole. The distribution of the carbon as seen by electron microscopy is described. No "labelling" was seen after furyl carbamate. The effects of the synthetic pyrrole esters were similar to those of monocrotaline pyrrole. Although both the pyrrole carbamates were less active on a molecular basis they had a broader action on the pulmonary vasculature causing venular as well as capillary "labelling". To affect the lungs acutely the compound had to have the pyrrole ring structure and at least one ester side-chain.
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The infusion of calcitonin into intact rats increases the accumulation of 1,25-dihydroxy-[26-27-3H]vitamin D3 from 25-hydroxy-[26,27,-3H]vitamin D3 in blood, but has no effect on thyroparathyroidectomized rats using a variety of protocols. Furthermore, the vitamin D status of the animals did not alter the results. Inasmuch as no effect of calcitonin could be found on the accumulation of other vitamin D metabolites as well as 1,25-dihydroxyvitamin D3, it is concluded that calcitonin apparently plays no direct role in the regulation of vitamin D metabolism and that the previous report of an effect of calcitonin on vitamin D metabolism in vivo is probably the result of a secondary response of the parathyroid gland.
Gingival hyperplasia may be inherited in a variety of ways, usually in an autosomal dominant or autosomal recessive manner. Additional phenotypic abnormalities are frequently associated with the gingival hyperplasia. To our knowledge, the family described here represents the first instance of autosomal dominantly inherited gingival hyperplasia associated with progressive neural hearing loss.
1,25-Dihydroxyvitamin D2 has been prepared from 25-hydroxyvitamin D2 using rachitic chick kidney mitochondria. This metabolite was highly purified by Sephadex LH-20 chromatography and by preparative high-pressure liquid chromatography. Its purity was assessed by analytical high-pressure liquid chromatography which revealed no other 254-nm absorbing material and by mass spectrometry. The concentration of dilute solutions of 1,25-dihydroxyvitamin D2 was determined by high-pressure liquid chromatography and deflection of the 254-nm column monitor. The 1,25-dihydroxyvitamin D2 was then shown to be 1/5 to 1/10 as active as 1,25-dihydroxyvitamin D3 in the chick while it had previously been shown to be equal in activity in the rat. Thus, discrimination against the vitamin D2 side chain by the chick persists in the metabolically active 1,25-dihydroxyvitamin D compounds.
An in vitro study of the liver 25-hydroxylation of vitamin D2 and the kidney 1- and 24-hydroxylations of 25-hydroxyvitamin D2 was undertaken in order to determine whether the discrimination against vitamin D2 seen in chicks in vivo is the result of a block of one or more of the steps in the activation of the vitamin D2 molecule. Vitamin D2 hydroxylation reactions in the chick are virtually identical with those observed with the vitamin D3 series. It is, therefore, concluded that the chick possesses the required enzymatic machinery to synthesize 1,25-dihydroxyvitamin D2 and that the discrimination must be because of some unknown metabolic reaction of the vitamin D2 compounds, to a defect in the transport of vitamin D2 metabolites, or to target organ discrimination.
Digoxin absorption was studied in healthy volunteers by determination of peak plasma concentrations, areas under plasma concentration curves, and urinary excretion after single-dose administration. By comparison with an aqueous solution, increased rate and extent of absorption occurred from experimental soft gelatin formulations of digoxin in solution. Enhanced bioavailability of the capsules was not affected by altered volume of contained solvent. Digoxin was considerably better absorbed from capsules than from tablets of moderately high dissolution rate. Mean percentage intestinal absorption was 75% from tablet and 97% from capsules. Reduced between-subject variability accompanied the enhanced absorption from capsules.
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The effects of feeding adult rats for 6 weeks with a carcinogenic regimen of aflatoxin-contaminated diet are described. Effects on the histological appearance of liver sections are related to changes observed in nuclear separations carried out using zonal centrifugation. Changes in the levels of nuclear RNA and DNA synthesis have been studied in the populations of hepatic nuclei separated in the zonal rotor. The first 3 weeks of the feeding period was accompanied by continuing inhibitions of nucleic acid synthesis, terminating in a loss of the majority of the tetraploid hepatocyte nuclear population. The subsequent 3 weeks of feeding was predominantly a period of proliferation, restoration of the lobular architecture, and recovery of nucleic acid-synthetic activity. The possible bases of these two opposite effects, inhibition followed by stimulation, which occurred sequentially during the continued feeding of the toxic diet, are discussed.
A basic assumption of current guide lines to test drug therapy for benign prostatic hypertrophy is that the clinical disease is caused by bladder neck obstruction and its sequelae and complications. Asymptomatic non-prostatic hypertrophy, no matter how large the adenoma, is considered to be a pre-clinical phase of the disease as long as bladder trabeculation, impairment of the flow rate and residual urine are absent. The guide lines recognize that histological changes and gross anatomical enlargement of the prostate are the essence of the disease but objective signs of current therapeutic relief of symptoms lend themselves more practically to measurement of progression or remission, whereas no current drug has a clear enough effect on prostatic histology to predict subsidence of the clinical picture. Since no one criterion or single test serves this purpose a cluster of symptoms, with flow rate and residual urine, provides the hardest data. It would be preferable for each patient to serve as his own control in a prospective double-blind randomized study, since the literature shows no uniformity of approach, methodology, patient population or other useful data for clinical norms. Guide lines have been developed with the aid of clinical pharmacologists, biostatisticians, lawyers and government officials and approved by the Food and Drug Administration. Misconceptions outside of the profession of Urology need to be dispelled and further research in methodology, urodynamics, ultrasonic evaluation of the prostate, definition of symptoms, criteria for efficacy, etiology of the disease, and mode of action of drugs, placebo and surgery were highlighted. The literature does not have an overabundance of data but does contain evidence of definite but weak drug efficacy in the treatment of this condition.
In C57BL/6 mice a single oral dose of 2,3,7,8-tetrachlorodibenzodioxin (LD50 126 mug/kg) results in loss of body weight and death with an enlarged fatty liver after ca. 21 days. A progressive necrotic centrilobular liver lesion is also seen.
The chemical synthesis of [3alpha-3H]vitamin D2 of high specific activity has been described. With the use of this radioactive material, the existence of a polar metabolite believed to be the active form of vitamin D2 in the rat and chick has been demonstrated. It has been isolated in pure form from an in vitro chick kidney mitochondrial system and identified as 1,25-dihydroxyvitamin D2 by means of mass spectrometry, ultraviolet absorption spectrophotometry, and specific derivative synthesis. Its antirachitic activity equals that of 1,25-dihydroxyvitamin D3 in the rat.
A histochemical study of plasma-membrane associated enzymes in rat liver demonstrated a significant lesion 3 days after a single oral dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin). The complete loss of canalicular ATPase reaction in the parenchymal cells of the centrilobular zone remained the prominent feature of the liver throughout the 6-wk period studied. Involvement of the periportal and midzonal regions occurred in moribund animals and improvement in the health of two surviving animals at 9 mth was associated with a normal distribution of ATPase in the liver. Qualitative changes in 5-nucleotidase and acid phosphatase were secondary to the parenchymal cell damage. This lesion supports the morphological evidence, reported previously, that the parenchymal cell plasma-membrane is a specific subcellular site of the toxic action of dioxin.
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