Biomedical subjects
J C Martin
Publications and source records attributed to J C Martin.
Recapping of disposable dental syringe needles: also a transparent face shield barrier.
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How do we cure low staff morale?
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[Experimental study in the cat on the alveolar density and heterogeneity in the obstructed lung. Comparison with the emphysematous lung in the aged].
An experimental model of lung obstruction has been achieved in the cat reared in our laboratory. 30 young adults (J) and one adult subject (A) had tracheal stenosis from 8 to 15 weeks and were the object of a study of pulmonary airways and were compared with four young controls and seven older controls. The presence of emphysema was revealed by microscopy. The size of the alveoli was measured by the mean linear intercept (MLI). The study was systematized by an image analyser giving the ratio of airway spaces to pulmonary tissue (% of surface). The mean value S represented the alveolar section in the lung. Alveolar heterogeneity was expressed by the dispersion of the point values S around the mean S. The animals had episodes of ventilatory distress. Cytology of the broncho-alveolar lavage performed when the animals were sacrificed did not distinguish between the obstructive and other subjects. Emphysema was found in 10 out of 22 of the young stenosed animals. No control J were abnormal. 5 adults were emphysematous through ageing (5 years or more). The mean linear intercept of the alveoli was increased in the emphysematous (115%) and even more in the obstructive cases without or with emphysema where MIL attained 173%. The obstructive lung, whether emphysematous or not, is heterogeneous. Emphysema, always focal, corresponded to an alveolar section which was weakened (S less than S controls - 2 standard deviations) for 40% of the older subjects and for 50% of the J obstruction, up to two times more often than in obstruction without emphysema.(ABSTRACT TRUNCATED AT 250 WORDS)
Intracellular localization of beta-glucuronidase in fibroblasts after direct transfer from macrophages.
The subcellular distribution of beta-glucuronidase acquired by deficient human fibroblasts during co-culture with peritoneal macrophages was compared with that taken up by receptor-mediated endocytosis. Labelled enzyme taken up via receptors was located initially in a low-density endosomal fraction and was transferred to lysosomes within a few minutes. The beta-glucuronidase acquired during 24 h of co-culture was present almost entirely within lysosomes and had a distribution profile identical with that of endogenous beta-hexosaminidase. Monensin prevented transfer of radiolabelled enzyme from endosomes to lysosomes and had a similar effect on the distribution of enzyme acquired by direct transfer, causing beta-glucuronidase to accumulate within endosomes. When the temperature was lowered from 37 degrees C to 19 degrees C, the rate of transfer of enzyme from endosomes to lysosomes was decreased during both direct transfer and indirect receptor-mediated endocytosis. These results show that a lysosomal enzyme acquired by direct transfer during cell-to-cell contact follows a similar intracellular route and has a similar distribution to that of enzymes taken up via cell-surface receptors.
Late effects of fractionated pi-mesons compared to X rays on mouse lung.
Early and late delayed effects of up to 20 fractions of pions and X rays were investigated in the mouse lung. The whole thorax of female CD-1 mice was irradiated under Ethrane/O2 anesthesia. Respiration rate was measured by whole body plethysmography at biweekly to monthly intervals. With signs of irreversible respiratory distress, animals were sacrificed and their lungs evaluated histologically. In addition to the effect of fractionation, the influence of dose-rate and anesthesia was studied as well. The degree of injury for the most predominant lesions (macrophage accumulation, fibrosis, vascular congestion) was scored, and the correlation with the relative change in respiratory rate and survival was analyzed. This analysis showed the primary lesion to be radiation pneumonitis at a median survival time of approximately 100 days. Focal fibrosis was observed to occur soon thereafter, and no evidence was obtained for an independent second wave of fibrotic injury. Fibrosis seemed primarily the result of pathological organization in areas with heavy concentration of macrophages. It was observed that the mice were unusually sensitive, with a single dose X ray ED50/180 of 8.8 Gy. A similar value was found for unanesthetized mice. This might have been the result of performing these studies at an altitude of 2100 m. The fractionation effect also seemed more pronounced, with alpha/beta values of 0.6 Gy for X rays and 4 Gy for pions, which is significantly lower compared to reported values. At the pion dose-rate of 0.25 Gy.min-1, RBE values for single doses were 0.9 when compared to high dose-rate X rays, and 1.36 at equivalent dose rates. This clearly shows that significant repair occurs during the relatively low dose-rate pion irradiations. With smaller doses per fraction, the dose-rate effect became less dominant, and for 20 fractions of pions the RBE was 1.4 compared to fractionated high dose-rate X rays. These RBE's are similar to values reported for acute effects in skin.
Synthesis and antiviral evaluation of 6'-substituted aristeromycins: potential mechanism-based inhibitors of S-adenosylhomocysteine hydrolase.
New carbocyclic adenosine analogues substituted at the 6'-position with fluorine, hydroxyl, methylene, or hydroxymethyl have been synthesized as potential mechanism-based inhibitors of S-adenosylhomocysteine (AdoHcy) hydrolase. The synthetic routes began with a functionalized (+/-)-azidocyclopentane 2, which was elaborated to the adenosine analogue, or with functionalized cyclopentane epoxides 11, 20, and 27, which were opened directly with adenine in the presence of base. The 6' alpha-fluoro, 6' beta-fluoro, and 6'-methylene carbocyclic adenosine analogues were potent inhibitors of AdoHcy hydrolase. None of the compounds displayed significant activity against herpes simplex virus type 1 or type 2, but several demonstrated potent inhibition of vaccinia virus replication.
Sources of variability in coagulation factor assays.
Estimates of the components of variation of a number of coagulation factor assays are presented and are compared with those for other haematological and biochemical variables. They have been derived from a study in which fourteen volunteers gave blood samples approximately bi-monthly for three years. The systematic between-batch variation was generally only a small component of the total variation. However, the proportion of the total variation due to differences between people ranged from about 15% in the case of two measures of antithrombin III to about 85% for cholesterol and haemoglobin. For factor VII activity and fibrinogen, the figure was just over 70%. These estimates of the components of variation are not generally available in the literature. In view of the increasing interest in the role of coagulation factors in the pathogenesis of arterial disease, estimates of this kind are needed both for the interpretation of observed relationships as well as for planning sample sizes for future studies.
DNP-phycobiliproteins, fluorescent antigens to study dynamic properties of antigen-IgE-receptor complexes on RBL-2H3 rat mast cells.
In RBL-2H3 rat mucosal mast cells, the crosslinking of cell-surface IgE-receptor complexes by multivalent antigens initiates a sequence of responses leading to degranulation. We have developed a family of dinitrophenol (DNP)-conjugated fluorescent antigens to study dynamic membrane events associated with these responses. Lysyl groups on the phycobiliproteins, B-phycoerythrin and C-phycocyanin, were labelled with DNP, yielding fluorescent conjugates that cause the release of [3H]serotonin from anti-DNP-IgE-primed RBL-2H3 cells. The binding of these antigens to IgE-receptor complexes was observed by fluorescence microscopy and quantified by flow cytometry. Incubation with 1 microgram/ml DNP42-B-phycoerythrin stimulates maximum degranulation from IgE-saturated cells. Under these conditions, approximately 26 X 10(3) molecules of DNP42-B-phycoerythrin are bound per cell at equilibrium. The rate and extent of antigen binding and of antigen-stimulated mediator release decrease in parallel as the concentration and DNP:protein ratio of the fluorescent conjugates is reduced. Secretion stops immediately when the nonfluorescent monovalent antigen, DNP-lysine, is added to degranulating cell suspensions. DNP-lysine also displaces surface-bound antigen when added during the first minutes after multivalent antigen. However, the ability of DNP-lysine to displace surface-bound DNP42-B-phycoerythrin from IgE-receptor complexes decreases progressively with time. Treatment with dihydrocytochalasin B and several analogs that prevent antigen-stimulated F-actin assembly enhances secretion and delays the transition of antigen to its DNP-lysine-resistant form. Cytochalasin treatment also permits the long-range movement of antigen into surface caps.(ABSTRACT TRUNCATED AT 250 WORDS)
Synthesis and antiviral activity of various esters of 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine.
The synthesis and in vivo biological activity of a series of mono-O-, di-O-, and N2-acyl derivatives of 9-[(1,3-dihydro-2-propoxy)-methyl]guanine (DHPG) are described.
Growth and activity but not maturation are affected by perinatal diet.
Growth, maturation and activity in Sprague-Dawley rat offspring were studied as a function of two diets which were offered both pre- and postnatally. Day 1 gravid rats were placed ad lib on either Purina chow or Ensure, a total liquid diet. Half of each group was switched to the other diet on day 21 of gestation and maintained on it through weaning. Offspring remained on the same diet until sacrificed on postnatal day 60. Seven developmental measures were assessed daily until all of the animals reached criterion. The type of diet significantly affected maternal weight gain during the second third of gestation, and neonatal weight gain as measured on days 7, 14, 21, 28 and 45. Females were affected more than were male littermates. Males were significantly heavier than female littermates at all postnatal weighings. Diet had little or no effect on the developmental measures. Male/female differences were found for voluntary activity in the wheel which was measured on day 45. The use of liquid diets in behavioral teratology studies and the wisdom of using pellet diets as a control are discussed. The possibility of substituting careful measures of growth as an alternative to developmental testing is discussed.
1-(2-Deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-ethyluracil. A highly selective antiherpes simplex agent.
The protected nucleoside 1-(2-deoxy-2-fluoro-3,5-di-O-benzoyl-beta-D-arabinofuranosyl)-5-ethylura cil (10) was prepared by condensation of 3,5-dibenzoyl-2-deoxy-2-fluoro-alpha-D-arabinofuranosyl bromide (9) with 2,4-bis-O-(trimethylsilyl)-5-ethyluracil (8). The ratio in this coupling reaction has been raised to 17:1 in favor of the desired beta-anomer. Deprotection by aminolysis gave 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-ethyluracil (FEAU, 1) in 67% isolated yield from the bromo sugar 9. In vitro data show that FEAU has activity against herpes simplex virus types 1 and 2 comparable to that of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-methyluracil (FMAU, 2), 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodouracil (FIAU, 3), and acyclovir (ACV, 12). The cellular toxicity of FEAU was found to be much lower than that of the other nucleoside analogues. Biochemical experiments indicate that FEAU has similar affinity toward thymidine kinases encoded by HSV 1 and 2 and a much lower affinity for cellular thymidine kinase than thymidine. The in vivo antiviral effects of FEAU, FMAU, FIAU, and ACV were evaluated against herpes infection in a systemic mouse encephalitis model and a cutaneous guinea pig model. While FEAU showed activity comparable to that of ACV in the systemic infection model, it was superior in the cutaneous herpes infection model.
Experimental study on long-term effects of inhaled MMMF on the lungs of rats.
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The Institute for Health Care Facilities of the Future.
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Association between dietary fat intake and plasma factor VII coagulant activity--a predictor of cardiovascular mortality.
Repeated measurements were made in 8 adults of factor VII coagulant activity (VIIc) and fibrinogen concentration (two haemostatic variables associated with cardiovascular mortality), together with factor VII concentration, factor X, prothrombin, and serum cholesterol and triglyceride concentrations, while the usual diet was recorded by precise weighing over 12-14 days. In 6 subjects measurements were continued while low-fat and high-fat diets were taken for a further 2 and 3 weeks respectively. Plasma VIIc was related positively and independently to fat and protein intake, whereas factor VII concentration was associated only with protein consumption. In a second study, consumption of 50% extra energy for one day increased VIIc significantly when taken mainly as fat but not when taken mostly as carbohydrate. The character of the VIIc response to fat intake suggested an association with post-prandial lipaemia. A high fat intake may lead not only to coronary atheroma but also to fibrin deposition and thrombus formation through direct activation of the coagulation system.
Synthesis and antiherpes virus activity of phosphate and phosphonate derivatives of 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine.
A series of phosphate esters of 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine (DHPG, 1) were synthesized and evaluated for antiherpes virus activity. The cyclic phosphate esters were made by a new, efficient method utilizing stannic chloride as a solubilizing agent. Monophosphate 2 and bisphosphate 4 showed comparable activity to DHPG and probably acted as prodrugs of DHPG. On the other hand, the cyclic phosphate of DHPG 3 was taken up by cells and bypassed the virus-specified thymidine kinase. As a result, 3 was active against DHPG-resistant HSV mutants that lacked the viral-specified thymidine kinase and was more toxic than DHPG to uninfected cells. The phosphonate 5, the least toxic of the derivatives tested, was only marginally active against HSV but showed substantial activity against human cytomegalovirus in vitro.
Synthesis and anti-herpes-virus activity of acyclic 2'-deoxyguanosine analogues related to 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine.
Several "sugar" modified acyclic nucleoside analogues related to 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine (DHPG, 2) were synthesized and evaluated for antiviral activity. The preparation generally involved the condensation of the acetoxymethyl ether of alcohols 6c-g and 10-12a with diacetylguanine to give adducts 7c-g and 14-16, which were then deprotected to afford analogues 9c-g and 17-19. Alternatively, alcohols 12a and 13a were converted to iodides via their tosylates 12b and 13b and then reacted with the sodium salt of guanine to afford, after deprotection, analogues 22 and 23. A crossed aldol-Cannizzaro reaction on aldehyde 27 readily afforded 28, which was deprotected to give analogue 29. An in vitro assay against HSV-1 showed that all compounds tested were less active than DHPG, though several were good substrates for the viral thymidine kinase. The more promising acyclic nucleosides 9c, 19, and 29 were evaluated in a mouse encephalitis model and proved ineffective at preventing death at a dose of 20 mg/kg.